FDA Amalgam Health Effects Review- DAMS, Inc. (Documentation Submitted)

I. Exposure from Amalgam

1. Amalgam fillings are the largest source of inorganic and methyl mercury in most people.

2. Exposure from metal crowns over amalgam base

3. Galvanic and EMF effects on mercury exposure from amalgam

4. Exposure reduction after amalgam replacement

5. Mercury vapor/inorganic mercury causes some developmental and neurolgical effects at levels of exposure much lower than methyl mercury and more autoimmune effects

II. Environmental Effects of Amalgam

1. Amalgam is the largest source of mercury in municipal sewers

2. Amalgam from sewers is a major source of mercury in lakes, rivers, bays, fish, wildlife

3. Amalgam from sewer sludge is a major source of mercury in crops, atmosphere, and rain

III. Health Effects of Mercury from Amalgam

1. Neurological effects of mercury from amalgam

2. Immune and Autoimmune effects

3. Endocrine Disrupting(Hormonal) effects of mercury from amalgam

4. Cardiovascular effects of mercury from amalgam

5. Effects on Kidneys

6. Gastrointestinal effects

7. Reproductive Effects

8. Occupational effects on dentists and dental workers

9. Develpmental effects of prenatal and neonatal exposure from mother's amalgam

IV. Mechanisms of Causality of Chronic Conditions

1. Oral Conditions

2. Lou Gerhig's Disease(ALS)

3. Chronic Fatigue Syndrome(CFS)

4. Fibromyalgia(FMS)

5. Alzheimer's Disease

6. Rheumetoid Arthritis

7. Multiple Sclerosis(MS)

8. Parkinson's Disease

9. Lupus

10. Degenerative Eye Conditions

11. Allergies

12. Epilepsy

V. Recovery after Amalgam Replacement

1. Oral conditions

(Papers on each of these topics are being sent to FDA; 50 submissions. The submissions

include lists of peer-reviewed references, with abstract on each)

I. 1. Annotated bibliography with peer-review references

(amalgam is the largest source of inorganic and organic mercury exposure in most)

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A large National Institute of Dental Health(NIDH) study of the U.S. military population with an average of 19.9 amalgam surfaces and range of 0 to 60 surfaces found the average urine level was 3.1 ug/L, with 93% being inorganic mercury. The average in those with amalgam was 4.5 times that of controls and more than the U.S. EPA maximum limit for mercury(MRL). The average level of those with over 49 surfaces was over 8 times that of controls. The same study found that the average blood level was 2.55 ug/L, with 79 % being organic mercury. The total mercury level had a significant correlation to the number of amalgam fillings, with fillings appearing to be responsible for over 75% of total mercury. From the study results it was found that each 10 amalgam surfaces increased urine mercury by approx. 1 ug/L. (amalgam was clearly the primary source of mercury exposure for the population)

Kingman A, Albertini T, Brown LJ. National Institute of Dental Research, "Mercury concentrations in urine and blood associated with amalgam exposure in the U.S. military population", J Dent Res. 1998 Mar;77(3):461-71.

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In a population of women tested In the Middle East, the number of fillings was highly correlated with the mercury level in urine, mean= 7 ug/L. , and found to effect kidney function.

Mortada WL, Sobh MA, Mercury in dental restoration: is there a risk of nephrotoxicity? J Nephrol 2002 Mar-Apr;15(2):171-6

& al-Saleh I, Shinwari N. Urinary mercury levels in females: influence of dental amalgam fillings. Biometals 1997; 10(4): 315-23

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Amalgam has been found to be the largest source of organic mercury in most people

Leistevuo J, Pyy L, Osterblad M, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6

& Sellars WA, Sellars R. Univ. Of Texas Southwestern Medical School "Methyl mercury in dental amalgams in the human mouth", Journal of Nutritional & Environmental Medicine 1996; 6(1): 33-37

& Kingman A, Albertini T, Brown LJ. National Institute of Dental Research, "Mercury concentrations in urine and blood associated with amalgam exposure in the U.S. military population", J Dent Res. 1998 Mar;77(3):461-71

The reference average level of mercury in feces(dry weight) for the thousands tested at Doctors Data Lab with amalgam fillings is .26 mg/kg, compared to the reference average level for those without amalgam fillings of .02 mg/kg. (13 times that of the population w/o amalgam). (thus the largest source of all mercury)

Doctors Data Inc.; Fecal Elements Test; P.O.Box 111, West Chicago, Illinois, 60186-0111; www.doctorsdata.com ;

A Swedish lab that does fecal tests for mercury had similar results.

Biospectron Lab, LMI, Lennart Mansson International AB, lmi.analyslab@swipnet.se; http://home.swipnet.se/misac/research11.html#biospectrons

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A large study was carried out at the Univ. Of Tubingen Health Clinic in which the level of mercury in saliva of 20,000 persons with amalgam fillings was measured(199). The level of mercury in unstimulated saliva was found to average 11.6 ug Hg/L, with the average after chewing being 3 times this level. Several were found to have mercury levels over 1100 ug/L, 1 % had unstimulated levels over 200 ug/L, and 10 % had unstimulated mercury saliva levels of over 100 ug/L.. The level of mercury in saliva has been found to be proportional to the number of amalgam fillings, and generally was higher for those with more fillings. The following table gives the average daily mercury exposure from saliva alone for those tested, based on the average levels found per number of fillings and using daily saliva volumes of 890 ml for unstimulated saliva flow and 80 ml for stimulated flow (estimated from measurements made in the study and comparisons to other studies). It also gives the 84th percentile mercury exposure from saliva for the 20,000 tested by number of fillings. Note that 16% of all of those tested with 4 amalgam fillings had daily exposure from their amalgam fillings of over 17 ug per day, and even more so for those with more than 4 fillings.

Table: Average daily mercury exposure in saliva by number of amalgam fillings

Number of fillings: 4 5 6 7 8 9 10 11 12 13 14 15 16

Av. Daily Hg(ug) 6.5 8 9.5 11 2.4 14 15.4 16.9 18.3 19.8 21.3 22.8 24.3

84th percentile(ug) 17 23.5 26 30.5 35 41.5 43.8 48.6 50.3 46.7 56.6 61.4 64.5

Dr. P.Kraub & M.Deyhle, Universitat Tubingen- Institut fur Organische Chemie, "Field Study on the Mercury Content of Saliva", 1997 www.uni-tuebingen.de/uni/coa/ak_kra.html

(20,000 people tested for mercury level in saliva and health status/symptoms compiled)

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Similar results have been documented in many other studies(since 1996:

Monaci F, Bargagli E, Bravi F, Rottoli P. Concentrations of major elements and mercury in unstimulated human saliva. Biol Trace Elem Res. 2002 Dec;89(3):193-203.

(Average of 1.9 ug/L of mercury in saliva for each additional amalgam filling)

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(daily mercury exposure as measured in saliva and feces declined approximately 90 percent after amalgam replacement and level in blood and urine declined over 60%)

Bjorkman L, Sandborgh-Englund G, Ekstrand J. "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62;

& Bjorkman L et al, J Dent Res 75: 38-, IADR Abstract 165, 1996.

& Berglund A, Molin M, "Mercury levels in plasma and urine after removal of all amalgam restorations: the effect of using rubber dams", Dent Mater 1997 Sep;13(5):297-304

& A. Engqvist et al, "Speciation of mercury excreted in feces from individuals with amalgam fillings", Arch Environ Health, 1998, 53(3):205-13

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(Chewing, hot liquids, etc. greatly increase mercury release from amalgam)

G.Sallsten et al, "long term use of chewing gum and mercury exposure from dental amalgam", J Dental Research, 1996, 75(1):594-598.

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(Challange test best measure of mercury body burden and dental staff and those with large number of fillings have much higher body burder and excretion after challange)

H.V.Aposhian, Mobilization of mercury and arsenic in humans by sodium 2,3-dimercapto-1-propane sulfonate (DMPS).
Environ Health Perspect. 1998 Aug;106 Suppl 4:1017-25.

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(mercury levels proportional to number of fillings and toxic metals affect reproductive health)

Gerhard I, Monga B, Waldbrenner A, Runnebaum B "Heavy Metals and Fertility", J of Toxicology and Environmental Health,Part A, 54(8):593-611, 1998;

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[Patterns of mercury release from amalgam fillings into the oral cavity]

[Article in Russian]

Motorkina AV, Barer GM, Volozhin AI. Stomatologiia (Mosk). 1997;76(4):9-11.

Seventy-five subjects aged 20 to 57 with 1 to 15 fillings of silver amalgam were examined. The level of mercury vapors in the oral cavity was assessed using an AGP-01 device and the method developed by the authors. Emission of mercury vapors in the oral cavity increased with the number of fillings. The concentration of mercury in the oral cavity depends largely on the number of silver amalgam fillings and less so on these fillings' length of service.

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I. 2. Summary and References Documenting mechanisms which result in high exposure from dental amalgam due to galvanic currents between mixed metals in amalgam and metal crowns and braces, etc. along with continuous vaporization of mercury from amalgam.

Having dissimilar metals in the teeth(e.g.-amalgam, or gold and mercury, or stainless steel and mercury) causes galvanic action, electrical currents, and much higher mercury vapor levels and levels in oral tissues. (1-11,14). The amount of mercury in saliva was found to increase on average about 1.5 to 1.9 micrograms per liter for each additional amalgam filling(26). The amount of mercury released by a gold alloy bridge over amalgam over a 10 year period was measured to be approx. 101 milligrams(mg)(60% of total) or 30 micrograms(ug) per day(7), and other studies have found similar results( 4). Average mercury levels in gum tissue near amalgam fillings are about 200 ppm, and are the result of flow of mercury into the mucous membrane because of galvanic currents with the mucous membrane serving as cathode and amalgam metals as anode(1-4). Concentrations of mercury in oral mucosa for a population of patients with 6 or more amalgam fillings taken during oral surgery were 20 times the level of controls(14), and levels in root tips of 41 ppm(5). Amalgam also releases significant amounts of silver, tin, and copper which also have toxic effects, with organic tin compounds formed in the body being even more neurotoxic than inorganic mercury.

Mercury and other metals accumulate in the oral cavity in fibroblasts, macrophages, and multinuclear giant cells of connective tissue, in blood vessel walls, along nerve sheath fibres, in basement-membranes of mucosal epithelium, striated muscle fibres, along collagen bundles and elastic tissue, in acini of salivary glands, and in tooth roots and jaw bones(5,11). Such mercury including that in the commonly formed amalgam tattoos moves to other parts of the body over time in significant amounts and more rapidly than the other metals. Macrophages remove mercury by phagocytosis and the mercury moves to other parts of the body through the blood and along nerves(5). Most dentists are not aware of the main source of amalgam tattoos, oral galvanism, where electric currents caused by mixed metals in the mouth take the metals into the gums and oral mucosa, accumulating at the base of teeth with large fillings or metal crowns over amalgam base(1-5). Such metals are documented to cause local and systemic lesions and health effects, which usually recover after removal of the amalgam tattoo by surgery(5fghi). The high levels of accumulated mercury also are dispersed to other parts of the body.

Amalgam fillings produce electrical currents which increase mercury release and may have other harmful effects(1-14,20,38). These currents are measured in micro amps, with some measured at over 5 micro amps. A clinic with considerable experience dealing with problems of oral galvanism found that currents over 5 microamps usually cause significant health problems such as headaches, migraines, dizzyness, nausea,etc. which was eliminated when amalgam fillings were replaced(20). The central nervous system operates on signals in the range of nano-amps, which is 1000 times less than a micro amp(38). Negatively charged fillings or crowns push electrons into the oral cavity since saliva is a good electrolyte and cause higher mercury vapor losses(11,1-6). Patients with autoimmune condtions like MS, or epilepsy, depression, etc. are often found to have a lot of high negative current fillings(11).

Some studies have also found persons with chronic exposure to electromagnetic fields(EMF) to have higher levels of mercury exposure and excretion(33c,38). Magnetic fields are known to induce current in metals and would increase the effects of galvanism.

Studies have shown that mercury in the gums such as from root caps for root canaled teeth or "amalgam tattoos" result in chronic inflammation, in addtion to migration to other parts of the body(5,10,15). Mercury, tin, and silver from amalgam fillings can be seen in the tissues as amalgam "tattoos", which have been found to accumulate in the oral mucosa as granules along collagen bundles, blood vessels, nerve sheaths, elastic fibers, membranes, striated muscle fibers, and acini of minor salivary glands(5,10). Dark granules are also present intracellularly within macrophasges, multinucleated giant cells, endothelial cells, and fibroblasts. There is in most cases chronic inflammatory response or macrophagic reaction the the metals(5,30), usually in the form of a foreign body granuloma with multinucleated giant cells of the foreign body and Langhans types. Mercury levels are often over 1000 ppm near a gold cap on an amalgam filling due to higher currents when gold is in contact with amalgam (8,9,11,12,13). Similar levels as high as 5000 ppm have been found by German oral surgeons in jaw bone under large fillings or gold crowns(37). These levels are among the highest levels ever measured in tissues of living organisms, exceeding the highest levels found in tissues of chronically exposed chloralkali workers, those who died in Minamata, or animals that died from mercury poisoning. The FDA Action Level for mercury in fish or food is 1 ppm. Warnings are given at 0.5 ppm, and the EPA health criterion level is 0.3 ppm. Some of the oral effects of mercury that have been documented include gingivitis, oral lesions, pain and discomfort, burning mouth, "metal mouth", chronic inflamatory response, lichen planus, autoimmune response, oral cancer, trigeminal neuralgia, etc.(1-6,9,11,15,19,22,25,26,31-35)

The component mix in amalgams has also been found to be an important factor in mercury vapor emissions. The level of mercury and copper released from high copper amalgam is as much as 50 times that of low copper amalgams(16,22b). Studies have consistently found modern high copper non gamma-two amalgams have greater release of mercury vapor than conventional silver amalgams (17-21). While the non gamma-two amalgams were developed to be less corrosive and less prone to marginal fractures than conventional silver amalgams, they have been found to be unstable in a different mechanism when subjected to wear/polishing/ chewing/ brushing: they form droplets of mercury on the surface of the amalgams(3,22b). This has been found to be a factor in the much higher release of mercury vapor by the modern non gamma-two amalgams. Recent studies have concluded that because of the high mercury release levels of modern amalgams, mercury levels higher than Government health guidelines are being transferred to the lungs, blood, brain, CNS, kidneys, liver, etc. of large numbers of people with amalgam fillings and widespread neurological, immune system, and endocrine system effects are occuring(22b,25-27,31,32,other submissions).

(1 )Kucerova H, Dostalova T, Prochazkova J, Bartova J, Himmlova L. Influence of galvanic phenomena on the occurrence of algic symptoms in the mouth. Gen Dent. 2002 Jan-Feb;50(1):62-5; & Toumelin-Chemla F, Lasfargues JJ. Unusual in vivo extensive corrosion of a low-silver amalgam restoration involving galvanic coupling: a case report. Quintessence Int. 2003 Apr;34(4):287-94; & N.Nogi, "Electric current around dental metals as a factor producing allergic metal ions in the oral cavity", Nippon Hifuka Gakkai Zasshi, 1989, 99(12):1243-54;

(2) A.J.Certosimo et al, National Naval Dental Center, "Oral Electricity", Gen Dent, 1996, 44(4):324-6;

Cheshire, William P., Jr. The shocking tooth about trigeminal neuralgia. New England Journal of Medicine, Vol. 342, June 29, 2000, p. 2003 (correspondence)

(3) Karov J, Hinberg I. Galvanic corrosion of selected dental alloys. J Oral Rehabil. 2001 Mar;28(3):212-9.;& R.H.Ogletree et al, School of Materials Science, GIT, Atlanta,"Effect of mercury on corrosion of etaÆÆ Cu-Sn phase in dental amalgams", Dent Mater, 1995, 11(5):332-6;

(4) Pistorius A, Willershausen B. Biocompatibility of dental materials in two human cell lines. Eur J Med Res. 2002 Feb 21;7(2):81-8; & & R.D.Meyer et al, "Intraoral galvanic corrosion",Prosthet Dent, 1993,69(2):141-3

(5) (a) Lau JC, Jackson-Boeters L, Daley TD, Wysocki GP, Cherian MG. Metallothionein in human gingival amalgam tattoos. Arch Oral Biol. 2001 Nov;46(11):1015-20; &

(b) M. Forsell et al, Mercury content in amalgam tattoos of human oral mucosa and its relation to local tissue reactions. Euro J Oral Sci 1998; 106(1):582-7; &(a)A. Buchner et al, "Amalgam tattoo of the oral mucosa: a clinicopatholigic study of 268 cases", Surg Oral Med Oral Pathol, 1980, 49(2):139-47; & Owens BM, Johnson WW, Schuman NJ. Oral amalgam pigmentations (tattoos): a retrospective study. Quintessence Int. 1992 Dec;23(12):805-10;

& (i) Kissel SO, Hanratty JJ. Periodontal treatment of an amalgam tattoo. Compend Contin Educ Dent. 2002 Oct;23(10):930-2, 934, 936.

(6) M.D.Rose et al, Eastman Dental Institute, "The tarnished history of a posteria restoration", Br Dent J 1998;185(9):436;

(8) S. Olsson et al, "Release of elements due to electrochemical corrosion of dental amalgam" J of Dental Research, 1994, 73:33-43.

(9)Williamson R.Clinical management of galvanic current between gold and amalgam. Gen Dent. 1996 Jan-Feb;44(1):70-3; & Lemons JE et al, Interoral corosion resulting from coupling dental implants and restorative metallic systems, Implant Dent, 1992, 1(2):107-112;

(10) Effects of particle size and amount of implanted amalgam tattoos, Biomaterials 1987; 8(5):401-3; & The release, tissue distribution and excretion of mercury from experimental amalgam tattoos, Br J Exp Pathol, 1986; 67(6):925-35

(11) (a)Huggins HA, Levy,TE, Uniformed Consent: the hidden dangers in dental care, 1999, Hampton Roads Publishing Company Inc; & Hal Huggins, Its All in Your Head, 1997;

(12) H.Freden et al, "Mercury in gingival tissues adjacent to amalgam fillings", Odontal Revy,1974, 25(2): 207-210

(14) B.Willershausen et al, "Mercury in the mouth mucosa of patients with amalgam fillings", Dtsch Med Wochenschr, 1992, 117:46, 1743-7.

(15) V.Nadarajah et al, "Localized cellular inflamatory response to subcutaneously implanted dental mercury", J Toxicol Environ Health, 1996,49(2):113-25.

(18) A.Berglund,"A study of the release of mercury vapor from different types of amalgam alloys", J Dent Res, 1993, 72:939-946;

(19) H. Lichtenberg, "Mercury vapor in the oral cavity in relation to the number of amalgam fillings and chronic mercury poisoning", Journal of Orthomolecular Medicine, 1996, 11:2, 87-94.

(20) Raue H., "Resistance to therapy; Think of tooth fillings", Medical Practice, vol. 32, n.72, p.2303- 2309, 6 Sept 1980 (see Abstract of clinical cases at end of reference)

(21) L.E.Moberg, "Long term corrosion studies of amalgams and Casting alloys in contact", Acta Odontal Scand 1985, 43:163-177;

(22) T. Weaver et al, An amalgam tattoo causing local and systemic disease; Oral Surg Oral Med Oral Pathol 1987; 63(1):137-40; & Pleva J, "Dental mercury - a public health hazard", Rev Environ Health 10(1):1-27 (1994)

(25) H.J.Lichtenberg, "Elimination of symptoms by removal of dental amalgam from mercury poisoned patients", J Orthomol Med 8:145-148, 1993; & "Symptoms before and after removal of amalgam",J of Orth Med,1996,11(4):1954-59.

(26) Dr. P.Kraub & M.Deyhle, Universitat Tubingen- Institut fur Organische Chemie, "Field Study on the Mercury Content of Saliva", 1997 http://www.uni-tuebingen.de/KRAUSS/amalgam.html; (20,000 people tested for mercury level in saliva and health status/symptoms compiled) ;

& Monaci F, Bargagli E, Bravi F, Rottoli P. Concentrations of major elements and mercury in unstimulated human saliva. Biol Trace Elem Res. 2002 Dec;89(3):193-203.

(27) Public Statement: BBC Panorama Program on Dental Amalgam:"The Poison in Your Mouth", June 1994. by World Health Organizaition Scientific Panel Members: Dr. Lars Friburg- chairman, Dr. Fritz Lorscheider, Professor of Medical Physiology, Univ. Of Calgary; Dr. Murray Vimy, Professor of Oral Biology and Dental Medicine, Univ. Of Calgary Medical School. Dr. Vasken Aposhian, Dept. Head, Molecular and Cellular Biology, Univ. Of Arizona; Dr. David Eggleston, Univ. Of Califoria, researcher on mercury in the brain; Dr. Boyd Haley, Univ. Of Kentucky reasearcher on mercury in the brain and Alzheimer's Disease Dr. Gustav Drasch, Univ. Of Munich, reaearcher on mercury in brains of dead infants and fetuses; Dr. D. Echeverria, Neuro-Toxicologist, researcher on reproductive problems and birth defects in dental workers; Batelle Center for Public Health Reseach, Seattle, Wash.

(31) G. Sasaki et al, "Three cases of oral lichenosis caused by metallic fillings", J. Dermatol, 23 Dec, 1996; 12:890-892; & J.Bratel et al, "Effect of Replacement of Dental Amalgam on OLR", Journal of Dentistry, 1996, 24(1-2):41-45(161 cases); & A Dunsche et al, "Oral lichenoid reactions associated with amalgam: improvement after amalgam removal." British Journal of Dermatology 2003 Jan;148:1:70-6; & Little MC, Watson RE, Pemberton MN, Griffiths CE, Thornhill MH. Activation of oral keratinocytes by mercuric chloride: relevance to dental amalgam-induced oral lichenoid reactions.Br J Dermatol. 2001 May;144(5):1024-32.

(32) P.O.Ostman et al, "Clinical & histologic changes after removal of amalgma", Oral Surgery, Oral Medicine, and Endodontics, 1996, 81(4):459-465; & S.H.Ibbotson et al, "The relevance of amalgam replacement on oral lichenoid reactions", British Journal of Dermatology, 134(3):420-3, 1996; (270 cases); & L. Wong and S. Freeman, Oral lichenoid lesions (OLL) and mercury in amalgam fillings, Contact Dermatitis, Vol 48 Issue 2 Page 74 - February 2003.

(33) Omura, Yoshiaki; Abnormal Deposits of Al, Pb, and Hg in the Brain, Particularly in the Hippocampus, as One of the Main Causes of Decreased Cerebral Acetylcholine, Electromagnetic Field Hypersensitivity, Acupuncture & Electro-Therapeutics Research, 2000, Vol. 25 Issue 3/4, p230, 3p

(37) Schiwara, H.-W. (Medical Laboratory) Arzte fur Laboratoriumsmedizen, D-28357 Bremen; & Heavy Metal Bulletin, 1999, No. 1, p28.

EMF causes higher galvanic currents and higher exposure from amalgam

(38) F.Schmidt et al, "Mercury in urine of employees exposed to magnetic fields", Tidsskr Nor Laegeforen, 1997, 117(2): 199-202;

& Granlund-Lind R, Lans M, Rennerfelt J. [Computers and amalgam are the most common causes of hypersensitivity to electricity according to the sufferers' reports][Article in Swedish]
Lakartidningen. 2002 Feb 14;99(7):682-3.

& Ortendahl T W, Hogstedt P, Holland RP, "Mercury vapor release from dental amalgam in vitro caused by magnetic fields generated by CRT's", Swed Dent J 1991 p 31 Abstract

; & Bergdahl J, Anneroth G, Stenman E. Description of persons with symptoms presumed to be caused by electricity or visual display units--oral aspects. Scand J Dent Res. 1994, 102(1):41-5.

(39) Aldinucci C; Palmi M; Sgaragli G; Benocci A; Meini A; Pessina F; Pessina GP. The effect of pulsed electromagnetic fields on the physiologic behaviour of a human astrocytoma cell line. Biochim Biophys Acta 2000, 11;1499(1-2):101-108.

(40) Pablos MI; Agapito MT; Gutierrez-Baraja R; Reiter RJ; Recio JM. Effect of calcium on melatonin secretion in chick pineal gland I. Neurosci Lett 1996 Oct18;217(2-3):161-4;

& Nikaido SS; Takahashi JS. Calcium modulates circadian variation in cAMP-stimulated melatonin in chick pineal cells. Brain Res 1996 15;716(1-2):1-10; & Youbicier-Simo BJ; Boudard F; Cabaner C; Bastide M. Biological effects of continuous exposure of embryos and young chickens to electromagnetic fields emitted by video display units. Bioelectromagnetics 1997;18(7):514-23 ;

(41) Juutilainen J; Stevens RG; et al; Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields. J Pineal Res 2000 ;28(2):97-104;

& Akerstedt T; Arnetz B; Ficca G; Paulsson LE; Kallner A. A 50-Hz electromagnetic field impairs sleep. J Sleep Res 1999 Mar;8(1):77-81

(42) Savitz DA; Checkoway H; Loomis DP. Magnetic field exposure and neurodegenerative disease mortality among electric utility workers. Epidemiology 1998 Jul;9(4):398-404;

& Davanipour Z; Sobel E; Bowman JD; Qian Z; Will AD. Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields. Bioelectromagnetics 1997;18(1):28-35.

(43) Sobel E; Dunn M; Davanipour Z; Qian Z; Chui HC. Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure. Neurology 1996 ;47(6):1477-81;

& Sobel E, Davanipour Z. Electromagnetic field exposure may cause increased production of amyloid beta and eventually lead to Alzheimer's disease. Neurology. 1996 Dec;47(6):1594-600;

& Sobel E; Davanipour Z; Sulkava R; Erkinjuntti T; Wikstrom J et al; Occupations with exposure to electromagnetic fields: a possible risk factor for Alzheimer's disease. Am J Epidemiol 1995 Sep 1;142(5):515-24.

& Caplan LS; Schoenfeld ER; O'Leary ES; Leske MC. Breast cancer and electromagnetic fields--a review. Ann Epidemiol 2000 Jan;10(1):31-44;

(47) Rob Edwards and Duncan Graham-Rowe. "Electrical connection" New Scientist 6 March 2002; & Dr. Mae-Wan Ho, National Radiological Protection Board (NRPB), "Electromagnetic Fields Double Leukemia Risks" 2002; & Richard Doll et al, Cancer Studies Unit, Oxford Univ., March 2002;

Evidence EMF/Mercury cause chronic neurological conditions, cancer, and depression/suicide

Some studies have also found persons with amalgam fillings and chronic exposure to electromagnetic fields(EMF) to have higher levels of mercury exposure and excretion(38). Magnetic fields are known to induce current in metals and would increase the effects of galvanism. EMF is also documented in animal and human studies to cause cellular calcium efflux and affect calcium homeostasis (39,40), which may be a factor in the reduction of melatonin levels caused by EMF exposure in animal and human studies(40,41). In studies on chicks this had significant adverse effects on viability of embryos and chicks. Melatonin is known to be protective against mercury and free radical activity, as well as regulating the circadium rhythym cycle and sleep cycle. EMF exposure lowers melatonin production and disrupts the sleep cycle(41). Since mercury is known to have some of these same effects and EMF exposure increases mercury exposure in those with amalgam, it is not clear in humans the relative role of the causality mechanisms. Occupational exposure to higher levels of EMF have also been found in many studies to result in much higher risk of chronic degenerative neurological conditions(42a,45), such as ALS(42c), Alzheimer''s Disease(43), depression/suicide(42b,46), as well as Leukemia and Cancer(44). Since EMF causes increased mercury exposure in those with amalgam, and mercury is also known to cause these conditions, again it is not clear the relative importance of the factors since the studies were not controlled for mercury levels or number of amalgam fillings.

(38) F.Schmidt et al, "Mercury in urine of employees exposed to magnetic fields", Tidsskr Nor Laegeforen, 1997, 117(2): 199-202; & Sheppard AR and EisenbudM., Biological Effects of electric and magnetic fields of extremely low frequency. New York university press. 1977; & Ortendahl T W, Hogstedt P, Holland RP, "Mercury vapor release from dental amalgam in vitro caused by magnetic fields generated by CRT's", Swed Dent J 1991 p 31

(40) Pablos MI; Agapito MT; Gutierrez-Baraja R; Reiter RJ; Recio JM. Effect of calcium on melatonin secretion in chick pineal gland I. Neurosci Lett 1996 Oct18;217(2-3):161-4; & Nikaido SS; Takahashi JS. Calcium modulates circadian variation in cAMP-stimulated melatonin in chick pineal cells. Brain Res 1996 15;716(1-2):1-10; & Youbicier-Simo BJ; Boudard F; Cabaner C; Bastide M. Biological effects of continuous exposure of embryos and young chickens to electromagnetic fields emitted by video display units. Bioelectromagnetics 1997;18(7):514-23 ;

(41) Juutilainen J; Stevens RG; et al; Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields. J Pineal Res 2000 ;28(2):97-104; & Akerstedt T; Arnetz B; Ficca G; Paulsson LE; Kallner A. A 50-Hz electromagnetic field impairs sleep. J Sleep Res 1999 Mar;8(1):77-81

(42) (a) Savitz DA; Checkoway H; Loomis DP. Magnetic field exposure and neurodegenerative disease mortality among electric utility workers. Epidemiology 1998 Jul;9(4):398-404; & Savitz DA; Loomis DP; Tse CK. Electrical occupations and neurodegenerative disease: analysis of U.S. mortality data.Arch Environ Health 1998 Jan-Feb;53(1):71-4; & (b) Edwin van Wijngaarden, David Savatz, Robert C Kleckner, Jianwen Cai, Dana
Loomis. Exposure to electromagnetic fields and suicide among electric utilityWorkers: a nested case-control study. Occup Environ Med 2000; 57:258-263. & (c) Johansen C; Olsen JH. Mortality from amyotrophic lateral sclerosis, other chronic disorders, and electric shocks among utility workers.Am J Epidemiol 1998 Aug 15;148(4):362-8; & Davanipour Z; Sobel E; Bowman JD; Qian Z; Will AD. Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields. Bioelectromagnetics 1997;18(1):28-35.

(43) Sobel E; Dunn M; Davanipour Z; Qian Z; Chui HC. Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure. Neurology 1996 ;47(6):1477-81; & Sobel E, Davanipour Z. Electromagnetic field exposure may cause increased production of amyloid beta and eventually lead to Alzheimer's disease. Neurology. 1996 Dec;47(6):1594-600; & Sobel E; Davanipour Z; Sulkava R; Erkinjuntti T; Wikstrom J et al; Occupations with exposure to electromagnetic fields: a possible risk factor for Alzheimer's disease. Am J Epidemiol 1995 Sep 1;142(5):515-24.

& Caplan LS; Schoenfeld ER; O'Leary ES; Leske MC. Breast cancer and electromagnetic fields--a review. Ann Epidemiol 2000 Jan;10(1):31-44

**************

Clinical Cases: Oral Galvanism Effects

Raue H., "Resistance to therapy; Think of tooth fillings", Medical Practice, vol. 32, n.72, p.2303- 2309, 6 Sept 1980

I introduced oral current measurements into my practice in 1977 on a routine basis. During the period from mid 1977 to mid february 1980, values of 6 microampere or more were found in the mouth of 978 patients of my practice and when these high values were associated with related symptoms, removal of suspicious amalgam fillings was suggested. Measurements below 3 microampere are regarded as not suspicious, readings between 3 and 5 microampere may originally be neglected but later control measurement are indicated.

The symptoms that these people with positive galvanic readings were complaining of before amalgam removal were:

headaches (57 cases), dizziness (20), nausea and emesis (6), migraine (6), fainting spells (4), ocular fibrillation (3), tinnitus (1), bitter taste in the mouth (1), soreness of mandible (1).

These symptoms from these 99 patients with high galvanic readings had been resistant to different therapeutic attempts by other clinics and physicians, and have completely resolved after amalgam removal.

Based on my own examinations I can make two firm statements:

1. increased oral current differential are observed not only between amalgam and gold fillings, but may be found as well between adjacent amalgam to amalgam and amalgam to steel in almost 50% of such cases.

2. my two-year observation lead to the discovery of almost 100 cases of disease related high galvanic readings (>5 microampere) in the mouth, which resolved following dental amalgam removal.

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I.3. Evidence EMF/Mercury cause chronic neurological conditions, cancer, and depression/suicide

(44) London SJ; Bowman JD; Sobel E; Thomas DC; Garabrant DH; Pearce N; Bernstein L; Peters JM. Exposure to magnetic fields among electrical workers in relation to leukemia risk in Los Angeles County. Am J Ind Med 1994 Jul;26(1):47-60; & Caplan LS; Schoenfeld ER; O'Leary ES; Leske MC. Breast cancer and electromagnetic fields--a review. Ann Epidemiol 2000 Jan;10(1):31-44

(45) B.Windham, Mercury connection to chronic neurological conditions.

www.myflcv.com/damspr9.html

(46) B.Windham, Mercury connection to depression. www.home.earthlink.net/~berniew1/depress.html

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Health Effects of EMF Exposure: the Mercury Connection

In a long term comprehensive electromagnetic fields(EMF) risk assessment study by the California Dept. of Health Services, all reviewers concluded that it is highly likely that EMF causes some forms of cancer, along with chronic neurological conditions like ALS(Lou Gerhig's disease) and depression. They also found a significant likelihood that EMF causes cardiovascular problems and increased suicide(1). People are commonly exposed to electromagnetic fields from computer monitors, microwaves, televisions, other appliances, and power lines.

Actually there is strong evidence in the medical literature already supporting these conclusions and documenting mechanisms by which the effects occur. The evidence is based on the fact that chronic mercury exposure has been documented to cause all of these conditions (12-16), and EMF exposure has been documented to cause significant release of mercury into the body, including the brain and Central Nervous System, from those who have amalgam(2). Studies have found persons with chronic exposure to electromagnetic fields(EMF) to have higher levels of mercury exposure and excretion(2,9). Electromagnetic fields are known to induce current in metals and would increase the documented effects of galvanism(9,12-16). Amalgam has also been documented to be the largest source of mercury exposure in most people who have amalgam fillings(12,16).

EMF is also documented in animal and human studies to cause cellular calcium efflux and affect calcium homeostasis(3,4), which may be a factor in the reduction of melatonin levels caused by EMF exposure in animal and human studies(4,5). In studies on chicks this had significant adverse effects on viability of embryos and chicks. Melatonin is known to be protective against mercury and free radical activity, as well as regulating the circadian rhythm cycle and sleep cycle. EMF exposure lowers melatonin production and disrupts the sleep cycle(5,8c). Another study provides evidence for an association between occupational electromagnetic fields and suicide(10). The authors indicate that a plausible mechanism related to melatonin and depression provides a direction for additional laboratory research as well as epidemiological evaluation. Occupational exposure to higher levels of EMF have also been found in many studies to result in much higher risk of chronic degenerative neurological conditions such as ALS(6), Alzheimer's Disease(7), Depression(11), as well as Leukemia and Cancer(8,6e). Since EMF causes increased mercury exposure in those with amalgam, and mercury is also known to cause these conditions(13-16), again it is not clear the relative importance of the factors since the studies were not controlled for mercury levels or number of amalgam fillings.

References

(1) California Dept. of Health Services, California EMF Program, Draft of final risk evaluation report,

www.dhs.cahwnet.gov/ehib/emf/RiskEvaluation/riskeval.html

(2) F.Schmidt et al, "Mercury in urine of employees exposed to magnetic fields", Tidsskr Nor Laegeforen, 1997, 117(2): 199-202; & Granlund-Lind R, Lans M, Rennerfelt J, "Computers and amalgam are the most common causes of hypersensitivity to electricity according to sufferers' reports", Läkartidningen 2002; 99: 682-683 (Swedish); & Sheppard AR and EisenbudM., Biological Effects of electric and magnetic fields of extremely low frequency. New York university press. 1977; & Ortendahl T W, Hogstedt P, Holland RP, "Mercury vapor release from dental amalgam in vitro caused by magnetic fields generated by CRT's", Swed Dent J 1991 p 31

(3) Aldinucci C; Palmi M; Sgaragli G; Benocci A; Meini A; Pessina F; Pessina GP. The effect of pulsed electromagnetic fields on the physiologic behaviour of a human astrocytoma cell line. Biochim Biophys Acta 2000, 11;1499(1-2):101-108; & Fitzsimmons RJ, Ryaby JT, Magee FP, Baylink DJ. Combined magnetic fields increased net calcium flux in bone cells. Calcif Tissue Int 1994 Nov;55(5):376-80

(4) Pablos MI; Agapito MT; Gutierrez-Baraja R; Reiter RJ; Recio JM. Effect of calcium on melatonin secretion in chick pineal gland I. Neurosci Lett 1996 Oct18;217(2-3):161-4; & Nikaido SS; Takahashi JS. Calcium modulates circadian variation in cAMP-stimulated melatonin in chick pineal cells. Brain Res 1996 15;716(1-2):1-10; & Youbicier-Simo BJ; Boudard F; Cabaner C; Bastide M. Biological effects of continuous exposure of embryos and young chickens to electromagnetic fields emitted by video display units. Bioelectromagnetics 1997;18(7):514-23 ;

(5) Juutilainen J; Stevens RG; et al; Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields. J Pineal Res 2000 ;28(2):97-104; & Akerstedt T; Arnetz B; Ficca G; Paulsson LE; Kallner A. A 50-Hz electromagnetic field impairs sleep. J Sleep Res 1999 Mar;8(1):77-8 & Ronco AL, Halberg F. The pineal gland and cancer. Anticancer Res 1996 Jul-Aug;16(4A):2033-9; &

& Zecca L, Mantegazza C, Margonato V, Cerretelli P, Caniatti M, Piva F, Dondi D,

Hagino N. Biological effects of prolonged exposure to ELF electromagnetic

fields in rats: III. 50 Hz electromagnetic fields. Bioelectromagnetics 1998;19(1):57-66

(6) Savitz DA; Checkoway H; Loomis DP. Magnetic field exposure and neurodegenerative disease mortality among electric utility workers. Epidemiology 1998 Jul;9(4):398-404; & Savitz DA; Loomis DP; Tse CK. Electrical occupations and neurodegenerative disease: analysis of U.S. mortality data.Arch Environ Health 1998 Jan-Feb;53(1):71-4; & Johansen C; Olsen JH. Mortality from amyotrophic lateral sclerosis, other chronic disorders, and electric shocks among utility workers.Am J Epidemiol 1998 Aug 15;148(4):362-8; & Davanipour Z; Sobel E; Bowman JD; Qian Z; Will AD. Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields. Bioelectromagnetics 1997;18(1):28-35; & (e)Ahlbom II, Cardis E, Green A, Linet M, Savitz D, Swerdlow A. Review of the Epidemiologic Literature on EMF and Health. Environ Health Perspect 2001 Dec;109 Suppl 6:911-933; &(f)Ahlbom A. Neurodegenerative diseases, suicide and depressive symptoms in relation to EMF. Bioelectromagnetics 2001;Suppl 5:S132-43

(7) Sobel E; Dunn M; Davanipour Z; Qian Z; Chui HC. Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure. Neurology 1996 ;47(6):1477-81; & Sobel E, Davanipour Z. Electromagnetic field exposure may cause increased production of amyloid beta and eventually lead to Alzheimer's disease. Neurology. 1996 Dec;47(6):1594-600; & Sobel E; Davanipour Z; Sulkava R; Erkinjuntti T; Wikstrom J et al; Occupations with exposure to electromagnetic fields: a possible risk factor for Alzheimer's disease. Am J Epidemiol 1995 Sep 1;142(5):515-24; & Hansen NH, Sobel E, Davanipour Z, Gillette LM, Niiranen J, Wilson BW. EMF exposure assessment in the finnish garment industry: evaluation of proposed EMF exposure metrics. Bioelectromagnetics 2000, Jan;21(1):57-67

(8) London SJ; Bowman JD; Sobel E; Thomas DC; Garabrant DH; Pearce N; Bernstein L; Peters JM. Exposure to magnetic fields among electrical workers in relation to leukemia risk in Los Angeles County. Am J Ind Med 1994 Jul;26(1):47-60; & Caplan LS; Schoenfeld ER; O'Leary ES; Leske MC. Breast cancer and electromagnetic fields--a review. Ann Epidemiol 2000 Jan;10(1):31-44; & (c)Stevens RG, Davis S. The melatonin hypothesis: electric power and breast cancer. Environ Health Perspect 1996 Mar;104 Suppl 1:135-40

(9) Mercury Exposure and Health Effects from Dental Amalgam Galvanism,

www.home.earthlink.net/~berniew1/galv.html

(10)van Wijngaarden E, Savatz D, Kleckner R, Cai J, Loomis D. Exposure to electromagnetic fields and suicide among electric utility Workers: a nested case-control study. Occup Environ Med 2000; 57:258-263

(11) Zyss T, Dobrowolski JW, Krawczyk K. Neurotic disturbances, depression and anxiety disorders in the population living in the vicinity of overhead high-voltage transmission line 400 kV. Epidemiological pilot study Med Pr 1997;48(5):495-505

(12) Kingman A, Albertini T, Brown LJ, Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population., J Dent Res 1998 Mar;77(3):461-71

(population of over 1000 Air Force personnel; found each 10 amalgam surfaces increased mercury in urine by approx. 1 microgram per liter); &

(b) Leistevuo J, Pyy L, Osterblad M, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6; &

(c) Bjorkman L, Sandborgh-Englund G, Ekstrand J. "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62;

(13) previous submission, and also : ALS: the Mercury Connection, www.myflcv.com/als.html

(14)previous submission, and also: Alzheimer's Disease: the Mercury Connection, www.myflcv.com/alzhg.html

(15) previous submission, and also: Depression: the Mercury Connection: www.myflcv.com/depress.html

(16) Mercury exposure and related health effects from amalgam fillings, (B.Windham(Ed.), www.myflcv.com/amalg6.html

over 2000 peer-reviewed medical studies reviewed and referenced),

**********************

The Risk Evaluation

An Evaluation of the Possible Risks From Electric and Magnetic Fields
(EMFs) From Power Lines, Internal Wiring, Electrical Occupations and Appliances

The Risk Evaluation analyzes the potential human health risks of
magnetic field exposure. Specifically, this document provides an
evaluation of the animal, laboratory and human evidence that shows how
exposure to 50/60 Hz magnetic fields may or may not increase human
health risks. The Risk Evaluation is based on the results of published
research studies, with emphasis on new studies, the National Institute of
Environmental Health Sciences (NIEHS) Working Group Report, and
the results of the California EMF Program Studies.

Draft 3 for Public Comment
Final Version Due August 2002

Based on the study evidence reviewed:

All 3 reviewers all put the probability that EMF causes some ALS is greater than 50%.
prob. that EMF causes childhood leukemia between 55 & 95%
prob. that EMF causes adult leukemia between 40 and 85%
prob. that EMF causes adult brain cancer between 55 and 99%
prob. that EMF causes breast cancer between 15 and 50%
prob. that EMF causes spontaneous abortions between 50 & 95%
prob. that EMF causes suicide between 45 & 50%
prob. that EMF causes cardiovascular problems between 30 & 45 %

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I.4. After proper(safe) amalgam replacement, the level of mercury in blood temporarily is increased as much as 100% but then declines significantly over time, usually over 60% by 6 months. Urine levels simiarly decline by over 60% by 6 months. Daily exposure as measured by saliva and fecess declined over 90 %.

Bjorkman L, Sandborgh-Englund G, Ekstrand J. "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62;

& Bjorkman L et al, J Dent Res 75: 38-, IADR Abstract 165, 1996.

& Berglund A, Molin M, "Mercury levels in plasma and urine after removal of all amalgam restorations: the effect of using rubber dams", Dent Mater 1997 Sep;13(5):297-304

& A. Engqvist et al, "Speciation of mercury excreted in feces from individuals with amalgam fillings", Arch Environ Health, 1998, 53(3):205-13

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Mercury Vapor has developmental and other effects at levels of exposure much lower than inorganic mercury and methyl mercury

********************

(references & abstracts at end of summary)

1. Mercury vapor is lipid soluble and has an affinity for red blood cells and Central Nervous System(CNS) cells. Mercury vapor is the most significant exposure from dental amalgam fillings and dental office exposures.

2. Only a few micrograms of mercury severely disturb cellular function and inhibits nerve growth. Prenatal or neonatal exposures have been found to have life long effects on nerve function and other toxic developmental effects.

3. Elemental mercury vapor is more rapidly transmitted throughout the body than other forms of mercury and has more toxic effects on the CNS and other parts of the body.

4. Exposure to mercury vapor causes rapid transmittal across the blood-brain barrier and through the placenta of pregnant women to the fetus and significant developmental effects.

5. Developmental learning and behavioral effects have been found from mercury vapor at much lower levels than for exposure to methyl mercury.

6. More people have immune reactions to mercury vapor/inorganic mercury than to methyl mercury. Immune reactions to mercury are documented to cause autoimmunity and autoimmune conditions like chronic fatigue syndrome(CFS), fibromyalgia, lupus, multiple sclerosis(MS), rheumatoid arthritis, ALS, etc.

7. Exposure to mercury vapor/inorganic mercury causes chronic neurological effects at lower levels of exposure than to methyl mercury.

8. Exposure to low levels of mercury vapor causes chronic cardiovascular effects.

9. Mercury vapor and inorganic mercury are methylated in the body to methyl mercury by bacteria, yeast, and other methyl donors.

10. Dental amalgam fillings are the largest source of both inorganic and methyl mercury in most people with amalgam.

Documentation:

There is a lot of misunderstanding about the toxic effects significance of the various types of mercury people are exposed to: vapor, inorganic, organic(methyl) mercury. The American Dental Assoc., some at Gov't agencies, and other researchers have argued that methyl mercury is much more toxic than other forms, and mercury from fish thus a more important problem than vapor from fillings. However the pharmakinetics of mercury in the body is complex and the evidence seems contrary to that.

Mercury vapor may be the biggest problem even for equal exposures, in addition to the fact it is well documented that mercury from dental fillings is the largest source of both inorganic and methyl mercury in most people.

[Leistevuo J, Pyy L, Osterblad M, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6

& Sellars WA, Sellars R. Univ. Of Texas Southwestern Medical School "Methyl mercury in dental amalgams in the human mouth", Journal of Nutritional & Environmental Medicine 1996; 6(1): 33-37

& Kingman A, Albertini T, Brown LJ. National Institute of Dental Research, "Mercury concentrations in urine and blood associated with amalgam exposure in the U.S. military population", J Dent Res. 1998 Mar;77(3):461-71

& L.Bjorkman et al, "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62; & Eur J Oral Sci 1998 Apr;106(2 Pt 2):678-86

& Doctors Data Inc.; Fecal Elements Test; P.O.Box 111, West Chicago, Illinois, 60186-0111; www.doctorsdata.com ;

& A Swedish lab that does fecal tests for mercury had similar results.

Biospectron Lab, LMI, Lennart Mansson International AB, lmi.analyslab@swipnet.se; http://home.swipnet.se/misac/research11.html#biospectrons

**************************************************************

Elemental and inorganic mercury in the body are methylized to methyl mercury by bacteria in the mouth and intestines, and by yeast and other methyl donors (51,53,54,225).

Some people tested who do not eat fish have been found to have high levels of methyl mercury.

Methylation of Mercury from dental amalgam and mercuric chloride by oral Streptococci. Heintz, Edwardson, Derand, Birkhed Scan. J. Dent. Res. 1983, 91:150-152;

& W.A.Sellars et al, Univ. Of Texas Southwestern Medical School, "Methyl Mercury in the Human Mouth from Dental Amalgams", Journal of Nutritioanl & Environmental Medicine(1996), 6:33-36.

& The Methylation of Mercuric Chloride by Human Intestinal Bacteria. Rowland, Grasso, Davies Experientia. Basel 1975 ,31: 1064-1065

& Formation of methyl Mercury Compounds from inorganic Mercury . by Chlostridium cochlearium Yamada, Tonomura J Ferment Technol1972 50:159-1660

& S. Yannai et al, "Transformationss of inorganic mercury by candida albicans and saccharomyces cerevisiae", Applied Envir Microbiology,1991, 57:245-247;

& I.R.Rowland et al, "The methylization of mercuric chloride by human intestinal bacteria", Experentia, Sept 1975, 31(9):1064-5.

*************************************************************

An interesting finding is evidence that indicates that mercury vapor is 10 times more toxic to the fetal brain than methyl mercury.

M.C. Newland et al,"Behavioral consequences of in utero exposure to mercury vapor", Toxicology & Applied Pharmacology, 1996, 139: 374-386;

& K.Warfvinge et al, "Mercury distribution in neonatal cortical areas ...after exposure to mercury vapor",Environmental Research, 1994, 67:196-208.

& Soderstrom S, Fredriksson A, Dencker L, Ebendal T, "The effect of mercury vapor on cholinergic neurons in the fetal brain, Brain Research & Developmental Brain Res, 1995, 85:96-108; & Toxicol Lett 1995; 75(1-3):133-44.;

& E.M. Abdulla et al, "Comparison of neurite outgrowth with neurofilament protein levels In neuroblastoma cells following mercuric oxide exposure", Clin Exp Pharmocol Physiol, 1995, 22(5): 362-3;

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Richardson M(paper for Swedish Scientific Panel FRN-1999) has estimated that about 20% of the population suffers a subclinical impairment of kidney or CNS function related to amalgam mercury.

************************************************

Inorganic mercury causes various forms of neurological damage at lower levels of exposure than

methylmercury.

Aschner M, Rising L, Mullaney KJ. Differential sensitivity of neonatal rat astrocyte cultures to mercuric chloride (MC) and methylmercury (MeHg): studies on K+ and amino acid transport and metallothionein (MT) induction. Neurotoxicology. 1996 Spring;17(1):107-16.

A. Szucs et al, Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons. Cell Mol Neurobiol, 1997,17(3): 273-8;

***********************************************************

The following is a summary snipped from the review paper(500) with further documentation:

Mercury vapor is lipid soluble and has an affinity for red blood cells and CNS cells (21). Only a few micrograms of mercury severely disturb cellular function and inhibits nerve growth (175,147,226,255,305,149). Prenatal or neonatal exposures have been found to have life long effects on nerve function and susceptibility to toxic effects. Prenatal mercury vapor exposure that results in levels of only 4 parts per billion in newborn rat brains was found to cause decreases in nerve growth factor and other effects(305). Elemental mercury vapor is more rapidly transmitted throughout the body than most other forms of mercury and has more toxic effects on the CNS and other parts of the body according to the World Health Organization and other studies(38,183,265,282,287). Exposure to mercury vapor causes rapid transmittal across the blood-brain barrier and through the placenta of pregnant women to the fetus (38,85,113,146,162,262, 281,287)-much more damage to the fetus than for maternal exposure to inorganic mercury(281,287,38) and significant developmental effects(305).

Developmental learning and behavioral effects have been found from mercury vapor at much lower levels than for exposure to methyl mercury. (287,304,276e,etc.). The OSHA health standard level for mercury vapor in air is 50% lower than for organic mercury in air, as is the ATSDR MRL(217).

More people have autoimmune reactions, related to chronic autoimmune conditions, to mercury vapor/inorganic mercury than to methyl mercury(60,313,375). Immune reactions to mercury are documented to cause autoimmunity and autoimmune conditions like chronic fatigue syndrome(CFS), fibromyalgia, lupus, mutiple sclerosis(MS), rheumatoid arthritis, ALS, etc.(313,375,405,500).

Mercury vapor/inorganic mercury is documented to have neurological effects at much lower levels of exposure than methyl mercury(114,175,333). Mercury vapor exposure at very low levels is also documented to be a common cause of chronic cardiovascular effects(59).

**********************************************************************

References

(21) R.A.Goyer,"Toxic effects of metals"in: Caserett and Doull's Toxicology- TheBasic Science of Poisons, McGraw-Hill Inc., N.Y., 1993;

(38) Ziff S. and Ziff M. Infertility and Birth Defects: Is Mercury from Dental Fillings a Hidden Cause?, Bio-Probe, Inc. ISBN: 0-941011-03-8.1987

(51) Methylation of Mercury from dental amalgam and mercuric chloride by oral Streptococci. Heintz, Edwardson, Derand, Birkhed Scan. J. Dent. Res. 1983, 91:150-152;

& W.A.Sellars et al, Univ. Of Texas Southwestern Medical School, "Methyl Mercury in the Human Mouth from Dental Amalgams", Journal of Nutritioanl & Environmental Medicine(1996), 6:33-36.

(53} The Methylation of Mercuric Chloride by Human Intestinal Bacteria. Rowland, Grasso, Davies Experientia. Basel 1975 ,31: 1064-1065

(54) Formation of methyl Mercury Compounds from inorganic Mercury . by Chlostridium cochlearium Yamada, Tonomura J Ferment Technol1972 50:159-1660

(59) Souza de Assis GP, et al; Effects of small concentrations of mercury on the contractile activity of the rat ventricular myocardium. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):375-83; & Lorscheider F, Vimy M. Mercury and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2000 Mar 1;35(3):819-20; & A. Frustaci et al, "Marked elevation of myocardial trace elements in Idiopathic Dilated Cardiomyopathy", J of American College of Cardiology, 1999, 33(6):1578-83; & Hisatome I, Kurata Y, et al; Block of sodium channels by divalent mercury: role of specific cysteinyl residues in the P-loop region. Biophys J. 2000 Sep;79(3):1336-45.

(57) N.Campbell & M.Godfrey,"Confirmation of Mercury Retention and Toxicity using DMPS provocation" ,J of Advancement in Medicine, 7(1) 1994;(80 cases);

(60) VDM Stejskal et al, "MELISA: tool for the study of metal allergy", Toxicology in Vitro, 8(5):991-1000, 1994; & Tibbling L, Stejskal VDM, et al, Immunological and brain MRI changes in patients with suspected metal intoxication", Int J Occup Med Toxicol 4(2):285-294,1995. www.melisa.org

(79) L.Bjorkman et al, "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62; & Eur J Oral Sci 1998 Apr;106(2 Pt 2):678-86

(85) J.A.Weiner et al,"The relationship between mercury concentration in human organs and predictor variables",138(1-3):101-115,1993; & "An estimation of the uptake of mercury from amalgam fillings", Sci Total Environ,v168,n3, p255-265, 1995.

(113) M.J.Vimy et al, Maternal-fetal distribution of mercury released from amalgam fillings", Am J Physiol 258:R939-R945,1990. See also (238)

(114) Aschner M, Rising L, Mullaney KJ. Differential sensitivity of neonatal rat astrocyte cultures to mercuric chloride (MC) and methylmercury (MeHg): studies on K+ and amino acid transport and metallothionein (MT) induction. Neurotoxicology. 1996 Spring;17(1):107-16;

(146) T.Colborn(Ed.),Chemically Induced Atlerations in Functional Development, Princeton Scientific Press,1992 & Developmental Effects of Endocrine- Disrupting Chemicals",Eniron Heath Perspectives, V 101, No.5, Oct 1993.

(147) M.Wood,"Mechanisms for the Neurotoxicity of Mercury", in Organotransitional Metal Chemistry, Plenum Publishing Corp, N.Y, N.Y, 1987. & R.P. Sharma et al, "Metals and Neurotoxic Effects", J of Comp Pathology, Vol 91, 1981.

(149) B.Choi et al, "Abnormal neuronal migration of human fetal brain", Journal of Neurophalogy, Vol 37, p719-733, 1978; & L.Larkfors et al,"Methyl mercury induced alterations in the nerve growth factor level in the developing brain ", Res Dev Res,62(2),1991,287-

(162) N.K.Mottet et al, "Health Risks from Increases in Methylmercury Exposure",vol63:133-140,1985.

(175) F. Monnet-Tschudi et al, "Comparison of the developmental effects of 2 mercury compounds on glial cells and neurons in the rat telencephalon", Brain Research, 1996, 741: 52-59; & Chang LW, Hartmann HA, "Quantitative cytochemical studies of RNA in experimental mercury poisoning", Acta Neruopathol(Berlin), 1973, 23(1):77-83.

(183) World Health Organization(WHO),1991, Environmental Health Criteria 118, Inorganic Mercury, WHO, Geneva; & Environ metal Health. Criterion. 101, Methyl Mercury; 1990.

(216) T.W. Clarkson et al, in Biological Monitoring of Toxic Metals, 1988,Plenum Press, N.Y., "The prediction of intake of mercury vapor from amalgams",p199-246 & p247-260; Environmental Health Perspective, 1993,April, 100:31-8; & F.L. Lorscheider et al, Lancet, 1991, 337,p1103.

(217) Apr 19,1999 Media Advisory, New MRLs for toxic substances, MRL:elemental mercury vapor/inhalation/chronic & MRL: methyl mercury/ oral/acute; & http://www.atsdr.cdc.gov/mrls.html

& Occupational Safety and Health Administration(OSHA), www.osha-slc.gov/SLTC/pel/

(225) S. Yannai et al, "Transformationss of inorganic mercury by candida albicans and saccharomyces cerevisiae", Applied Envir Microbiology,1991, 57:245-247; & I.R.Rowland et al, "The methylization of mercuric chloride

by human intestinal bacteria", Experentia, Sept 1975, 31(9):1064-5.

(226)(a)B.J. Shenker et al, Dept. Of Pathology, Univ. Of Penn. School of Dental Med.,"Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes: Alterations in cell viability" Immunopharmacologicol Immunotoxical, 1992, 14(3):555-77; & M.A.Miller et al, "Mercuric chloride induces apoptosis in human T lymphocytes", Toxicol Appl Pharmacol, 153(2):250-7 1998;& Rossi AD,Viviani B, Vahter M. Inorganic mercury modifies Ca2+ signals, triggers apoptosis, and potentiates NMDA toxicity in cerebral granule neurons. Cell Death and Differentiation 1997; 4(4):317-24. & Goering PL, Thomas D, Rojko JL, Lucas AD. Mercuric chloride-induced apoptosis is dependent on protein synthesis. Toxicol Lett 1999; 105(3): 183-95; & National Research Council, Toxicological Effects of Methyl mercury (2000), pp. 304-332: Risk Characterization and Public Health Implications, Nat'l Academy Press 2000. ( p55)

(260) J.S. Woods et al, "Urinary porphyrin profiles as biomarker of mercury exposure: studies on dentists", J Toxicol Environ Health, 40(2-3):1993, p235-; & "Altered porphyrin metabolites as a biomarker of mercury exposure and toxicity", Physiol Pharmocol, 1996,74(2):210-15, & Canadian J Physiology and Pharmacology, Feb 1996; & M.D.Martin et al, "Validity of urine samples for low-level mercury exposure assessment and relationship to porphyrin and creatinine excretion rates", J Pharmacol Exp Ther, Apr 1996 & J.S. Woods et al, "Effects of Porphyrinogenic Metals on Coproporphrinogen Oxidase in Liver and Kidney" Toxicology and Applied Pharmacology, Vol 97, 183-190, 1989.

(262) L.W.Chang, "Neurotoxic effects of mercury", Environ. Res.,1977, 14:329-

(281) T.W. Clarkson et al, "Transport of elemental mercury into fetal tissues", Biol. Neonate. 21:239-244, 1972; &

M.R.Greenwood et al, "Transfer of metallic mercury into the fetus", Experientia, 28:1455-1456, 1972.

(287) M.C. Newland et al,"Behavioral consequences of in utero exposure to mercury vapor", Toxicology & Applied Pharmacology, 1996, 139: 374-386; & Fredriksson, A., Dencker, L., Archer, T., Danielsson, B.R. "Prenatal Coexposure to Metallic Mercury Vapor and Methyl Mercury Produce Interactive Behavioral Changes in Adult Rats." Neurotoxicol Teratol., 18(2): 129-34, (1996). K.Warfvinge et al, "Mercury distribution in neonatal cortical areas ...after exposure to mercury vapor",Environmental Research, 1994, 67:196-208.

(304) M.J.Vimy et al, "Mercury from Maternal Silver Tooth Fillings: a source of neonatal exposure", Biological Trace Element Research, 56: 143-52,1997.

(305) Soderstrom S, Fredriksson A, Dencker L, Ebendal T, "The effect of mercury vapor on cholinergic neurons in the fetal brain, Brain Research & Developmental Brain Res, 1995, 85:96-108; & Toxicol Lett 1995; 75(1-3):133-44.; & E.M. Abdulla et al, "Comparison of neurite outgrowth with neurofilament protein levels In neuroblastoma cells following mercuric oxide exposure", Clin Exp Pharmocol Physiol, 1995, 22(5): 362-3;

& Leong CC, Syed NI, Lorscheider FL. Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Neuroreport 2001 Mar 26;12(4):733-7

(313) V.D.M.Stejskal et al, "Mercury-specific Lymphocytes: an indication of mercury allergy in man", J. Of Clinical Immunology, 1996, Vol 16(1);31-40;

& Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999

(333) P.R.Yallapragoda et al,"Inhibition of calcium transport by Hg salts" in rat cerebellum and cerebral cortex", J Appl toxicol, 1996, 164(4): 325-30; & A. Szucs et al, Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons. Cell Mol Neurobiol, 1997,17(3): 273-8;

(375) Stejskal V, Hudecek R, Mayer W, "Metal-specific lymphocytes: risk factors in CFS and other related diseases", Neuroendocrinology Letters, 20: 289-298, 1999

(405) Stejskal J, Stejskal V. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999. www.melisa.org/knowledge/education14.html

(500) B.Windham, Health Effects of amalgam fillings and results of replacement of amalgam filings. Over 2000 medical study references(most in Medline) documenting common high mercury exposures from amalgam, mechanisms by which mercury causes over 30 chronic conditions, and that vapor from amalgam is the most dangerous form of mercury to the fetus, along with results of approx. 60,000 clinical cases of those conditions of amalgam replacement followed by doctors; www.home.earthlink.net/~berniew1/amalg6.html

(503) Center for Chemical Hazard Assessment, Potential Occupational Hazards: Dentistry, Syracuse Research, Contract No.210-78-0019, 1980; & Merck Manuel, 14th Edition, p1552.

(506) Leistevuo J et al, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6; & www.myflcv.com

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II. 1. 2. 3. Environmental Effects

www.myflcv.com/damspr2f.html

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III. 1. Neurological Effects

Neurological effects of extremely low levels of mercury exposure ( annotated bibliography)

Leong et al. (2001), added HgCl₂to cultures of neurons from a snail with growing nerve germs. They were able to show that concentrations of HgCl₂below and close to 0.1 �M inhibit the growth of nerve germs and also cause retrograde degradation of the cytoskeleton in nerve cells.

Leong CC, Syed NI, Lorscheider FL (2001) Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Neuroreport 12: 733-737

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Monnet-Tschudi (1998) studied the incidence of apoptosis (programmed natural cell death) in cultures of foetal rat brain. She found that a concentration of 1 nM of HgCl₂ speeds up spontaneous apoptosis in immature cultures. A concentration of methyl mercury a thousand times higher was required for the same effect. A high proportion of the apoptotic cells were astrocytes. Similar findings by others.

Monnet-Tschudi F (1998) Induction of apoptosis by compounds depends on maturation and is not associated with microglial activation. J Neurosci Res 53: 361-367

& M.A.Miller et al, "Mercuric chloride induces apoptosis in human T lymphocytes", Toxicol Appl Pharmacol, 153(2):250-7 1998;

& Rossi AD,Viviani B, Vahter M. Inorganic mercury modifies Ca2+ signals, triggers apoptosis, and potentiates NMDA toxicity in cerebral granule neurons. Cell Death and Differentiation 1997; 4(4):317-24.

& Goering PL, Thomas D, Rojko JL, Lucas AD. Mercuric chloride-induced apoptosis is dependent on protein s synthesis. Toxicol Lett 1999; 105(3): 183-95;

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Only a few micrograms of mercury severely disturb cellular function and inhibits nerve growth .

Monnet-Tschudi F, Zurich MG, Honegger P, "Comparison of the developmental effects of 2 mercury compounds on glial cells and neurons in the rat telencephalon", Brain Research, 1996

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The period of dosing did not yield abnormal observations. Abnormalities including kyphosis, obesity, and severe neurological deficits were observed only as the animals aged. (note amalgam is a major source of mercury since bacteria and yeast in the body methylate other forms to methyl mercury)

D.C. Rice, "Evidence of delayed neurotoxicity produced by methyl mercury developmental exposure", Neurotoxicology, Fall 1996, 17(3-4), p583-96

& Leistevuo J, Pyy L, Osterblad M, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6

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Prenatal or neonatal exposures have been found to have life long effects on nerve function and susceptibility to toxic effects. Prenatal mercury vapor exposure that results in levels of only 4 parts per billion in newborn rat brains was found to cause decreases in nerve growth factor and other effects

Soderstrom S, Fredriksson A, Dencker L, Ebendal T, "The effect of mercury vapor on cholinergic neurons in the fetal brain, Brain Research & Developmental Brain Res, 1995, 85:96-108; & Toxicol Lett 1995; 75(1-3):133-44.;

& E.M. Abdulla et al, "Comparison of neurite outgrowth with neurofilament protein levels In neuroblastoma cells following mercuric oxide exposure", Clin Exp Pharmocol Physiol, 1995, 22(5): 362-3;

& P.Grandjean et al, "MeHg and neurotoxicity in children", Am J Epidemiol, 1999, 150(3):301-5:

& Budtz-Jorgensen E, Grandjean P, Keiding N, White RF, Weihe P. Benchmark dose calculations of methylmercury-associated neurobehavioral deficits. Toxicol Lett 2000 Mar 15;112-113:193- ;

& Crump KS, Kjellstrom T, Shipp AM, Silvers A, Stewart A. Influence of prenatal mercury exposure upon scholastic and psychological test performance: benchmark analysis of a New Zealand cohort. Risk Anal 1998 Dec;18(6):701-13;

& Grandjean P, Weihe P, Murata K, Sorensen N, Dahl R, Jorgensen PJ. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997 Nov-Dec;19(6):417-28

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III.2. Immune effects

Immune effects & mercury

Amalgam fillings in the teeth of mercury-sensitive rats give sufficiently high mercury exposure to provoke an autoimmune syndrome with a rise of immunoglobulins in plasma and immunocomplex deposition in the kidneys (Hultman et al. 1998).

Hultman P, Lindh U, Horsted-Bindslev P (1998) Activation of the immune system and systemic immune-complex deposits in Brown Norway rats with dental amalgam restorations. J Dent Res 77: 1415-1425

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In animal experiments, mercury can modify the functioning of the immune system in various pathological states. Mice treated with injections of subtoxic doses of HgCl₂are, for example, more susceptible to leishmaniasis infestation than untreated animals (Bagenstose et al. 2001).

Bagenstose LM, Mentink-Kane MM, Brittingham A, Mosser DM, Monestier M (2001) Mercury enhances susceptibility to murine leishmaniasis. Parasite Immunol 23: 633-640

Both mercury-sensitive and mercury-resistant mice show reduced immunity against malaria protozoa after injection of subtoxic doses of HgCl₂(Silbergeld et al. 2000).

Silbergeld EK, Sacci Jr JB, Azad AF (2000) Mercury exposure and murine response to Plasmodium yoelii infection and immunization. Immunopharmacol Immunotoxicol 22: 685-695

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In mice with a genetically conditioned tendency to develop the autoimmune syndrome systemic lupus erythematosus (SLE), development of the disease is accelerated if mercury is injected in subtoxic doses (Pollard et al, 2001).

Pollard KM, Pearson DL, Hultman P, Deane TN, Lindh U, Kono DH (2001) Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice. Environ Health Perspect 109: 27-33

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Lichen

One side-effect of amalgam fillings that is not particularly unusual is oral lichen. Larsson (1998) describes accumulation of mercury in the tissue affected, and accumulation of dendritic cells.

Larsson Å (1998) Oral lichen och amalgam - finns det en förklaringsmodell? ('Oral lichen and amalgam -- does an explanatory model exist?') Tandlakartidningen 90: 35-39

Little et al. (2001) showed that a culture of human oral keratocytes, on exposure to subtoxic concentrations of HgCl₂(10 �M), expresses ICAM-1, which in turn induces T cell binding, release of TNF- and interleukin-8 and down-regulation of interleukin-1. This induces activation of the immune system, which is not seen in experiments with cutaneous keratocytes.

Little MC, Watson RE, Pemberton MN, Griffiths CE, Thornhill MH (2001) Activation of oral keratinocytes by mercuric chloride: relevance to dental amalgam-induced oral lichenoid reactions. Br J Dermatol 144: 1024-1032

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Another group of 19 workers exposed to mercury vapour had a mean urinary secretion of mercury of 9.7 + 5.5 �g/l. In this group, Vimercati et al. (2001) found an inverse correlation between mercury in urine and the numbers of CD13+ and CD15+ leucocytes and NK cells. A reduced capacity for chemotaxis in polymorphonuclear leucocytes was also found. Loftenius et al. (1998) studied the effect of amalgam removal on mononuclear lymphocytes from 10 patients. They found a rise in IL-6 in plasma after 48 hours. The mercury concentration in plasma rose by some 10 per cent.

Vimercati L, Santarelli L, Pesola G, Drago I, Lasorsa G, Valentino M, Vacca A, Soleo L (2001) Monocyte-macrophage system and polymorphonuclear leukocytes in workers exposed to low levels of metallic mercury. Sci Total Environ 270: 157-163

***********************Autoimmune diseases

The tendency of mercury to induce autoimmunity gives rise to suspicion that mercury may boost the risk of autoimmune diseases, such as multiple sclerosis (MS). In a Canadian case-reference study, this hypothesis was tested (Bangsi et al. 1998). The findings of this survey, which covered 143 MS patients and 128 controls, provided no support for the hypothesis. True, persons with more than 15 fillings showed an excess risk of 2.57 times the risk of getting MS among persons without fillings, but this difference was not statistically significant.

Bangsi D, Ghadirian P, Ducic S, Morisset R, Ciccocioppo S, McMullen E, Krewski D (1998) Dental amalgam and multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol 27: 667-671

Similar results were obtained in an Italian survey comprising 132 MS patients and 423 controls (Casetta et al. 2001).

Casetta I, Invernizzi M, Granieri E (2001) Multiple sclerosis and dental amalgam: case-control study in Ferrara, Italy. Neuroepidemiology 20: 134-137

A British survey of 39 female MS patients and 62 matched controls showed a significant correlation between the prevalence of caries and the risk of MS. However, no significant difference was found between the MS patients and the controls in terms of how many amalgam fillings they had (McGrother et al. 1999).

McGrother CW, Dugmore C, Phillips MJ, Raymond NT, Garrick P, Baird WO (1999) Multiple sclerosis, dental caries and fillings: a case-control study. Br Dent J 187: 261-264 ??

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3.7 Polymorphism

During the five-year period under review, several case descriptions involving acute mercury exposure, with concentrations usually well above what may be expected from amalgam, have been published. These case descriptions have been published because the symptoms are unexpected. Mercury concentrations are documented with urine and blood figures, and the symptoms have subsided when the exposure ceased. Accordingly, there is no doubt that the high mercury concentrations genuinely caused the symptoms.

Besides oral lichen -- which is sometimes combined with facial exanthema -- the symptoms present have been a range of dermal syndromes, such as systemic contact dermatitis (baboon syndrome) (Alegre et al. 2000; Bartolome et al. 2000).

Alegre M, Pujol RM, Alomar A (2000) A generalized itchy flexural eruption in a 7-year-old boy. Arch Dermatol 136: 1055-1060

Bartolome B, Cordoba S, Sanchez-Perez J, Fernandez-Herrera J, Garcia-Diez A (2000) Baboon syndrome of unusual origin. Contact Dermatitis 43: 113.

Three cases of nummular dermatitis, which were cured by amalgam removal, are described by Adachi et al. (2000) and Pigatto et al. (2002).

Adachi A, Horikawa T, Takashima T, Ichihashi M (2000) Mercury-induced nummular dermatitis. J Am Acad Dermatol 43: 383-385

In a review article, Britschgi and Pichler (2000) assert that mercury can induce acute generalised exanthematous pustulosis. In another review article, Boyd et al. (2000) summarise experience of skin diseases caused by mercury.

Boyd AS, Seger D, Vannucci S, Langley M, Abraham JL, King Jr LE (2000) Mercury exposure and cutaneous disease. J Am Acad Dermatol 43: 81-90

Britschgi M, Pichler WJ (2002) Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inflammatory processes orchestrated by T cells. Curr Opin Allergy Clin Immunol 2: 325-331

There have also been descriptions of several cases where, in children with hypertension and elevated catecholamine secretion induced by mercury exposure, the symptomatology has resembled phaeochromocytoma (Laurans et al. 2001; Torres et al. 2000; Wössmann et al. 1999; Kosan et al. 2001).

Laurans M, Brouard J, Arion A, Kauffmann D, Duhamel JF (2001) Familial mercury intoxication presenting with cardiovascular abnormalities and acrodynia. Acta Paediatr 90: 593-594

Kosan C, Topaloglu AK, Ozkan B (2001) Chronic mercury intoxication simulating pheochromocytoma: effect of captopril on urinary excretion. Pediatrics International 43: 429-430

Torres AD, Rai AN, Hardiek ML (2000) Mercury intoxication and arterial hypertension: report of two patients and review of the literature. Pediatrics 105: E34.

Wossmann W, Kohl M, Gruning G, Bucsky P (1999) Mercury intoxication presenting with hypertension and tachycardia. Arch Dis Child 80: 556-557

A 48-year-old man developed aspects of severe, acute polyarthritis (Karatas et al. 2002) as a result of massive mercury exposure. Dalén (2000) describes a historical case with symptoms suggesting gastroenteral influence.

Dalén, P (2000) En amalgamsanering 1916 ('An amalgam removal in 1916'). Svensk medicinhistorisk tidskrift 4: 219-223

Karatas GK, Tosun AK, Karacehennem E, Sepici V (2002) Mercury poisoning: an unusual cause of polyarthritis. Clin Rheumatol 21: 73-75

The cases referred to above evince pronounced polymorphism in ways of reacting to mercury exposure. The conclusion is that the clinical picture of exposure to mercury vapour may vary greatly.

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Mercuric chloride damages cellular DNA by a non-apoptotic mechanism.

Ben-Ozer EY, Rosenspire AJ, McCabe MJ Jr, Worth RG, Kindzelskii AL, Warra NS, Petty HR.
Mutat Res. 2000 Oct 10;470(1):19-27.

Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.

Mercury is a xenobiotic metal that is well known to adversely affect the immune system, however, little is known as to the molecular mechanism. Recently, it has been suggested that mercury may induce immune dysfunction by triggering apoptosis in immune cells. Here, we studied the effects of Hg(2+) (HgCl(2)) on U-937 cells, a human cell line with monocytic characteristics. We found that these cells continued to proliferate when exposed to low doses of mercury between 1 and 5 microM. Using the single cell gel electrophoresis (SCGE) or 'comet' assay, we found that mercury damaged DNA at these levels. Between 1 and 50 microM Hg(2+), comet formation was concentration-dependent with the greatest number of comets formed at 5 microM mercury. However, the appearance of mercury-induced comets was qualitatively different from those of control cells treated with anti-fas antibody, suggesting that although mercury might damage DNA, apoptosis was not involved. This was confirmed by the finding that cells treated with 5 microM mercury were negative for annexin-V binding, an independent assay for apoptosis. These data support the notion that DNA damage in surviving cells is a more sensitive indicator of environmental insult than is apoptosis, and suggests that low-concentrations of ionic mercury may be mutagenic.
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ADP-ribosylation of brain neuronal proteins is altered by in vitro and in vivo exposure to inorganic mercury.

Palkiewicz P, Zwiers H, Lorscheider FL.
J Neurochem. 1994 May;62(5):2049-52.

Department of Medical Biochemistry, Faculty of Medicine, University of Calgary, Alberta, Canada.

ADP-ribosylation is an essential process in the metabolism of brain neuronal proteins, including the regulation of assembly and disassembly of biological polymers. Here, we examine the effect of HgCl2 exposure on the ADP-ribosylation of tubulin and actin, both cytoskeletal proteins also found in neurons, and B-50/43-kDa growth-associated protein (B-50/GAP-43), a neuronal tissue-specific phosphoprotein. In rats we demonstrate, with both in vitro and in vivo experiments, that HgCl2 markedly inhibits the ADP-ribosylation of tubulin and actin. This is direct quantitative evidence that HgCl2, a toxic xenobiotic, alters specific neurochemical reactions involved in maintaining brain neuron structure.

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Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity.

Pollard KM, Pearson DL, Hultman P, Hildebrandt B, Kono DH.
Environ Health Perspect. 1999 Oct;107 Suppl 5:729-35.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. mpollard@scripps.edu

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. ************************************************************************

The autoimmunity-inducing xenobiotic mercury interacts with the autoantigen fibrillarin and modifies its molecular and antigenic properties.

Pollard KM, Lee DK, Casiano CA, Bluthner M, Johnston MM, Tan EM.
J Immunol. 1997 Apr 1;158(7):3521-8.

Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.

The heavy metal mercury elicits a genetically restricted, anti-nucleolar autoantibody response that targets fibrillarin, a 34-kDa protein component of many small nucleolar ribonucleoprotein particles. The mechanisms by which a toxin such as mercury elicits an autoantibody response that predominantly targets a single intracellular protein autoantigen remain uncertain, but may be prefaced by mercury gaining access to the intracellular environment. Mercury-induced cell death was associated with loss of fibrillarin antigenicity and modification of the molecular properties of fibrillarin as revealed by aberrant migration under nonreducing conditions in SDS-PAGE. Addition of mercury to isolated nuclei also resulted in aberrant migration of fibrillarin, but not other nuclear autoantigens. The sensitivity of the HgCl2-induced modification of fibrillarin to 2-ME, iodoacetamide, and hydrogen peroxide suggested interaction of mercury with the two cysteines in the fibrillarin sequence. This was confirmed by mutation of the cysteines to alanines, which abolished the aberrant migration of fibrillarin in the presence of HgCl2. The modification of the molecular structure of fibrillarin by mercury reduced immunoprecipitation by anti-fibrillarin autoantibodies, pointing to unmodified fibrillarin as the B cell Ag and implicating mercury-modified fibrillarin as the source of T cell antigenicity. These observations demonstrate for the first time that an environmental toxin can alter the physicochemical properties of an autoantigen and may help to explain the antigenic specificity of mercury-induced murine autoimmunity.
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HgCl2-induced interleukin-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels.

Badou A, Savignac M, Moreau M, Leclerc C, Pasquier R, Druet P, Pelletier L.
J Biol Chem. 1997 Dec 19;272(51):32411-8.

INSERM Unite 28, Institut Federatif de Recherche 30, Hopital Purpan Place du Dr. Baylac, Toulouse 31059 cedex, France. Abdellah.Badou@purpan.inserm.fr

Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
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Mercury exposure and murine response to Plasmodium yoelii infection and immunization.

Silbergeld EK, Sacci JB Jr, Azad AF.

Immunopharmacol Immunotoxicol. 2000 Nov;22(4):685-95.

Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore 21201, USA.

Malaria has re-emerged in Amazonia over the past two decades. Many factors have been proposed for this, among them changes in population distribution, failures of vector control and pharmacologic management, and local as well as global environmental changes. Among the latter factors, we have studied the potential role of increasing exposures to the immunotoxic metal mercury, which is widely used in Amazonia for artisanal extraction of alluvial gold deposits. We report here that Hg impairs host resistance to malaria infection at exo-erythrocytic stages. Hg exposed mice have higher parasitemia following infection with sporozoites, but not after transfusion of infected red cells. In mice inoculated with irradiated sporozoites, Hg blocks acquisition of immunity. In addition Hg affects immunologic parameters that are known to be involved in host response to malaria infection. These results have potential implications for the incidence and prevalence of malaria among populations exposed to mercury from artisanal goldmining and consumption of contaminated fish regions with high rates of malaria and other infectious diseases.
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Influence of mercuric chloride on resistance to generalized infection with herpes simplex virus type 2 in mice.

Christensen MM, Ellermann-Eriksen S, Rungby J, Mogensen SC.
Toxicology. 1996 Nov 15;114(1):57-66.

Department of Medical Microbiology and Immunology, University of Aarhus, Denmark.

The effect of mercuric chloride on resistance to generalized infection with herpes simplex virus type 2 (HSV-2) in mice was studied. The severity of the infection was evaluated by the amount of infectious virus in the liver. Mercury at a single dose of 20 micrograms aggravated the infection, and neither increasing the single dose to 80 micrograms nor giving repeated doses of 20 micrograms further intensified the infection. Examination of the course of infection after mercury exposure revealed an increased virus replication and dissemination during the first days of the infection, indicating that the early, nonspecific defence mechanisms were affected. Virus clearance and elimination, which is mediated by specific immunity, seemed not to be influenced. Examination of cells from the peritoneal cavity and of livers from virus-infected mice showed that mercury detectable by autometallography was exclusively found in mature peritoneal macrophages and in Kupffer cells of the liver. Inflammatory cells, recruited to the peritoneal cavity or infiltrating the infectious foci of the liver, did not show any mercury deposits. Attempts to demonstrate an effect in vivo of mercury on potential antiviral macrophage functions like interferon-alpha/beta (IFN-alpha/beta) and tumour necrosis factor-alpha (TNF-alpha) secretion and oxidative burst capacity were not successful, possibly because recruited, inflammatory cells, which have not been exposed to the high mercury concentrations at the site of injection, take over these functions of intoxicated macrophages

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Mercuric chloride activates the Src-family protein tyrosine kinase, Hck in myelomonocytic cells.

Robbins SM, Quintrell NA, Bishop JM.
Eur J Biochem. 2000 Dec;267(24):7201-8.

Departments of Oncology, Biochemistry and Molecular Biology, University of Calgary, Canada. srobbins@ucalgary.ca

Hck is a member of the Src-family of protein tyrosine kinases that appears to function in mature leukocytes to communicate a number of extracellular signals including various cytokines. In this study we show that the thiol-reactive heavy metal, mercuric chloride (HgCl2) induces rapid and robust activation of tyrosine phosphorylation within human myelomonocytic cells. This increase in tyrosine-phosphorylated proteins requires the activity of Hck because both kinase inactive alleles of Hck and pharmacological inhibitors selective for the Src-family kinases are able to abrogate the cellular response to HgCl2. Furthermore, ectopic expression of Hck in murine fibroblasts is able to confer HgCl2 responsiveness, as indicated by an increase in tyrosine-phosphorylated proteins to a normally nonresponsive cell line. Concomitant with the activation of Hck, there is a physical association of Hck with another cytoplasmic protein tyrosine kinase, Syk. The ability of HgCl2 to activate Src-family kinases such as Hck in hematopoietic cells may help explain why exposure to the heavy metal is associated with immune system dysfunction in rodents as well as humans.
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Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity.

Pollard KM, Pearson DL, Hultman P, Hildebrandt B, Kono DH.

Environ Health Perspect. 1999 Oct;107 Suppl 5:729-35

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. mpollard@scripps.edu

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.
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The genotype determines the B cell response in mercury-treated mice.

Johansson U, Hansson-Georgiadis H, Hultman P.
Int Arch Allergy Immunol. 1998 Aug;116(4):295-305.

Divisions of Pathology, Linkoping University, Linkoping, Sweden.

Background: Mercury causes in mouse strains of the H-2s haplotype an autoimmune syndrome with antibodies to the nucleolar protein fibrillarin and systemic immune complex (IC) deposits. Other strains, like BALB/C (H-2d), develop only IC deposits, and most strains are resistant. However, mercury activates the murine immune system and causes lymphoproliferation in most strains: H-2s strains are high-responders also in this respect, while the relation between lymphoproliferation and autoimmune manifestations is unclear for other strains. We examined the B cell response to mercury in order to better understand the relation between lymphoproliferation and systemic autoimmunity, using the high-responder H-2s strains (A.SW and SJL), the intermediate responder strain BALB/C (H-2d), and the A. TL (H-2tl) and DBA/2 (H-2d) strains which are resistant to systemic autoimmunity. Methods: During 4-7 weeks of subcutaneous mercuric chloride injections, the number of B cells and the expression of cell surface activation and proliferation markers was monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig isotype levels as well anti-ssDNA and anti-DNP antibodies were determined by ELISA. Serum ANA were monitored weekly by indirect immunofluorescence technique. Results: Mercury-treated A.SW and SJL mice (H-2s) developed an increased expression of the proliferation marker CD71 on B cells, an increased number of B cells in the spleen, and an early, strong, but transient increase in serum Ig concentrations of Th1- as well as Th2-regulated Ig isotypes. Mercury-treated H-2s mice rapidly developed a polyclonal B cell response including the IgM isotype, but also antinucleolar antibodies (ANoA) of the IgG isotype with a clumpy pattern, characteristic for antifibrillarin antibodies. The IgG ANoA response was of a long duration and high titer. The A.TL strain (H-2tl) showed only a slight, restricted B cell activation. The BALB/C strain developed a slight, transient B cell activation dominated by IgG1 and IgE, and antinuclear antibodies (ANA). The DBA/2 strain showed only a minimal B cell response without ANA. Conclusion: Mercury induces an early, transient, polyclonal B cell activation linked to the H-2A or H-2K locus in H-2s strains on the A background. This polyclonal response differs from the long-lasting, high-titered IgG autoantibody response to a nucleolar antigen with characteristics of fibrillarin in H-2s strains, which indicates that these responses arise from separate mechanisms. Another group of strains, exemplified by BALB/C (H-2d), responds to mercury with a slight, transient, Th2-dominated B cell response, a restricted antibody specificity targeting the cell nucleus, and systemic IC deposits. Another H-2d strain, DBA, is essentially resistant to mercury, illustrating the importance of non-H-2 genes for regulating the response to mercury.

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Murine systemic autoimmune disease induced by mercuric chloride: T helper cells reacting to self proteins.

Kubicka-Muranyi M, Kremer J, Rottmann N, Lubben B, Albers R, Bloksma N, Luhrmann R, Gleichmann E.
Int Arch Allergy Immunol. 1996 Jan;109(1):11-20.

Division of Immunology, Heinrich Heine University Dusseldorf, Germany.

HgCl2 induces a CD4+ T-cell-dependent systemic autoimmune disease in susceptible strains of rats and mice. In rats, autoreactive T cells were shown to be involved, whereas in mice, attention has focussed on the demonstration of 'Hg-specific' T cells. To clarify these seemingly different T cell involvements, T cells from B10.S mice treated with HgCl2 for 1 or 8 weeks were analyzed for their capacity to mount anamnestic responses against various self antigens (Ags) which either contained Hg or did not. T cells from donors short-term treated with HgCl2 failed to mount memory responses to Hg-free Ags, but mounted a significant response to HgCl2 and also reacted with Hg-containing self Ags. Interestingly, T cells from donors long-term treated with HgCl2 showed a different pattern of reactivity. They hardly reacted to HgCl2 and reacted poorly to Hg-containing splenic proteins, but responded vigorously to nuclei and fibrillarin irrespective of whether these self constituents had been treated with HgCl2 or not. Conceivably, the initial activation of T cells that recognize Hg in combination with nuclear self proteins, such as fibrillarin, eventually results in activation of T cells specific for the unaltered self proteins.
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Mechanism of mercury-induced autoimmunity: both T helper 1- and T helper 2-type responses are involved.

Hu H, Moller G, Abedi-Valugerdi M.
Immunology. 1999 Mar;96(3):348-57

Department of Immunology, Arrhenius Laboratories for Natural Sciences, Stockholm University, Stockholm, Sweden.

Mercury can induce a systemic autoimmune disease in susceptible mouse strains. H-2s mice are particularly susceptible to mercury-induced autoimmunity and other mouse strains are more or less resistant. T helper 1/T helper 2 (Th1/Th2) dichotomy has been proposed for resistance or susceptibility, respectively. In the current study we show that mercury treatment induced a full autoimmune response in both C57BL/6 (H-2b) wild-type and interleukin-4 (IL-4)-deficient mice. Antibody production of all isotypes were induced, except that in IL-4-deficient mice there was no immunoglobulin E (IgE) and very low levels of immunoglobulin G1 (IgG1) antibody synthesis. Autoantibodies of different specificities were produced. The granular pattern of all IgG subclasses deposits were detected in the kidneys. In contrast to mercury-treated H-2s seconds mice, we did not detect any anti-nucleolar autoantibodies in the sera of mercury-treated wild-type or IL-4-deficient mice. To further explore the role of Th1/Th2 cytokines in the mercury model, we performed anti-interferon-gamma antibody treatment in IL-4-deficient mice together with mercury treatment and found that the production of IgG2a and IgG3, but not IgG2b, antibodies was downregulated. This indicated that besides Th2-type cytokines, Th1-type and other cytokines were involved as well in mercury-induced autoimmune response. Thus, C57BL/6 mice with H-2b genotype are highly susceptible to mercury-induced autoimmunity, and the genetic susceptibility to mercury involves more than a predisposition of a Th1-or Th2-type response.

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Lichenoid reactions of murine mucosa associated with amalgam.

Dunsche A, Frank MP, Luttges J, Acil Y, Brasch J, Christophers E, Springer IN.
Br J Dermatol. 2003 Apr;148(4):741-8.

Departments of Oral and Maxillofacial Surgery, Conservative Dentistry and Periodontology, Pathology and Dermatology, University of Kiel, Arnold-Heller-Str. 16, D-24105 Kiel, Germany.

Background In 97% of all patients with oral lichenoid reactions (OLR) associated with dental amalgam a removal of the fillings leads to a decline of the lesions, as a minimum. Objectives The aim of this study was to determine if contact allergic or local toxic effects or both may contribute to OLR using an animal model with mercury-sensitive and non-sensitive rats. Methods Twenty Brown Norway rats, which have a genetic predisposition for an autoimmune syndrome after exposure to mercury and 20 Lewis rats, not mercury sensitive, were treated as follows: 10 animals of each group were sensitized with a low dose of mercuric chloride. Half of all animals received local exposure of the right buccal mucosa to amalgam (left: control), the others to amalgam alloy free of mercury. All rats were patch tested with an amalgam series. Results After 20 days of exposure 96% of all animals showed white mucosal lesions restricted to the contact zone of the alloy on the treated side, but only up to 25% had a positive patch test reaction to amalgam or inorganic mercury (INM). The lesions showed no relation to species, alloy, sensitization or patch test reaction. Conclusions While allergic mechanisms may contribute to mucosal contact lesions in Brown Norway rats, this is less probable in Lewis rats. Mercury in general appears to be irrelevant in the development of ORL in this study. If this holds true for humans as well, patch testing with an amalgam series may be helpful in a minor fraction of all patients with OLR.
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Mercury causes autoimmune thyroiditis and other HLA endocrine conditions.

Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228. www.melisa.org

Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60. www.melisa.org ;

Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31

Autoimmune thyroiditis usually results in hypothyroid and other significant chronic degenerative condtions. (See submittal on endocrine effects)

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Mercury causes autoimmunity and results in autoimmune conditions such as CFS, FM, MS, ALS, Rheumatoid Arthritis. Those who reduce exposure usually get significant improvement in health.

Stejskal VDM, Danersund A, Lindvall A. Metal-specific memory lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters 1999;

Stejskal V, Hudecek R, Mayer W, "Metal-specific lymphocytes: risk factors in CFS and other related diseases", Neuroendocrinology Letters, 20: 289-298, 1999 www.melisa.org

Stejskal J, Stejskal V. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999.

see www.home.earthlink.net/~berniew1/immunere.html

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III. 3. Endocrine Effects

Endocrine effects

Mercury has been found to be an endocrine system disrupting chemical in animals and people, disrupting function of the pituitary gland, thyroid gland, thymus gland, adrenal gland, enzyme production processes, and affecting many hormonal functions at very low levels of exposure .

Mercury accumulates in the endocrine glands(pituitary, thyroid, hypothallamus, thymus, adrenal)

Lichtenberg H, "Mercury vapor in the oral cavity in relation to number of amalgam surfaces and the classic symptoms of chronic mercury poisoning", J Orthomol Med (1996), v11, n.2, 87-94 .

Warvinge K, Mercury distribution in the neonatal and adult cerebellum after mercury vapor exposure of pregnant squirrel monkeys, Environ Res 2000, 83(2): 93-101.

Falnoga I, Tusek-Znidaric M, Horvat M, Stegnar P. Mercury, selenium, and cadmium in human autopsy samples from Idrija residents and mercury mine workers. Environ Res. 2000 Nov;84(3):211-8

Studies have documented that mercury causes hypothyroidism.

(most references on this are from prior to 1996, there is a lot of clinical evidence also)

Ellingsen DG, Efskind J, Haug E, Thomassen Y, Martinsen I, Gaarder PI (2000b) Effects of low mercury vapour exposure on thyroid function in chloralkali workers. J Appl Toxicol 20: 483-489

B.Lindqvist et al, "Effects of removing amalgam fillings from patients with diseases affecting the immune system", Med Sci Res 24(5): 355-356, 1996.

Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228. www.melisa.org

Watanabe C, Yoshida K, Kasanuma Y, Kun Y, Satoh H. In utero methylmercury exposure differentially affects the activities of selenoenzymes in the fetal mouse brain.Environ Res 1999 Apr;80(3):208-14.

Sin YM, Teh WF, Wong MK, Reddy PK - "Effect of Mercury on Glutathione and Thyroid Hormones" Bulletin of Environmental Contamination and Toxicology 44(4):616-622, 1990.

Ghosh N, Bhattacharya S. Thyrotoxicity of cadmium and mercury. Biomed Environ Sci 1992, 5(3): 236-40;

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Mercury causes damage of thyroid RNA.

Dowling AL, Iannacone EA, Zoeller RT. Maternal Hypothyroidism Selectively Affects the Expression of Neuroendocrine-Specific Protein A Messenger Ribonucleic Acid in the Proliferative Zone of the Fetal Rat Brain Cortex. Endocrinology 2001 Jan 1;142(1):390-399

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Mercury causes autoimmune thyroiditis.

Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228. www.melisa.org

Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60. www.melisa.org ;

Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31

B.Lindqvist, Mornstat H , "Effects of removing amalgam fillings from patients with diseases affecting the immune system", Med Sci Res 24(5): 355-356, 1996.

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Thyroid and muscular atrophy

Ellingsen et al reported finding impaired thyroid function in a group of 47 chloralkali workers, whom they compared with 47 controls. The exposed workers showed a statistically significant rise in reverse T3 (rT3) -- a rise that was dose-related. The mean urinary concentration of mercury was 5.9 nmol/mmol creatinine, with a range of 1.1-16.8.

Ellingsen DG, Efskind J, Haug E, Thomassen Y, Martinsen I, Gaarder PI (2000b) Effects of low mercury vapour exposure on thyroid function in chloralkali workers. J Appl Toxicol 20: 483-489

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Atrophy and capillary damage in thigh muscle were observed in five out of six workers in dental care who had a urinary mercury-secretion rate of 13-67 �g/l at the time of the biopsy. These changes may, according to the authors, have been induced by the effect of the mercury on the nervous system or on capillaries. There might also be a direct effect on muscle fibres.

Nadorfy-Lopez E, Torres SH, Finol H, Mendez M, Bello B (2000) Skeletal muscle abnormalities associated with occupational exposure to mercury vapours. Histol Histopathol 15: 673-682

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In general immune activation from toxics such as mercury and other heavy metals resulting in cytokine release and abnormalities of the hypothalamus-pituitary-adrenal axis can cause changes in the brain, fatigue, and severe psychological symptoms such as profound fatigue, muscoskeletal pain, sleep disturbances, gastrointestinal and neurological problems as are seen in CFS, Fibromyalgia, and autoimmune thyroiditis..

Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228. www.melisa.org

Stejskal VDM, Danersund A, Lindvall A. Metal-specific memory lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters 1999;

Stejskal V, Hudecek R, Mayer W, "Metal-specific lymphocytes: risk factors in CFS and other related diseases", Neuroendocrinology Letters, 20: 289-298, 1999 www.melisa.org

Komaroff AL, Buchwald DS. Chronic fatigue syndrom: an update. Ann Rev Med 1998; 49: 1-13;

Buchwald DS, Wener MH, Kith P. Markers of inflamation and immune activation in CFS. J Rheumatol 1997; 24:372-76.

Turnbull AV, Rivier C. Regulation of the HPA axis by cytokines. Brain Behav Immun 1995; 20:253-75;

Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60. www.melisa.org ;

Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31 ;

Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999; 20: 289-98.

Kohdera T, Koh N, Koh R. Antigen-specific lymphocyte stimulation test on patients with psoriasis vulgaris. XVI International Congress of Allergology and Clinical Immunology, Oct 1997, Cancoon, Mexico;

Blumer W, "Mercury toxicity and dental amalgam fillings", Journal of Advancement in Medicine, v.11, n.3, Fall 1998, p.219

Ionescu G,. Heavy metal load with atopic Dermatitis and Psoriasis, Biol Med 1996; 2:65-68;

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Such hypersensitivity has been found most common in those with genetic predisposition to heavy metal sensitivity, such as found more frequently in patients with HLA-DRA antigens. A significant portion of the population appears to fall in this category.

Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228. www.melisa.org

Stejskal V, Hudecek R, Mayer W, "Metal-specific lymphocytes: risk factors in CFS and other related diseases", Neuroendocrinology Letters, 20: 289-298, 1999 www.melisa.org

Turnbull AV, Rivier C. Regulation of the HPA axis by cytokines. Brain Behav Immun 1995; 20:253-75

Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60. www.melisa.org ;

Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31 ;

Saito K. Analysis of a genetic factor of metal allergy-polymorphism of HLA-DR-DO gene. Kokubyo Gakkai Zasschi 1996; 63: 53-69;

Prochazkova J, Ivaskova E, Bartova J, Stejskal VDM. Immunogentic findings in patients with altered tolerance to heavy metals. Eur J Human Genet 1998; 6: 175.

Stejskal J, Stejskal V. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999.

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Mercury can have significant effects on thyroid function even though the main hormone levels remain in the normal range, so the usual thyroid tests are not adequate in such cases. Prenatal methylmercury exposure severely affects the activity of selenoenzymes, including glutathione peroxidase (GPx) and 5-iodothyronine deiodinases(5-Di and 5'-DI) in the fetal brain, even though thyroxine(T4) levels are normal. Gpx activity is severely inhibited, while 5-DI levels are decreased and 5'-DI increased in the fetal brain, similar to hypothyroidism. Thus normal thyroid tests will not pick up this condition.

Watanabe C, Yoshida K, Kasanuma Y, Kun Y, Satoh H. In utero methylmercury exposure differentially affects the activities of selenoenzymes in the fetal mouse brain.Environ Res 1999 Apr;80(3):208-14.

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According to survey tests, 8 to 10 % of untreated women were found to have thyroid imbalances and even larger percentages of women had elevated levels of antithyroglobulin(anti-TG) or antithyroid peroxidase antibody(anti-TP). 2.5 % of pregnant

women tested in New England had highly elevated TSH levels. Fifty-eight per cent of women with TSH concentrations above 6 mU/l and 90% of the women with elevated TSH concentrations and at least one thyroxine index more than two standard deviations below the control means had positive titres of antithyroid antibodies as opposed to 11% of the controls

Postpartum thyroid disease occurs in 5 to 9% of women and thyroid dysfunction postpartum is seen in 50% of thyroid peroxidase antibody positive women.

Bonar DB, McColgan B, Smith DR, Darke C, Guttridge MG, Williams HSmyth PPA, Hypothyroidism and aging: The Rosses' Survey. Thyroid 2000, 10(9):821-827;

Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000, 160(4):526-34.

Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, Mitchell ML.. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf). 1991 Jul;35(1):41-6.

Lazarus JH., Thyroid dysfunction: reproduction and postpartum thyroiditis.. Semin Reprod Med. 2002 Nov;20(4):381-8.

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Studies indicate that slight imbalances (subclinical) of thyroid hormones in expectant mothers can cause permanent neuropsychiatric damage in the developing fetus. Low first trimester levels of free T4 and positive levels of anti-TP antibodies in the mother during pregnancy have been found to result significantly reduces IQs and causes psychomotor deficits. Hypothyroidism is a well documented cause of mental retardation. Women with the highest levels of thyroid-stimulating-hormone(TSH) and lowest free levels of thyroxine 17 weeks into their pregnancies were significantly more likely to have children who tested at least one standard deviation below normal on an IQ test taken at age 8. Based on study findings, maternal hypothyroidism appears to play a role in at least 15% of children whose IQs are more than 1 standard deviation below the mean, millions of children..Studies have also established a connection between maternal thyroid disease and babies born with heart defects. The American Assoc. of Clinical Endocrinologists advises that all women considering becoming pregnant should get a serum thyrotropin test so that hypothyroidism can be diagnosed and treated early.

Klein RZ, Sargent JD, Larsen PR, Waisbren Se, Haddow JE, Mitchell ML, Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen 2001: 8:18-20;

de Escobar DM, Orbregon MF, del Rey FE, Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrin Metab 2000; 3975-3987;

Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ.. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549-55.

Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest. 2003 Apr;111(7):1073-82.

Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL.. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. , Clin Endocrinol(Oxf), 50:149-55, 1999;

Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix JD, Klein RZ.
Maternal thyroid deficiency and pregnancy complications: implications for population screening J Med Screen. 2000;7(3):127-30.

Asami T, Suzuki H, Yazaki S, Sato S, Uchiyama M. Effects of thyroid hormone deficiency on electrocardiogram findings of congenenitally hypothyroid neonates. Thyroid. 2001 Aug;11(8):765-8.

Abstract # 274: Wolfberg, Adam J. and David A. Nagey, "Thyroid Disease During Pregnancy and Subsequent Congenital Anomalies."St Johns Univ., kblum@jhmi.edu ;

Pop VJ, de Vries E, et al, Maternal thyroid peroxidase antibodies during pregnancy: and impaired child development, J Clin Endocrinol Metab., 1995, 80:3561-3566

Thyroid Imbalances in Pregnancy Linked to Poor Child Neurodelopment, Great Smokies Diagnostic Lab, www.gsdl.com/news/connections/vol11/conn20010228.html

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Studies have also established a "clear association" between the presence of thyroid antibodies and spontaneous abortions. Levels of recurrent abortions in a population with positive levels of thyroid antibodies in one study were 40%, 5 times the normal rate. Hypothyroidism is a well documented risk factor in spontaneous abortions and infertility. Another study of pregnant women who suffer from hypothyroidism (underactive thyroid) found a four-times greater risk for miscarriage during the second trimester than those who don't, and women with untreated thyroid deficiency were four-times more likely to have a child with a developmental disabilities. Hypothyroidism is also a well documented cause of mental retardation.

Abramson J, Stagnaro-Green A, Thyroid antibodies and fetal loss, Thyroid 2001, 11(1): 57-63;

Thyroid Antibodies May Spur Pregnancy Loss, GSDL, www.gsdl.con/news/connections/vol12/conn20010411.html

Allan W.(MD), Maternal Hypothyroidism During Pregnancy Linked to Increased Risk for Miscarriage, Journal of Medical Screening, November 22, 2000;

Abstract # 274: Wolfberg, Adam J. and David A. Nagey, "Thyroid Disease During Pregnancy and Subsequent Congenital Anomalies."St Johns Univ., kblum@jhmi.edu ;

Emerson, C.H. (1996). Thyroid Disease During and After Pregnancy. In L.E. Braverman

& R.D. Utiger (Eds.), The Thyroid, A Fundamental and Clinical Text, pp. 1021-1031;

Brent GA, Maternal hyrothyroidism: recognition and management, Thyroid, 1999, 9:661-5.

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Thyroid imbalances, which are documented to be commonly caused by mercury , have been

found to play a major role in chronic heart conditions such as clogged arteries, mycardial infarction, and chronic heart failure. In a recent study, published in the Annals of Internal Medicine, researchers reported that subclinical hypothyroidism is highly prevalent in elderly women and is strongly and independently associated with cardiac atherosclerosis and myocardial infarction. People who tested hypothyroid usually have significantly higher levels of homocysteine and cholesterol, which are documented factors in heart disease. 50% of those testing hypothyroid, also had high levels of homocysteine (hyperhomocysteinenic) and 90% were either hyperhomocystemic or hypercholesterolemic. These are also known factors in developing arteriosclerotic vascular disease. Homocysteine levels are significantly increased in hypothtyroid patients and normalize with treatment.

Morris MS, Bostom AG, Jacques PJ, Selhub J, Rosenberg IH, Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third U.S. National Health and Nutrition Examination Survey, Artherosclerosis 2001, 155:195-200;

Shanoudy H. Soliman A, Moe S, Hadian D, Veldhuis F, Iranmanesh A, Russell D, Early manifestations of "sick eythyroid syndrome" in patients with compensated chronic heart failure, J Card Fail 2001, 7(2):146-52;

AE. Hak, HAP. Pols, TJ. Visser, et al., The Rotterdam Study., Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women, Ann Int Med, 2000, vol. 132, pp. 270--278

Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002 Dec 3;137(11):904-14;

Hussein, WI, Green, R, Jacobsen, DW, Faiman, C. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med 1999; 131:348;

Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002 Dec 3;137(11):904-14;

B.G. Nedreboe, O. Nygard, et al, Plasma Total Homocysteine of hypothyroid patients during 12 months of treatment, Haukeland Univ. Hospital, Bergen, Norway, bjoern.gunnar.nedreboe@haukeland.no (references 7 other studies with similar findings);

Thyroid Dysfunction Linked to Elevated Cardiac Risk, GSDL, www.gsdl.com/news/connections/vol12/conn20010411.html.;

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overt autoimmune thyroiditis is preceded by a rise in levels of thyroid peroxidase antibodies. "Collectively, reports show that 30-60% of women positive for TPO antibodies in pregnancy develop postpartum thyroiditis," the researchers point out, calling it "a strong association." Without treatment, many of the women with thyroiditis go on to develop overt clinical hypothyroidism as they age and, eventually, associated complications such as cardiovascular disease. About 5% of pregnant women develop thyroiditis after birth.

Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endocrine Reviews 2001;22(5):605-30.

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An overactive thyroid gland, or hyperthyroidism, can trigger restlessness, hyperactivity, insomnia and irritability - symptoms that could be mistaken for mania. On the other hand, a thyroid gland that responds sluggishly in a hypothyroid state may result in feelings of coldness, depression, and low energy.

Nath J, Safar R. Late-onset bipolar disorder due to hyperthyroidism. Acta Psychiatr Scand 2001;104:72-75.

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Mercury through its affects on the endocrine system is also documented to cause other reproductive effects including infertility, low sperm counts, abnormal sperm, endometriosis, PMS, adverse effects on reproductive organs, etc.

Gerhard I, Monga B, Waldbrenner A, Runnebaum B "Heavy Metals and Fertility", J of Toxicology and Environmental Health,Part A, 54(8):593-611, 1998; &

Gerhard I, Waibel S, Daniel V, Runnebaum B "Impact of heavy metals on hormonal and immunological factors in women with repeated miscarriages", Hum Reprod Update 1998 May;4(3):301-309;

Yang JM, Jiang XZ, Chen QY, Li PJ, Zhou YF, Wang YL. , "The distribution of HgCl2 in rat body and its effect on fetus", Environ Sci , 1996, 9(4): 437-42

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Khayat A, Dencker L. Whole body and liver distribution of inhaled mercury vapor in the mouse: influence of ethanol and aminotriazole pretreatment. J Appl Toxicol. 1983 Apr;3(2):66-74. (new)

Inhalation of radioactive metallic mercury vapor (203Hg0) in the mouse resulted in an accumulation of mercury in several organs where no specific uptake was observed after i.v. injection of inorganic mercury (203Hg2+). This was true for the whole respiratory epithelium (including the lung parenchyma), myocardium, brain, retina of the eye, adrenal cortex, corpora lutea of the ovary, epididymis, brown fat and thyroid gland. It is assumed that these organs have a high capacity for oxidizing Hg0 to Hg2+, which will then be retained in the tissues.

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Kosuda LL, Hannigan MO, Bigazzi PE, Leif JH, Greiner DL., Thymus atrophy and changes in thymocyte subpopulations of BN rats with mercury-induced renal autoimmune disease. Autoimmunity. 1996;23(2):77-89.

Administration of low doses of mercury induces autoantibodies to laminin and autoimmune glomerulonephropathy in BN, MAXX and DZB rats as well as in (BN x LEW)F1 hybrids. LEW strain rats are resistant to these immunotoxic effects. Susceptible rats also show lymphoid hyperplasia in spleen and lymph nodes and severe thymic atrophy.

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Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica.

Cutolo M, Foppiani L, Minuto F. n
J Endocrinol Invest. 2002;25(10 Suppl):19-23.

University of Genova, Genova, Italy. mcutolo@unige.it

Stressful/inflammatory conditions activate the immune system and subsequently the hypothalamic-pituitary-adrenal (HPA) axis through the central and peripheral production of cytokines such as IL-6 and TNF-alpha. A relative adrenal hypofunction, as evidenced by inappropriately normal F levels and reduced DHEAS levels, has been recently claimed to play a causative role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR). Thus, we evaluated baseline levels of adrenal androgens, IL-6 and IL-12 together with HPA axis challenge by ovine CRH and low-dose ACTH in premenopausal RA women and aged PMR women. In addition, adrenal steroids, IL-6, and acute-phase reactant levels were measured at baseline and during 12 months of glucocorticoid tapering regimen in a cohort of PMR patients. Reduced DHEAS levels (p<0.05) associated to increased (p<0.05) IL-6 and IL-12 levels were found in RA patients as compared to controls (C). Irrespective of the inflammatory condition, basal and stimulated cortisol levels in RA were similar to C, whereas DHEA secretion after ACTH testing was significantly (p<0.01) reduced. During HPA challenge, F responses in PMR patients proved inadequate in the setting of the inflammatory status, confirmed by increased IL-6 levels. In addition, these patients showed significantly (p<0.05) increased 17-hydroxyprogesterone (17-OHP) responses after ACTH testing as compared to C. The longitudinal study in PMR patients showed that glucocorticoid therapy leads to a stable reduction of IL-6 and of acute-phase reactant levels, which persist even after glucocorticoid tapering. Our data show an inadequate adrenal secretion in RA and PMR, both characterized by increased levels of HPA axis-stimulating cytokines. The reduced basal levels of DHEAS in RA might be ascribed to a reduced biosynthesis as consequence of a cytokine-induced impairment of P450 17.20-lyase activity. In PMR, the ACTH-induced enhanced 17-OHP levels suggest a partial age- and cytokine-induced impairment of the P450 21 beta-hydroxylase, which eventually leads to inadequate glucocorticoid production. The clinical and biochemical improvement observed after glucocorticoid therapy in patient with RA and PMR, might thus be attributed to a direct dampening of pro-inflammatory factors as well as to the restoration of the steroid milieu. Given its multifaceted properties, including the ability to counteract the negative side effects of glucocorticoids, the therapeutical administration of DHEA might be considered in these pathologies, provided its safety is proved.
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The role of neuroendocrine system in the pathogenesis of rheumatic diseases (minireview).

Imrich R.
Endocr Regul. 2002 Jun;36(2):95-106.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 933 06 Bratislava, Slovak Republic. ueenmri@savba.sk

Interactions between the neuroendocrine and immune system play an important role in maintaining and restoring homeostasis. In susceptible individuals a dysfunction of the neuroendocrine system may be one of the risk factors involved in the pathogenesis of rheumatic diseases. Specific causes of altered neuroendocrine function are still not fully elucidated. Accumulation of genetical, environmental, behavioral and other risk factors during long preclinical period may result in chronic imbalances in homeostatic mechanisms maintained by neuroendocrine, microvascular and immune systems. Chronic inflammatory stress mediated by humoral and neural signals during active stages of the disease and autoantibodies against the structures of the neuroendocrine system may further participate in the neuroendocrine dysfunction. In a subset of patients with rheumatoid arthritis (RA), an assumed defect of the hypothalamic-pituitary-adrenocortical axis may be implicated in the pathogenesis. Results of some studies support the concept of adrenal dysfunction in women with premenopausal onset of the RA. Significantly lower levels of dehydroepiandrosterone sulfate (DHEAS) plasma levels of women who subsequently developed RA indicate that neuroendocrine dysfunction may be present already in preclinical period and thus are not only secondary due to ongoing inflammatory process. These findings are sketching the new prospects of possible primary prevention of RA in the future. The role of some other hormones including prolactin, growth hormone, sex hormones and involvement of autonomic nervous system in relation with the rheumatic diseases is also reviewed in the paper. Further research concerning their role in the pathogenesis of other rheumatic diseases will possibly provide new prospects in optimizing their therapy.
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Involvement of the hypothalamic-pituitary-adrenal axis in children with oligoarticular-onset idiopathic arthritis.

Picco P, Gattorno M, Sormani MP, Vignola S, Buoncompagni A, Battilana N, Pistoia V, Ravazzolo R.
Ann N Y Acad Sci. 2002 Jun;966:369-72.

Department of Pediatric Rheumatology, G. Gaslini Institute, Genova, Italy. Paolopicco@ospedale-gaslini.ge.it

Adult patients with rheumatic arthritis and other rheumatic disorders show inappropriate cortisol secretion and peculiar CRH promoter gene polymorphisms. So far, no data are available about this topic in children with juvenile idiopathic arthritis (JIA). We have studied a series of 13 prepubertal patients (10 female, 3 male) affected with oligoarticular JIA (o-JIA) without clinical and biological signs of disease activity (ESR and IL-6). ACTH plasma concentrations were significantly increased at 8 a.m. in o-JIA patients, whereas no differences were found in cortisol plasma concentrations. The ACTH/cortisol ratio was significantly increased in o-JIA patients with respect to the normal population both at 8 a.m. and at noon. DHEAS and testosterone plasma concentration did not statistically differ in the two populations. The genetic study was aimed at defining the prevalence of polymorphisms A1 and A2 in o-JIA patients, but we failed to find allelic or genotypic differences. Our study suggests the presence of a partial resistance to ACTH with a dysregulated pattern of secretion also in inactive o-JIA patients. These preliminary data need further confirmation in larger pediatric studies.
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Reduced levels of testosterone and dehydroepiandrosterone sulphate in the serum and synovial fluid of juvenile rheumatoid arthritis patients correlates with disease severity.

Khalkhali-Ellis Z, Moore TL, Hendrix MJ.
Clin Exp Rheumatol. 1998 Nov-Dec;16(6):753-6.

Department of Anatomy and Cell Biology, University of Iowa, Iowa City 52242, USA.

OBJECTIVE: The status of androgen levels and their significance in the pathogenesis of juvenile rheumatoid arthritis (JRA) has not been fully investigated. In the present study serum and synovial fluid (SF) from 20 JRA patients (grouped as pre-pubertal and pubertal) were analyzed for their content of testosterone, dehydroepiandrosterone (DHEA) and its sulphated conjugate DHEA-S, progesterone and 17 beta-estradiol. RESULTS: Comparison of the results from JRA patients with that of age-matched controls indicated no significant differences in progesterone and DHEA. Similarly, 17 beta-estradiol levels from the pubertal group were comparable to those of the controls; however, prepubertal patients had no detectable levels of this hormone. DHEA-S values were significantly lower in the pubertal JRA group, 1388.3 +/- 291.8 and 1663.9 +/- 354.1 nmol/l in the serum and SF, respectively (compared to 8206.6 +/- 848.12 in the serum of matching controls). These patients also presented with a much lower testosterone content in their SF than in their serum, 0.09 +/- 0.036 and 0.56 +/- 0.068 nmol/l, respectively (compared to 1.35 +/- 0.146 in the serum of corresponding controls). CONCLUSION: The data presented in this paper demonstrate for the first time an association between low androgen levels and disease in JRA patients. The significance of hypoandrogenicity with respect to the pathogenic mechanisms of arthritic disease and the possible therapeutic strategies that these imply warrants further investigation.
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Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A.
Ann N Y Acad Sci. 2002 Jun;966:131-42.

Laboratory and Division of Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy. mcutolo@unige.it

Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.

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Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis.

Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M.
Arthritis Rheum. 2002 Mar;46(3):654-62.

Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany. rainer.straub@klinik.uni-r.de

OBJECTIVE: To compare levels of steroid hormones in relation to cytokines and to study levels of cortisol or dehydroepiandrosterone (DHEA) in relation to other adrenal hormones in untreated patients with early rheumatoid arthritis (RA) and reactive arthritis (ReA) compared with healthy controls. METHODS: In a retrospective study with 34 RA patients, 46 ReA patients, and 112 healthy subjects, we measured serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF), adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17-OH-progesterone), androstenedione (ASD), DHEA, and DHEA sulfate (DHEAS). RESULTS: RA patients had higher serum levels of IL-6, TNF, cortisol, and DHEA compared with ReA patients and healthy subjects, but no difference was noticed with respect to ACTH and DHEAS. However, in RA and ReA patients compared with healthy subjects, levels of ACTH, cortisol, ASD, DHEAS, and 17-OH-progesterone were markedly lower in relation to levels of IL-6 and TNF. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL-6 in RA (R(Rank) = -0.582, P = 0.001) and, to a lesser extent, in ReA (R(Rank) = -0.417, P = 0.011). In RA patients, the mean grip strength of both hands was positively correlated with the ratio of serum cortisol to serum IL-6 (R(Rank) = 0.472, P = 0.010). Furthermore, in these untreated patients with RA and ReA, there was a relative decrease in the secretion of 17-OH-progesterone, ASD, and DHEAS in relation to DHEA and cortisol. This indicates a relative predominance of the nonsulfated DHEA and cortisol in relation to all other measured adrenal steroid hormones in the early stages of these inflammatory diseases. CONCLUSION: This study indicates that levels of ACTH and cortisol are relatively low in relation to levels of IL-6 and TNF in untreated patients with early RA and ReA compared with healthy subjects. The study further demonstrates that there is a relative increase of DHEA and cortisol in relation to other adrenal hormones, such as DHEAS. This study emphasizes that adrenal steroid secretion is inadequately low in relation to inflammation. Although changes in hormone levels are similar in RA and ReA, alteration of steroidogenesis is more pronounced in RA patients than in ReA patients.
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Low serum dehydroepiandrosterone sulfate in women with primary Sjogren's syndrome as an isolated sign of impaired HPA axis function.

Valtysdottir ST, Wide L, Hallgren R.
J Rheumatol. 2001 Jun;28(6):1259-65.
Units of Rheumatology and Clinical Chemistry, Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden. sigridur.valtysdottir@medicin.uu.se

OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in women with primary Sjogren's syndrome (pSS). METHODS: In 10 women with pSS and 10 age matched female controls, we evaluated serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, growth hormone, sex hormone binding globulin, cortisol, and adrenocorticotropin hormone (ACTH), in both basal condition and after stimulation with corticotropin releasing hormone, thyrotropin releasing hormone, and luteinizing hormone releasing hormone intravenously. Patients had not previously been treated with glucocorticoids. RESULTS: Patients with pSS had significantly lower basal mean DHEA-S values compared with healthy controls (2.4 +/- 0.4 vs 3.9 +/- 0.3 mumol/l; p < 0.05) and significantly lower DHEA-S values after stimulation. The cortisol/DHEA-S ratio in the patient group was higher than in controls (171 +/- 39 vs 76 +/- 5; p < 0.05). A correlation was found between basal ACTH and DHEA-S values in the patients (r = 0.650; p = 0.05). No correlation was seen between disease activity or age and the serum concentration of DHEA-S. The levels of other hormones both at baseline and after stimulation were similar in patients and controls. CONCLUSION: The results show that women with pSS have intact cortisol synthesis but decreased serum concentrations of DHEA-S and increased cortisol/DHEA-S ratio compared with healthy controls. The findings may reflect a constitutional or disease mediated influence on adrenal steroid synthesis. The thyroid axis and gonadotropin secretion were similar in patients and controls.

Hyposecretion of the adrenal androgen dehydroepiandrosterone sulfate and its relation to clinical variables in inflammatory arthritis.

Dessein PH, Joffe BI, Stanwix AE, Moomal Z.
Arthritis Res. 2001;3(3):183-8. Epub 2001 Feb 21.

Department of Rheumatology, Johannesburg Hospital, University of the Witwatersrand, Johannesburg, South Africa. Dessein@elink.co.za

Hypothalamic-pituitary-adrenal underactivity has been reported in rheumatoid arthritis (RA). This phenomenon has implications with regard to the pathogenesis and treatment of the disease. The present study was designed to evaluate the secretion of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) and its relation to clinical variables in RA, spondyloarthropathy (Spa), and undifferentiated inflammatory arthritis (UIA). Eighty-seven patients (38 with RA, 29 with Spa, and 20 with UIA) were studied, of whom 54 were women. Only 12 patients (14%) had taken glucocorticoids previously. Age-matched, healthy women (134) and men (149) served as controls. Fasting blood samples were taken for determination of the erythrocyte sedimentation rate (ESR), serum DHEAS and insulin, and plasma glucose. Insulin resistance was estimated by the homeostasis-model assessment (HOMAIR). DHEAS concentrations were significantly decreased in both women and men with inflammatory arthritis (IA) (P < 0.001). In 24 patients (28%), DHEAS levels were below the lower extreme ranges found for controls. Multiple intergroup comparisons revealed similarly decreased concentrations in each disease subset in both women and men. After the ESR, previous glucocorticoid usage, current treatment with nonsteroidal anti-inflammatory drugs, duration of disease and HOMAIR were controlled for, the differences in DHEAS levels between patients and controls were markedly attenuated in women (P = 0.050) and were no longer present in men (P = 0.133). We concluded that low DHEAS concentrations are commonly encountered in IA and, in women, this may not be fully explainable by disease-related parameters. The role of hypoadrenalism in the pathophysiology of IA deserves further elucidation. DHEA replacement may be indicated in many patients with IA, even in those not taking glucocorticoids.
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The hypothalamic-pituitary-adrenal and gonadal axes in rheumatoid arthritis.

Cutolo M, Villaggio B, Foppiani L, Briata M, Sulli A, Pizzorni C, Faelli F, Prete C, Felli L, Seriolo B, Giusti M.
Ann N Y Acad Sci. 2000;917:835-43.

Division of Rheumatology, Department of Internal Medicine, University of Genova, Italy. mcutolo@unige.it

The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid-treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone-replacement therapies in RA.

Weak androgen levels, glucocorticoid therapy, and bone mineral density in postmenopausal women with rheumatoid arthritis.

Fiter J, Nolla JM, Navarro MA, Gomez-Vaquero C, Rosel P, Mateo L, Roig-Escofet D.
Joint Bone Spine. 2000;67(3):199-203.

Rheumatology department, Princeps d'Espanya Hospital, ciutat sanitaria i universitaria de Bellvitge, Barcelona, Spain.

OBJECTIVE: To study dehydroepiandrosterone sulfate (DHEAS) and androstenedione (AND) status in postmenopausal women with rheumatoid arthritis (RA), the effects of glucocorticoid therapy on DHEAS and AND levels, and their relationship with bone mineral density (BMD). METHODS: Forty-six postmenopausal women with RA were separated into two groups based on whether they had a negative history for glucocorticoid therapy (n = 24) or were currently on glucocorticoid therapy (n = 22). The control group was composed of 39 postmenopausal women who had never received hormone replacement therapy. Serum DHEAS and AND levels were measured using a radioimmunoassay. BMD was determined at the lumbar spine (L2-L4) and femoral neck using a DEXA Hologic QDR-1000 densitometer. Results. RA patients and controls were similar in age, weight, body mass index, and years since menopause. DHEAS and AND levels were lower in the glucocorticoid-treated RA group than in the other two groups. The glucocorticoid-treated RA group also had a significantly lower femoral BMD value than the nonglucocorticoid-treated RA group. Lumbar BMD was similar in the two RA groups and in the controls. CONCLUSION: Decreases in DHEAS and AND levels in postmenopausal women with RA are probably related to glucocorticoid therapy rather than to the disease itself.

Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids.

Cutolo M, Foppiani L, Prete C, Ballarino P, Sulli A, Villaggio B, Seriolo B, Giusti M, Accardo S.
J Rheumatol. 1999 Feb;26(2):282-8.

Department of Internal Medicine, University of Genova, Italy.

OBJECTIVE: To assess hypothalamic-pituitary-adrenocortical axis function in patients with rheumatoid arthritis (RA) not previously treated with glucocorticoids in relation to their inflammatory condition and in comparison to healthy controls. METHODS: We evaluated, in 10 premenopausal patients with RA and 7 age matched controls, plasma dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and cortisol concentrations, together with inflammatory cytokine levels [interleukin 6 (IL-6) and IL-12], both in basal conditions and after stimulation with ovine corticotropin releasing hormone (oCRH) and with low dose intravenous (5 microg) adrenocorticotropic hormone (ACTH). RESULTS: DHEA and DHEAS basal concentrations were found to be significantly lower (p<0.05) in premenopausal patients with RA than in controls. As expected, significantly higher basal levels of IL-6 and IL-12 (p<0.05) were found in patients with RA. After the low dose ACTH testing, the DHEA area under the curve value was found to be significantly lower (p<0.01) in patients than controls. Similar results, but without statistical significance, were observed after oCRH stimulation. DHEA levels at basal time showed a significant negative correlation with the erythrocyte sedimentation rate and platelet count, as well as with the Steinbrocker class of the disease (p<0.05). Normal plasma cortisol levels during oCRH and ACTH testing were found in patients with RA in spite of their inflammatory condition. After ACTH testing, IL-6 levels decreased significantly (p<0.05), whereas IL-12 levels were unchanged. No significant changes in IL-6 and IL-12 levels were found after oCRH testing. CONCLUSION: The abnormal androgen concentrations observed during testing in patients with RA might support the implication of adrenal androgens in the immune/inflammatory cytokine mediated mechanisms involved in the pathophysiology and clinical aspects of RA.

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Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.

Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B.
J Clin Endocrinol Metab. 1998 Jun;83(6):2012-7.

Department of Internal Medicine I, University Medical Center, Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de

Interleukin-6 (IL-6) is one of the pathogenetic elements in inflammatory and age-related diseases such as rheumatoid arthritis, osteoporosis, atherosclerosis, and late-onset B cell neoplasia. In these diseases or during aging, the decrease in production of sex hormones such as dehydroepiandrosterone (DHEA) is thought to play an important role in IL-6-mediated pathogenetic effects in mice. In humans, we investigated the correlation of serum levels of DHEA, DHEA sulfate (DHEAS), or androstenedione (ASD) and IL-6, tumor necrosis factor-alpha, or IL-2 with age in 120 female and male healthy subjects (15-75 yr of age). Serum DHEA, DHEAS, and ASD levels significantly decreased with age (all P < 0.001), whereas serum IL-6 levels significantly increased with age (P < 0.001). DHEA/DHEAS and IL-6 (but not tumor necrosis factor-alpha or IL-2) were inversely correlated (all patients: r = -0.242/-0.312; P = 0.010/0.001). In female and male subjects, DHEA and ASD concentration dependently inhibited IL-6 production from peripheral blood mononuclear cells (P = 0.001). The concentration-response curve for DHEA was U shaped (maximal effective concentration, 1-5 x 10(-8) mol/L), which may be the optimal range for immunomodulation. In summary, the data indicate a functional link between DHEA or ASD and IL-6. It is concluded that the increase in IL-6 production during the process of aging might be due to diminished DHEA and ASD secretion. Immunosenescence may be directly related to endocrinosenescence, which, in turn, may be a significant cofactor for the manifestation of

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Occupational and environmental agents as endocrine disruptors: experimental and human evidence.

Baccarelli A, Pesatori AC, Bertazzi PA. J Endocrinol Invest. 2000 Dec;23(11):771-81.

In the last few years great concern has arisen from the description of adverse endocrine effects of several occupational and environmental chemical agents on human and/or wildlife health. Such agents may exert their effects directly, specifically binding to hormone receptors, and/or indirectly, by altering the structure of endocrine glands and/or synthesis, release, transport, metabolism or action of endogenous hormones. Many studies have been focused on the outcomes of the exposure to those chemicals mimicking estrogenic or androgenic actions. Nonetheless, the disruption of other hormonal pathways is not negligible. This paper reviews the experimental and human evidence of the effects of occupational and environmental chemical agents on hypothalamus-pituitary unit, pineal gland, parathyroid and calcium metabolism and adrenal glands. Melatonin has been proposed as the link between environmental/occupational factors and the immunologic and neoplastic diseases, which in addition to disturbances of the circadian timing system, feature pineal hormone reduction. Thyroid gland diseases (goiter, autoimmune thyroiditis, carcinoma) are associated with exposure to many chemical or physical agents. Disruptions of calcium control secondary to metal exposures, as well as the effect of radiation on parathyroid, are addressed. Adrenal cortex and medulla function alterations by several chemical agents are considered. Finally, diabetes mellitus as an outcome of occupational or environmental exposures and as susceptibility to occupational and environmental factors is discussed.

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Re: Dopamine beta hydroxylase and poisons that block it ( lead, mercury, manganese etc. )

Title: Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.

Author ": Manzo L; Artigas F; Martíínez E; Mutti A; Bergamaschi E; Nicotera P; Tonini M; Candura SM; Ray DE; Costa LG

Source: Hum Exp Toxicol, 1996 Mar, 15 Suppl 1:, S20-35

Address: Toxicology Unit, University of Pavia, Italy.

Abstract: Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. There is evidence that mercury can block the DBH enzyme. DBH is used to make the noradrenaline neurotransmitter and low noradrenaline can cause fatigue and depression. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.
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Thyroid dysfunction: reproduction and postpartum thyroiditis.

Lazarus JH. Semin Reprod Med. 2002 Nov;20(4):381-8.

Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.

Thyroid function during pregnancy is characterized by changes in circulating thyroid hormone concentrations related to alterations in thyroxine binding globulin (TBG), human chorionic gonadotropin (hCG), and iodine status. The immunology of normal pregnancy shows a reduction in antibody titer during gestation and an increase in T helper-2 (TH2) immune responses. Thyroid dysfunction may cause menstrual disturbances in hyper- and hypothyroidism but less marked disturbances of sexual function in men. Fertility is reduced in hypo- and hyperthyroid females. Accumulating evidence suggests a strong association between the presence of thyroid antibodies and fetal loss, although the data relating to recurrent abortion are not so convincing. Asymptomatic maternal gestational hypothyroidism may occur in up to 2.5% of women; studies have shown a significant impact of this condition in causing a decrease of child IQ, suggesting that screening for maternal hypothyroidism with intervention may be justified. Postpartum thyroid disease occurs in 5 to 9% of women and thyroid dysfunction postpartum is seen in 50% of thyroid peroxidase antibody positive (TPO Ab+ve) women. There is a significant rate of hypothyroidism in long-term follow-up of women who have transient postpartum thyroid dysfunction.
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[Autoantibodies to thyroid gland antigens in chronic relapsing urticaria]
[Article in Russian]

Sibgatulina NA, Kuz'mina NS, Rakhmatullina NM, Gevarzieva VB.
Zh Mikrobiol Epidemiol Immunobiol. 2002 Sep-Oct;(5):69-71.

Mechnikov Research Institute for Vaccines and Sera, Moscow, Russia.

The content of total IgE, antibodies to thyroglobulin (TG-Ab), antibodies to thyreoid peroxidase (TPO-Ab) in the blood serum and skin reaction to autologous serum were detected in patients with chronic relapsing urticaria (CRU). The skin test to autologous serum yielded positive results in 42% of the patients. The elevated levels of TG-Ab and TPO-Ab were detected in 30.7% and 35.4% of the patients, the elevated level of total IgE was detected in 60% of the patients. At the same time the detection rates of antithyreoid antibodies and the elevated level of IgE were not linked with skin reaction to autologous serum. Apparently, in addition to autoantibodies to IgE or its receptor (the positive skin test to autologous serum), thyroid gland antibodies may take part in the mechanism of the CRU formation.
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Thyroid dysfunction and autoimmunity in infertile women.

Poppe K, Glinoer D, Van Steirteghem A, Tournaye H, Devroey P, Schiettecatte J, Velkeniers B.
Thyroid. 2002 Nov;12(11):997-1001

Departments of Endocrinology, and Reproductive Medicine, Vrije Universiteit Brussel, Brussels, Belgium. hemopek@az.vub.ac.be

A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy parous controls with the aim of assessing the prevalence of autoimmune thyroid disease (AITD) and hitherto undisclosed alterations of thyroid function. Female origin of the infertility was diagnosed in 45% of the couples, with specific causes including endometriosis (11%), tubal disease (30%), and ovarian dysfunction (59%). Male infertility represented 38% and idiopathic infertility 17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L. Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were not more prevalent in the infertile women than in controls. The prevalence of positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated women of infertile couples, compared to controls (14% vs. 8%), but the difference was not significant. However, in infertility of female origin, a significant higher prevalence of positive TPO-Ab was present, compared to controls: 18% versus 8%. Furthermore, among the female causes, the highest prevalence of positive antibodies was observed in women with endometriosis (29%). When thyroid antibodies were positive, both hypothyroidism and hyperthyroidism were more frequent in all women of infertile couples and in the women with a female infertility cause, compared to women in the same groups but without positive TPO-Ab. The present study shows that in infertile women, thyroid autoimmunity features are significantly more frequent than in healthy fertile controls and this was especially the case for the endometriosis subgroup.
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Purine metabolism in leukocytes and erythrocytes in Graves' or Hashimoto's disease.

Karbownik M, Zasada K, Wyczechowska D, Lewinski A, Fabianowska-Majewska K.

Department of Thyroidology, Institute of Endocrinology, Medical University of Lodz, 5, Dr. Sterling St., 91425, Lodz, Poland.

INTRODUCTION: Adenosine deaminase (ADA), purine nucleoside phosphorylase (PNPase), S-adenosylhomocysteine hydrolase (SAHH), 5'-nucleotidase (5N), and deoxycytidine kinase (dCK) are involved in purine salvage metabolism. Changes of the activities of the above enzymes have been observed in blood cells in patients with immunological disorders. MATERIALS AND METHODS: The activities of ADA, PNPase, SAHH, 5'N, and dCK in lysates of leukocytes and erythrocytes, obtained from patients with Graves' or Hashimoto's disease, were measured, using chromatographic analysis. Serum concentrations of antithyroglobulin (Tg Ab) and antithyroperoxidase (TPO Ab) antibodies were measured by an immunoenzymatic method. RESULTS: (1) ADA activity in leukocytes, obtained from patients with Hashimoto's disease, was significantly higher than in control leukocytes, as well as in leukocytes from patients with Graves' disease; (2) dCK activities in leukocytes from patients with both Graves' and Hashimoto's diseases were approximately four and five times higher, respectively, than in leukocytes of control subjects; (3) a positive correlation was observed between dCK activity in leukocytes and serum Tg Ab concentration in patients with Graves' disease. In conclusion, the increased ADA and dCK activities in leukocytes from patients with Graves' and Hashimoto's diseases may be regarded as indicators of autoimmunological thyroid diseases.
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High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension.
Chu JW, Kao PN, Faul JL, Doyle RL.
Chest. 2002 Nov;122(5):1668-73.

Divisions of Endocrinology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5236, USA.

STUDY OBJECTIVES: An association between thyroid disease and pulmonary arterial hypertension (PAH) has been reported, yet the pathogenetic relationship between these conditions remains unclear. Because immune system dysfunction may underlie this association, we sought to determine the prevalence of autoimmune thyroid disease (AITD) in patients with PAH. DESIGN AND SETTING: Prospective observational study at a single academic institution. PATIENTS: Sixty-three consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure, > 25 mm Hg) were evaluated for clinical, biochemical, and serologic features of AITD. MEASUREMENTS: Thyroid gland dysfunction was determined by clinical examination for goiter, and by biochemical measurements of thyrotropin and free thyroxine. Immune system dysfunction was determined by serologic measurements of antibodies to thyroglobulin and thyroid peroxidase. First-degree family history of AITD also was ascertained in order to investigate for genetic clustering of autoimmunity. RESULTS: Thirty-one patients (49%; 95% confidence interval [CI], 37 to 62%) received diagnoses of AITD. Eighteen patients were newly diagnosed, and 9 patients required the initiation of pharmacologic treatment. There was no chronologic relationship between the diagnosis or treatment of PAH and that of AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family members with AITD. CONCLUSIONS: Approximately half of the patients with PAH have concomitant AITD. These two conditions may be linked by a common immunogenetic susceptibility, and the elucidation of this association may advance the understanding of the pathophysiology and treatment of PAH. Systematic surveillance for occult thyroid dysfunction in patients with PAH may prevent the hemodynamic exacerbation of right heart failure.
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Autoimmune thyroiditis in non-obese subjects with initial diagnosis of Type 2 diabetes mellitus.

Matejkova-Behanova M, Zamrazil V, Vondra K, Vrbikova J, Kucera P, Hill M, Andel M.
J Endocrinol Invest. 2002 Oct;25(9):779-84.

Institute of Endocrinology, Prague, Czech Republic. mbehanova@endo.cz

Autoimmune thyroiditis is often associated with Type 1 diabetes mellitus (T1DM). In non-obese adult-onset diabetes diagnosed initially as Type 2 diabetes mellitus (T2DM), there is a proportion of cases with so far undiagnosed T1DM. The objective of this study was to estimate the frequency of autoimmune thyroiditis (AT) among non-obese (BMI <30.0 kg/m2) patients with T2DM and to compare the frequency of AT in subgroups of patients according to the presence of glutamic acid decarboxylase antibodies (GADA), insulin requirement, and post-breakfast C-peptide levels. The study included 118 adult patients (55 men and 63 women) with the initial diagnosis of T2DM and age at the onset of diabetes > 35 yr. Median of age was 66 yr (range 39-82), and median duration of diabetes was 9 (range 1-27) yr. AT was diagnosed using thyroid peroxidase antibodies, TG-antibodies, US and TSH levels. Nineteen per cent of the subjects were found to have AT, and the frequency of AT did not significantly differ between the groups of GADA+ and GADA- subjects. There was no difference in the frequency of AT between the group treated with hypoglycemic agents and/or diet and the group requiring insulin. The frequency of AT was higher in the group with post-breakfast C-peptide levels < or = 0.8 nmol/l compared to the group with post-breakfast C-peptide levels > 0.8 nmol/l (37% vs 16%), however the group with post-breakfast C-peptide levels < or = 0.8 nmol/l had longer duration

of diabetes.
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Primary thyroid disorders in endogenous Cushing's syndrome.

Niepomniszcze H, Pitoia F, Katz SB, Chervin R, Bruno OD.
Eur J Endocrinol. 2002 Sep;147(3):305-11.

Division de Endocrinologia, Hospital de Clinicas Jose de San Martin, Piso, Argentina.

OBJECTIVE: To study the prevalence of primary thyroid disorders in patients who underwent endogenous hypercortisolism. DESIGN: Retrospective evaluation of 59 patients with Cushing's syndrome (CS) who had, at least, a record of thyroid palpation by expert endocrinologists and basal measurements of TSH by second generation assays. When available, tri-iodothyronine and thyroxine serum levels, TRH-TSH tests and anti-thyroid antibodies were also analyzed. There were two age- and gender-matched control groups. The 'goiter control group' comprised 118 healthy subjects who underwent thyroid palpation. The 'antibody control group' was composed of 40 individuals who attended the blood bank of our hospital. Antibodies against thyroperoxidase and measurements of TSH were analyzed in their blood samples. METHODS: Available files of 83 CS patients admitted to our endocrine unit from 1985 to 1998 were examined. Fifty-nine patients (52 women and 7 men) with a mean age of 36.2 years (range 14-61 years) met the above requirements. Diagnosis of hypercortisolism had been established by a standard 1-mg overnight dexamethasone suppression test and urinary free cortisol (UFC). Etiological diagnosis involved dynamic testing, measurements of ACTH levels and imaging techniques. After treatment, all but one of the patients were cured or controlled of their hypercortisolism. This was established by the finding of subnormal serum cortisol concentrations and/or subnormal 24-h UFC levels. Primary thyroid disorders were defined by the presence of one or more of the following diagnostic criteria: (i) goiter, (ii) positive anti-thyroid antibodies and/or (iii) primary thyroid function abnormalities. RESULTS: Eighteen (30.5%) patients had goiter (diffuse in 78% and nodular in 22%), 14 (23.7%) had primary subclinical hypothyroidism and 5 (8.4%) had hyperthyroidism. In 41 patients evaluated for antithyroid antibodies, it was found that 23 (56.1%) had positive titers. In a group of patients in which thyroid autoantibodies were measured both before and after resolution of hypercortisolism, prevalences of positive titers were 26.7% and 86.7% respectively (P=0.001). The overall frequency of primary thyroid abnormalities in our patients with Cushing's syndrome was 55.9%. CONCLUSIONS: Patients with endogenous Cushing's syndrome exhibit a remarkably high prevalence of primary thyroid disease. Resolution of hypercortisolism seems to trigger the development of autoimmune thyroid disorders in presumably predisposed subjects.
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Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996.

Sawka AM, Fatourechi V, Boeve BF, Mokri B.
Thyroid. 2002 May;12(5):393-8.

Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55906, USA.

Corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also called Hashimoto's encephalopathy) is a rare, life-threatening, treatable, and possibly autoimmune condition. We identified nine patients (with the diagnosis made after 1979) who had relapsing encephalopathy compatible with previous reports of Hashimoto's encephalopathy and no other identifiable cause of encephalopathy at Mayo Clinic Rochester. Of these nine patients, three were clinically hypothyroid, four were subclinically hypothyroid, and two were euthyroid. Thyroid antibodies were positive in eight of eight patients in whom these measurements were made. Electroencephalographic abnormalities were identified in eight of the nine patients (89%). Magnetic resonance imaging (MRI) abnormalities considered etiologically related to encephalopathy were present in three patients (33%). An increased protein concentration was noted on cerebrospinal fluid examination in seven patients (78%). Of the six patients who received high-dose glucocorticoid therapy, 5 (83%) had improvement of neurologic symptoms. In conclusion, encephalopathy associated with autoimmune thyroiditis is rare but important to recognize because it may be responsive to high-dose glucocorticoid therapy. We believe that this condition is not caused by thyroid dysfunction or antithyroid antibodies but represents an association of an uncommon autoimmune encephalopathy with a common autoimmune thyroid disease..
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Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).

Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE.
J Clin Endocrinol Metab. 2002 Feb;87(2):489-99.

Centers for Disease Control, National Center for Environmental Health, Division of Emergency and Environmental Services, Atlanta, Georgia 30341, USA. jgh3@mindspring.com

NHANES III measured serum TSH, total serum T(4), antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17,353 people aged > or =12 yr representing the geographic and ethnic distribution of the U.S. population. These data provide a reference for other studies of these analytes in the U.S. For the 16,533 people who did not report thyroid disease, goiter, or taking thyroid medications (disease-free population), we determined mean concentrations of TSH, T(4), TgAb, and TPOAb. A reference population of 13,344 people was selected from the disease-free population by excluding, in addition, those who were pregnant, taking androgens or estrogens, who had thyroid antibodies, or biochemical hypothyroidism or hyperthyroidism. The influence of demographics on TSH, T(4), and antibodies was examined. Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). (Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.) TgAb were positive in 10.4 +/- 0.5% and TPOAb, in 11.3 +/- 0.4%; positive antibodies were more prevalent in women than men, increased with age, and TPOAb were less prevalent in blacks (4.5 +/- 0.3%) than in whites (12.3 +/- 0.5%) (P < 0.001).

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Dental amalgam as one of the risk factors in autoimmune diseases.

Bartova J, Prochazkova J, Kratka Z, Benetkova K, Venclikova Z, Sterzl I.
Neuroendocrinol Lett. 2003 Feb-Apr;24(1-2):65-7

Institute of Dental Research, lst Medical Faculty, Charles University and General Faculty Hospital Prague, Vinohradska 48, 120 60 Prague 2, Czech Republic. jirina.bartova@post.cz

BACKGROUND: Experimental and clinical data published recently show that dental amalgam can give rise to undesirable immunological responses in susceptible individuals. In genetically susceptible strains of experimental animals, mercury and silver can induce autoimmune responses. Sera of patients sensitive to mercury were found to have a higher incidence of autoantibodies relative to controls. OBJECTIVE: The aim of this study was to determine possible presence of antinuclear SSB/La autoantibodies after the in vitro stimulation of peripheral blood lymphocytes with HgCl2. METHODS: Lymphocytes were obtained from patients with autoimmune thyroiditis and increased response to mercury in vitro. Mononuclear cells were cultivated for 6 days with 100 microl HgCl2 solution or with pure medium and the levels of antinuclear autoantibodies SSB/La were assayed by a commercial SSB/La ELISA kit. RESULTS: Increased production of SSB/La autoantibodies in the media following stimulation of peripheral blood lymphocytes with HgCl2 was found in all cases. Using the Student's paired test, the results were significant on the p=0.05 significance level. CONCLUSION: Results imply that, in some patients with thyroiditis, mercury from dental amalgam can stimulate the production of antinuclear antibodies. Dental amalgam may be a risk factor in some patients with autoimmune disease

for more info see: www.home.earthlink.net/~berniew1/endohg.html

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III.4. Cardiovascular Effects

Cardiovascular Effects of Mercury

Both organic and ionic mercury accumulates in the heart and has been associated with elevated blood pressure and abnormal heart rhythms such as, tachycardia and ventricular heart rhythmns (NAS, p.168)(U.S. EPA, p.3-20). It is unknown whether the main cardiovascular effects of mercury are due to direct cardiac toxicity or to indirect toxicity caused by effects on the neural control of cardiac function(EPA). The researchers believe that mercury promotes heart disease in several ways: mercury promotes free radical generation; it inactivates the body's natural antioxidant glutathione; and it binds with selenium thus making it unavailable as an antioxidant and component of glutathione peroxidase; it also affects the endocrine system which controls cardiovascular system. All these mechanisms would lead to an increased level of lipid peroxidation and subsequent heart disease. Researchers also point out that earlier studies have discovered a clear correlation between the number of amalgam tooth fillings and the risk of heart attack(Salonen).

National Research Council, Toxicological Effects of Methyl mercury (2000), pp. 304-332: Risk Characterization and Public Health Implications, Nat'l Academy Press 2000.

Office of Air Quality Planning & Standards and Office of Research and Development. (1997, December). Mercury study report to congress volume V: Health effects of mercury and mercury compounds. Retrieved October 27, 02, from U.S. Environmental Protection Agency Web Site: www.epa.gov

Salonen JT, Seppanen K, Nyyssonen K, Korpela H, Kauhanen J, Kantola M, Tuomilehto J, Esterbauer H, Tatzber F, Salonen R. , "Intake of mercury from fish and the risk of myocardial infarction and cardiovascular disease in eastern Finnish men", Circulation, 1995; 91(3):645-55;

Salonen JT, Seppanen K, Lakka TA, Salonen R, Kaplan GA. Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland. Atherosclerosis 2000 Feb;148(2):265-73;

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Mercury intoxication presenting with hypertension and tachycardia.

Wossmann W, Kohl M, Gruning G, Bucsky P. Arch Dis Child. 1999 Jun;80(6):556-7.

Department of Paediatrics, Medical University of Luebeck, 23538 Luebeck, Germany.

An 11 year old girl presented with hypertension and tachycardia. Excess urinary catecholamine excretion suggested phaeochromocytoma but imaging studies failed to demonstrate a tumour. Other symptoms included insomnia and weight loss, and she was found to have a raised concentration of mercury in blood and urine. Mercury intoxication should be considered in the differential diagnosis of hypertension with tachycardia even in patients presenting without the skin lesions

[Arterial hypertension due to mercury poisoning: diagnostic value of captopril] [Article in French]

Cloarec S, Deschenes G, Sagnier M, Rolland JC, Nivet H.
Arch Pediatr. 1995 Jan;2(1):43-6.
Service de pediatrie R, hopital Gatien-de-Clocheville, Tours, France.

BACKGROUND--Mercury poisoning is a rare cause of hypertension in children. Urinary excretion sometimes remains low despite severe clinical intoxication. CASE REPORT--A 32 month-old girl was admitted with hypertension, tachycardia, apathy, irritability and excessive sweating. Erythromelalgia and neurologic symptoms permitted the diagnosis of acrodynia. Urine mercury remained normal until chelation. Captopril significantly increased urine mercury concentration but failed to improve clinical manifestations. Clinical improvement required infusions of BAL for 5 days then oral dimercaptosuccinic acid for 3 months. Metal vapors originated from the mercury which spilled from a broken thermometer onto the carpet. COMMENTS--Low basal urine mercury could be associated with real mercury poisoning. Small amounts of metal mercury held in a thermometer could produce a high level of mercury vapor leading to intoxication in young children. The binding capacity of metal ions by captopril could be used to increase urine mercury output. Nevertheless, captopril therapy fails to improve acrodynia. Total elimination of mercury requires long-term therapy with BAL or dimercaptosuccinic acid. CONCLUSIONS--An unexpected mode of intoxication and low basal urine mercury are not decisive arguments against mercury poisoning, which is the only cause of acrodynia.

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Effects of small concentrations of mercury on the contractile activity of the rat ventricular myocardium.

Souza de Assis GP, Cunha Silva CE, Stefanon I, Vassallo DV.
Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):375-83
Departamento de Ciencias Fisiologicas, CBM/UFES, Av. Marechal Campos, 1468, Marui;pe, 29040-095, ES, Vitoria, Brazil

Personal exposure to mercury vapor and the release of mercury from or during removal of amalgam dental fillings increases its blood and plasma concentration. However, it is not known if these very small amounts affect cardiac function. The effects of continuous exposure to 5 and 20 nM of HgCl(2) on the cardiac contractility were investigated in isometric and tetanic contractions of right ventricular strips and in Langendorff perfused rat hearts. The continuous exposure for 2 h produced a small but significant reduction of the isometric twitch force and time to peak tension shortened. Relative post-rest potentiation was not affected by this concentration of HgCl(2) suggesting a lack of action of the metal on the sarcoplasmic reticulum activity. Tetanic tension, in contrast to twitch force, was intensively reduced suggesting an important depressant action on the activity of contractile proteins. In perfused hearts beating spontaneously, isovolumic systolic pressure reduced progressively and the diastolic pressure increased. Although occurring heart rate reduction, it was similar for both controls and mercury treated hearts. Also, time dependent changes in coronary perfusion pressure were similar to controls. Results suggested that cardiac effects may be observed after continuous exposure to very small concentrations of mercury, probably as a result of the cell capacity to concentrate mercury. These results also indicate that continuous professional exposure to mercury followed by its absorption might have toxicological consequences affecting cardiac function, and being considered hazardous.
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Thyroid imbalances, which are documented in another submittal to be commonly caused by mercury , have been found to play a major role in chronic heart conditions such as clogged arteries, mycardial infarction, and chronic heart failure. In a recent study, published in the Annals of Internal Medicine, researchers reported that subclinical hypothyroidism is highly prevalent in elderly women and is strongly and independently associated with cardiac atherosclerosis and myocardial infarction. People who tested hypothyroid usually have significantly higher levels of homocysteine and cholesterol, which are documented factors in heart disease. 50% of those testing hypothyroid, also had high levels of homocysteine (hyperhomocysteinenic) and 90% were either hyperhomocystemic or hypercholesterolemic. These are also known factors in developing arteriosclerotic vascular disease. Homocysteine levels are significantly increased in hypothtyroid patients and normalize with treatment.

Morris MS, Bostom AG, Jacques PJ, Selhub J, Rosenberg IH, Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third U.S. National Health and Nutrition Examination Survey, Artherosclerosis 2001, 155:195-200;

Shanoudy H. Soliman A, Moe S, Hadian D, Veldhuis F, Iranmanesh A, Russell D, Early manifestations of "sick euthyroid syndrome" in patients with compensated chronic heart failure, J Card Fail 2001, 7(2):146-52;

Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. , The Rotterdam Study., Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women, Ann Int Med, 2000, vol. 132, pp. 270--278

Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002 Dec 3;137(11):904-14;

Hussein, WI, Green, R, Jacobsen, DW, Faiman, C. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med 1999; 131:348;

Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002 Dec 3;137(11):904-14;

& Asami T, Suzuki H, Effects of thyroid hormone deficiency on electrocardiogram findings of congenenitally hypothyroid neonates. Thyroid 11: 765-8, 2001.

Thyroid Dysfunction Linked to Elevated Cardiac Risk, GSDL, www.gsdl.com/news/connections/vol12/conn20010411.html.;

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Subclinical thyroid conditions a major factor in cardiovascular disease

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Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.

Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC.

Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, The Netherlands.

BACKGROUND: Overt hypothyroidism has been found to be associated with cardiovascular disease. Whether subclinical hypothyroidism and thyroid autoimmunity are also risk factors for cardiovascular disease is controversial. OBJECTIVE: To investigate whether subclinical hypothyroidism and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction in postmenopausal women. DESIGN: Population-based cross-sectional study. SETTING: A district of Rotterdam, The Netherlands. PARTICIPANTS: Random sample of 1149 women (mean age +/- SD, 69.0 +/- 7.5 years) participating in the Rotterdam Study. MEASUREMENTS: Data on thyroid status, aortic atherosclerosis, and history of myocardial infarction were obtained at baseline. Subclinical hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>4.0 mU/L) and a normal serum free thyroxine level (11 to 25 pmol/L [0.9 to 1.9 ng/dL]). In tests for antibodies to thyroid peroxidase, a serum level greater than 10 IU/mL was considered a positive result. RESULTS: Subclinical hypothyroidism was present in 10.8% of participants and was associated with a greater age-adjusted prevalence of aortic atherosclerosis (odds ratio, 1.7 [95% CI, 1.1 to 2.6]) and myocardial infarction (odds ratio, 2.3 [CI, 1.3 to 4.0]). Additional adjustment for body mass index, total and high-density lipoprotein cholesterol level, blood pressure, and smoking status, as well as exclusion of women who took beta-blockers, did not affect these estimates. Associations were slightly stronger in women who had subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio for aortic atherosclerosis, 1.9 [CI, 1.1 to 3.6]; odds ratio for myocardial infarction, 3.1 [CI, 1.5 to 6.3]). No association was found between thyroid autoimmunity itself and cardiovascular disease. The population attributable risk percentage for subclinical hypothyroidism associated with myocardial infarction was within the range of that for known major risk factors for cardiovascular disease. CONCLUSION: Subclinical hypothyroidism is a strong indicator of risk for atherosclerosis and myocardial infarction in elderly women.
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Early manifestations of "sick euthyroid" syndrome in patients with compensated chronic heart failure.

Shanoudy H, Soliman A, Moe S, Hadian D, Veldhuis JD, Iranmanesh A, Russell DC.
J Card Fail. 2001 Jun;7(2):146-52.

Cardiology Section, Department of Veterans Affairs Medical Center, Salem, Virginia, USA.

BACKGROUND: A "sick euthyroid" syndrome occurs in patients with severe decompensated chronic heart failure (CHF) and other chronic illnesses and is related to adverse prognosis, but it has not been described in patients with compensated CHF. The aim of this study was to determine whether manifestations of the sick euthyroid syndrome occur in patients with compensated CHF caused by ischemic heart disease. METHODS AND RESULTS: Thyroid hormonal responses to thyrotropin-releasing hormone (TRH) stimulation were compared in 8 patients with New York Heart Association class I/II CHF considered secondary to ischemic heart disease and 7 control patients after serial 10-minute blood sampling over 3-hour periods. Secretory dynamics of TRH-induced thyroid-stimulating hormone (TSH) release were compared by using deconvolution analysis. Changes in serum thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3), and rT3/T4 concentration ratios were compared. Patients with CHF had lower baseline serum T3 concentrations (P <.001), with lower maximum serum T(3) (P <.01) and higher maximum serum rT(3) (P <.05) concentrations after TRH stimulation but similar estimated TRH-induced TSH secretory burst amplitude, mass, and 3-hour production rates, compared with control patients. CONCLUSIONS: Patients with compensated CHF display the derangements in thyroid hormone metabolism of impaired peripheral conversion of T4 and T3 and increased production of rT(3) in the presence of normal dynamic function of the hypothalamic-pituitary-thyroid axis, which are consistent with early manifestations of a sick euthyroid state.
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Subclinical Hypothyroidism and Euthyroid Sick Syndrome in Patients with Moderate-to-Severe Congestive Heart Failure.

Manowitz NR, Mayor GH, Klepper MJ, DeGroot LJ.
Am J Ther. 1996 Dec;3(12):797-801.

Knoll Pharmaceutical Company (Formerly Boots Pharmaceuticals, Inc.), Mount Olive, NJ, USA.

Thyroid function tests were performed on baseline plasma that had been taken from 34 patients with NYHA Class II or Class III congestive heart failure (CHF). All patients were negative for thyroid disease on history and physical examination and none was taking medication known to alter thyroid metabolism. Analysis of thyroid function revealed abnormalities in 16 of 31 patients. These abnormalities fell into two categories: nine patients had elevated baseline thryroid stimulating hormone (TSH) above the normal limit while only one of these nine had subnormal thyroxine (T(4)) concentrations, suggesting the possibility of subclinical hypothyroidism. Seven patients demonstrated changes consistent with euthyroid sick syndrome (ESS). Weak correlations were observed between age and concentrations of T(4) and tri-iodothyronine (T(3)) and this suggests that changes in thyroid function cannot be explained solely on the basis of age. Although previous studies have demonstrated the presence of ESS in CHF, the present study suggests the possibility of a significant prevalence of subclinical hypothyroidism.
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Subclinical thyroid disorders in patients with dilated cardiomyopathy.

Fruhwald FM, Ramschak-Schwarzer S, Pichler B, Watzinger N, Schumacher M, Zweiker R, Klein W, Eber B.
Cardiology. 1997 Mar-Apr;88(2):156-9.

Department of Internal Medicine Division of Cardiology, Karl Franzens University of Graz, Austria.

Severe thyrotoxicosis can cause irreversible congestive heart failure. To investigate the coincidence of subclinical thyroid disorders and idiopathic dilated cardiomyopathy (IDC) we investigated these patients with respect to their morphological and functional thyroid status. Thyroid sonography as well as thyroid hormone levels were measured in all patients. RESULTS: Sixty-one patients (50 male, 11 female) with chronic stable IDC were included. Two out of 61 patients showed completely normal thyroid morphology and function. The other 59 patients showed either morphological or functional abnormalities or both. Of the 53 patients with morphological abnormalities 23 patients (all male) showed diffuse goiter as opposed to 29 nodular enlarged organs (24 male, 5 female). No clinically significant hypothyroidism or thyrotoxicosis was seen. A good correlation was found between the duration of IDC and thyroid volume (r = 0.44; p < 0.001). Two patients died during the study period, 1 from sudden death and 1 from progressive heart failure. CONCLUSION: Subclinical thyroid disorders are frequently seen in patients with long-standing IDC when they live in an area of chronic iodine deficiency. This can be explained by chronic salt restriction as basic treatment for congestive heart failure. Therefore we conclude that examination of the thyroid gland should be done routinely in patients with IDC, especially when restriction of salt intake is recommended by the treating physician.
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Participation of the pituitary-thyroid axis in the cardiovascular system in elderly patients with congestive heart failure.

Kimura T, Kanda T, Kuwabara A, Shinohara H, Kobayashi I.

Department of Laboratory Medicine, Gunma University School of Medicine, Japan.

The relationship between the pituitary-thyroid axis and the cardiovascular system in patients with congestive heart failure (CHF) remains unknown. Therefore, we attempted to determine serum levels of thyroid hormones in relation to plasma atrial natriuretic peptide (ANP) levels and left ventricular (LV) function in patients with CHF. The echocardiographic ejection fraction significantly correlated with the thyroid stimulating hormone (TSH) (p < 0.005) and free triiodothyronine (FT3)/free thyroxine (FT4) ratio (p < 0.005), respectively, in patients with CHF but not in control subjects. TSH was positively correlated with the FT3/FT4 ratio (p < 0.01) in CHF. In patients with CHF, TSH and thyroid hormones may participate in regulatory mechanisms of the cardiovascular system and altered thyroid hormone metabolism, which was characterized by a euthyroid sick syndrome.
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Evidence for mecury connection to heart conditions and heart attacks.

A. Frustaci et al, "Marked elevation of myocardial trace elements in Idiopathic Dilated Cardiomyopathy", J of American College of Cardiology, 1999, 33(6):1578-83;

& Husten L. "Trace elements linked to cardiomyopathy", Lancet 1999; 353(9164): 1594;

& D.V. Vassalo, 1999,Effects of mercury on the isolated heart muscle are prevented by DTT and cysteine", Toxicol Appl Pharmacol 1999 Apr 15;156(2):113-8;

& Lorscheider F, Vimy M. Mercury and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2000 Mar 1;35(3):819-20

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These result in chronic inflamations and autoimmunities- shown in another submittal

Markovich et al, "Heavy metals (Hg,Cd) inhibit the activity of the liver and kidney sulfate transporter Sat-1", Toxicol Appl Pharmacol, 1999,154(2):181-7;

& S.A. McFadden, "Xenobiotic metabolism and adverse environmental response: sulfur-dependent detox pathways",Toxicology, 1996, 111(1-3):43-65;

& Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production. Wilkinson LJ, Waring RH. Toxicol In Vitro. 2002 Aug;16(4):481-3.

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Health effects at common levels of exposure. Note amalgam is also significant source of methyl mercury.

Amalgam is largest source of both inorganic and methyl mercury in many or most.

Leistevuo J et al, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6;

& Sellars WA, Sellars R. Univ. Of Texas Southwestern Medical School "Methyl mercury in dental amalgams in the human mouth", Journal of Nutritional & Environmental Medicine 1996; 6(1): 33-37

& Bjorkman L, Sandborgh-Englund G, Ekstrand J, "Mercury in Saliva and Feces after Removal of Amalgam Fillings", Toxicology and Applied Pharmacology, 1997, 144(1), p156-62; & Eur J Oral Sci 1998 Apr;106(2 Pt 2):678-86 &

& Kingman A, Albertini T, Brown LJ, Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population., J Dent Res 1998 Mar;77(3):461-71 (population of over 1000 Air Force personnel; found each 10 amalgam surfaces increased mercury in urine by approx. 1 microgram per liter) .

& Berglund A, Molin M, "Mercury levels in plasma and urine after removal of all amalgam restorations: the effect of using rubber dams", Dent Mater 1997 Sep;13(5):297-304 ;

& Choi SC, Chase T Jr, Bartha R. Enzymatic catalysis of mercury methylation by Desulfovibrio desulfuricans LS. Appl Environ Microbiol. 1994 Apr;60(4):1342-6.

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Mercury levels in high-end consumers of fish.

Hightower JM, Moore D. Environ Health Perspect. 2003 Apr;111(4):604-8.

California Pacific Medical Center, California Pacific Medical Center, San Francisco, California, USA.

Consumption of food containing mercury has been identified as a health risk. The U.S. Environmental Protection Agency (U.S. EPA) and the National Academy of Sciences recommend keeping the whole blood mercury level < 5.0 micro g/L or the hair level < 1.0 micro g/g. This corresponds to a reference dose (RfD) of 0.1 micro g/kg body weight per day. All patients in a 1-year period ((italic)n(/italic) = 720) who came for an office visit in a private internal medicine practice in San Francisco, California, were evaluated for mercury excess using the current RfD. One hundred twenty-three patients were tested (93 females, 30 males). Of these, data were statistically analyzed for 89 subjects. Mercury levels ranged from 2.0 to 89.5 micro g/L for the 89 subjects. The mean for 66 women was 15 micro g/L [standard deviation (SD) = 15], and for 23 men was 13 micro g/L (SD = 5); 89% had levels exceeding the RfD. Subjects consumed 30 different forms or types of fish. Swordfish had the highest correlation with mercury level. Sixty-seven patients with serial blood levels over time after stopping fish showed a decline in mercury levels; reduction was significant ( (italic)p(/italic) < 0.0001). A substantial fraction of patients had diets high in fish consumption; of these, a high proportion had blood mercury levels exceeding the maximum level recommended by the U.S. EPA and National Academy of Sciences. The mean level for women in this survey was 10 times that of mercury levels found in a recent population survey by the U.S. Centers for Disease Control and Prevention. Some children were > 40 times the national mean.

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Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A, Gomez-Aracena J, Kark JD, Riemersma RA, Martin-Moreno JM, Kok FJ Mercury, fish oils, and the risk of myocardial infarction, New England J of Medicine, 2002, 347

CONCLUSIONS: The toenail mercury level was directly associated with the risk of myocardial infarction, and the adipose-tissue DHA level was inversely associated with the risk. High mercury content may diminish the cardioprotective effect of fish intake.

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Cardiovascular effects from prenatal exposure

Sorensen N, Murata K, Budtz-Jorgensen E, Weihe P, Grandjean P. Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 1999 Jul;10(4):370-5;

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Salonen JT. Excessive intake of iron and mercury in cardiovascular disease. In: Sandströöm B, Walter P, eds. Role of Trace Elements for Health Promotion and Disease Prevention, p. 112-126. Basel: Karger, 1998. Bibliotheca Nutritio et Dieta 54.

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Many recovered from cardiovascular problems after amalgam replacement.

Lindqvist B, Mornstad H , "Effects of removing amalgam fillings from patients with diseases affecting the immune system", Med Sci Res 24(5): 355-356, 1996.

& Lichtenberg H, "Symptoms before and after proper amalgam removal in relation to serum-globulin reaction to metals", Journal of Orthomolecular Medicine,1996, 11(4): 195-203. (119 cases) www.lichtenberg.dk/experience_after_amalgam_removal.htm

& Engel P. [Observations on health before and after amalgam removal] [Article in German] Schweiz Monatsschr Zahnmed. 1998;108(8):811-3. www.melisa.org/articles/engel-e.pdf

& Lindh U, Hudecek R, Danersund A, Eriksson S, Lindvall A. Removal of dental amalgam and other metal alloys supported by antioxidant therapy alleviates symptoms and improves quality of life in patients with amalgam-associated ill health. Neuroendocrinol Lett. 2002

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Mercury blocks enzymatic processes and changes cell permeability(documented elsewhere) and results in major effects on other essential minerals needed for proper cardiovascular and other functions.

Goyer RA, National Institute of Environmental Health Sciences. Toxic and essential metal interactions. Annu Rev Nutr 1997; 17:37-50;

; & Lindh U, Carlmark B, Gronquist SO, Lindvall A. Metal exposure from amalgam alters the distribution of trace elements in blood cells and plasma. Clin Chem Lab Med 2001 Feb;39(2):134-142

& Goldberg AF, Gergans GA, Loevy HT, Rudman D, Schlenker RA., "Effect of Amalgam restorations on whole body potassium and bone mineral content in older men",Gen Dent, 1996, 44(3): 246-8;

& K.Schirrmacher,1998, "Effects of lead, mercury, and methyl mercury on gap junctions and [Ca2+]I in bone cells", Calcif Tissue Int 1998 Aug;63(2):134-9..

& G.Benga "Water exchange through erythrocyte membranes" Neurol Neurochir Pol 1997 Sep-Oct;31(5):905-13

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Many pregnant age women have dangerous levels of mercury for the fetus; more than shown here due to problem with test used; shown in another document

(125) National Research Council, Toxicological Effects of Methyl mercury (2000), pp. 304-332: Risk Characterization and Public Health Implications, Nat'l Academy Press 2000.; & U.S. CDC, National Center for Environmental Health , National Report on Human Exposure to Environmental Chemicals, 2001, www.cdc.gov/nceh/dls/report/Highlights.htm

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Mercury causes damage to vascular endothial cells at low levels of exposure.

Kishimoto T, "Methyl mercury injury of Cultured Human Vascular Endothelial Cells", Journal of Trace Elements in Experimental Medicine, 6(4): 155-163, 1993.

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Review of mercury and heart disease.

M.F. Ziff , A Persuasive New Look at Heart Disease As It Relates to Mercury, Bio-Probe, Inc., ISBN 0-941011-08-9; & J. of American College of Cardiology V33,#6, pp1578-1583, 1999.

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Effects of amalgam on blood conditions

Adolph Coors Foundation, "Coors Amalgam Study: Effects of placement and removal of amalgam fillings", International DAMS Newsletter, p17, Vol VII, Issue 2, Spring 1997. (31 cases); www.amalgam.org

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Metabolic effects of altered porphyrins by mercury have cardiovascular effects.

Woods JS., Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity.
Canadian J Physiology and Pharmacology, Feb 1996;

& Woods JS, Martin MD, Leroux BG. Validity of spot urine samples as a surrogate measure of 24-hour porphyrin excretion rates. Evaluation of diurnal variations in porphyrin, mercury, and creatinine concentrations among subjects with very low occupational mercury exposure.
J Occup Environ Med. 1998 Dec;40(12):1090-101

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Mercury effects calcium homeostasis which has cardiovascular and other effects. Inorganic mercury has significant effects at much lower levels of exposure than methyl mercury.

Freitas AJ, Rocha JB, Wolosker H, Souza DO. "Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in the rat brain", Brain Research, 1996, 738(2): 257-64;

& Yallapragada PR, Rajanna S, Fail S, Rajanna B.,"Inhibition of calcium transport by Hg salts" in rat cerebellum and cerebral cortex", J Appl toxicol, 1996, 164(4): 325-30;

& Chavez R, Corona N, Garcia C, Chavez E, "Mitochondrial calcium release by Hg+2",J Biol Chem, 1988, 263:8, 3582-;

& Szucs A, Angiello C, Salanki J, Carpenter DO. Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons.
Cell Mol Neurobiol, 1997,17(3): 273-8;

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Prenatal exposure from inorganic and organic mercury

Sundberg J, Ersson B, Lonnerdal B, Oskarsson A. Protein binding of mercury in milk and plasma from mice and man--a comparison between methyl mercury and inorganic mercury. Toxicology 1999 Oct 1;137(3):169-84;

& Vimy MJ, Hooper DE, King WW, Lorscheider FL.; Mercury from maternal "silver" tooth fillings in sheep and human breast milk. A source of neonatal exposure. Biol Trace Elem Res 1997 Feb;56(2):143-52.

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Mercury commonly induces autoimmune effects which have cardiovascular and metabolic and neurological effects.

Sterzl I, Prochazkova J, Hrda P, Bartova J, Matucha P, Stejskal VD, Mercury and nickel allergy: r risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228;

& Kosuda LL, Greiner DL, Bigazzi PE. Effects of HgCl2 on the expression of autoimmune responses and disease in diabetes-prone (DP) BB rats. Autoimmunity 1997; 26(3):173-87.

& Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60;

& Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31

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Effects of methyl mercury on cytokines, inflammation and virus clearance in a common infection (coxsackie B3 myocarditis).

Ilback NG, Wesslen L, Fohlman J, Friman G.
Toxicol Lett. 1996 Dec;89(1):19-28.

Pharmacia and UpJohn, Helsingborg, Sweden.

A myocarditic coxsackievirus B3 (CB3) infection in Balb/c mice was used to investigate the effects of 12 weeks of methyl mercury (MeHg) exposure (3.69 mg/g diet) on inflammatory heart lesions, virus in the heart, the cytokine response, i.e. cachectin/TNF-alpha and gamma-interferon (IFN-gamma) levels in plasma, and on disease complications and mortality. This dose of MeHg did not influence mortality in this infection model. The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered 2.2% of the tissue section area in infected control mice. This damage was increased (n.s.) by 50% (to 3.3% of the tissue section area) in MeHg-treated mice. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was corroborated using an immune histological technique. MeHg treatment tended to increase (2.2-fold, n.s.) the number of Mac 2+ cells (macrophages) in the heart muscle in this infection. Plasma levels of both TNF-alpha and IFN-gamma increased on day 3 of the infection in MeHg-treated as well as in non-MeHg-treated mice, but the mean IFN-gamma response was more pronounced in the MeHg-treated mice. On day 7 of the infection, when most animals still showed clinical signs of disease, cytokine levels were back to normal. MeHg-exposure in non-infected mice did not affect cytokine levels. In situ hybridization of virus RNA in myocardial tissue showed remaining virus in those mice who had the lowest plasma IFN-gamma levels. A 20% increased (P < 0.05) lymphoproliferative response to the T cell mitogen Con A was observed as a result of the MeHg treatment. Even heart tissue lesions and virus persistence tended to be influenced by MeHg in a direction compatible with the development of chronic disease.

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Excessive intake of iron and mercury in cardiovascular disease.

Salonen JT Bibl Nutr Dieta. 1998;(54):112-26.

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Mortality from cardiovascular diseases and exposure to inorganic mercury.

Boffetta P, Sallsten G, Garcia-Gomez M, Pompe-Kirn V, Zaridze D, Bulbulyan M, Caballero JD, Ceccarelli F, Kobal AB, Merler E. Occup Environ Med. 2002 Jul;59(7):494.

Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, Lyon, France. boffetta@iarc.fr

OBJECTIVE: To study the mortality from cardiovascular and other chronic non-neoplastic diseases after long term exposure to inorganic mercury. Limited information is available on the effect of chronic exposure to mercury on the cardiovascular system. METHODS: The mortality was studied among 6784 male and 265 female workers from four mercury mines and mills in Spain, Slovenia, Italy, and the Ukraine. Workers were employed between 1900 and 1990; the follow up period lasted from the 1950s to the 1990s. The mortality of the workers was compared with national reference rates. RESULTS: Among men, there was a slight increase in overall mortality (standardised mortality ratio (SMR) 1.08, 95% confidence interval (95% CI) 1.04 to 1.12). An increased mortality was found from hypertension (SMR 1.46, 95% CI 1.08 to 1.93), heart diseases other than ischaemic (SMR 1.36, 95% CI 1.20 to 1.53), pneumoconiosis (SMR 27.1, 95% CI 23.1 to 31.6), and nephritis and nephrosis (SMR 1.55, 95% CI 1.13 to 2.06). The increase in mortality from cardiovascular diseases was not consistent among countries. Mortality from hypertension and other heart diseases increased with estimated cumulative exposure to mercury; mortality from ischaemic heart disease and cerebrovascular diseases increased with duration of employment, but not with estimated exposure to mercury. Results among women were hampered by few deaths. CONCLUSION: Despite limited quantitative data on exposure, possible confounding, and likely misclassification of disease, the study suggests a possible association between employment in mercury mining and refining and risk in some groups of cardiovascular diseases.
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See www.myflcv.com/cardio.html

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III. 7. The Fertility/Reproductive Effects of Mercury Exposure

Significant correlations were found between different heavy metals and clinical gynecological conditions (uterine fibroids, miscarriages, hormonal disorders). Diagnosis and reduction of an increased heavy metal body load improved the spontaneous conception chances of infertile women.

Gerhard I, Monga B, Waldbrenner A, Runnebaum B. Heavy metals and fertility. J Toxicol Environ Health 1999 Mar 12;56(5):371.

& Gerhard I, Waibel S, Daniel V, Runnebaum B "Impact of heavy metals on hormonal and immunological factors in women with repeated miscarriages", Hum Reprod Update 1998 May;4(3):301-309

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Infertile couples had higher blood mercury concentrations than fertile couples. 'Infertile males with abnormal semen' and 'infertile females with unexplained infertility' also had higher blood mercury concentrations than their fertile counterparts.

(per other documentation, amalgam is a significant source of organic mercury exposure)

Choy CM, Lam CW, Cheung LT, Briton-Jones CM, Cheung LP, Haines CJ. Infertility, blood mercury concentrations and dietary seafood consumption: a case-control study. BJOG. 2002 Oct;109(10):1121-5.

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Effects of metallic mercury on the perimenstrual symptoms and menstrual outcomes of exposed workers.

Yang JM, Chen QY, Jiang XZ. Am J Ind Med. 2002 Nov;42(5):403-9.

Department of Occupational Health and Toxicology, Shanghai Medical University, Shanghai, People's Republic of China. jyang@scripps.edu

BACKGROUND: Mercury is an important environmental and industrial pollutant and its effect on perimenstrual symptoms and menstrual outcomes is unclear. METHODS: A retrospective epidemiological investigation was conducted on 296 female workers exposed to mercury vapor and 394 female workers from food processing plants. Both groups included women of 18-44 years of age currently working since last at least 1 year when studied. Women who were currently pregnant, using oral contraceptives (Ocs), an intrauterine device (IUD), and steroid hormones were excluded. RESULTS: The air concentration of mercury in the workplace ranged from 0.001-0.200 mg/m(3). The prevalence of abdominal pain in the exposed group was significantly higher than that in the control group (odds ratio (OR) = 1.47, 95% CI is 1.03-2.11). The prevalence of dysmenorrhea in the exposed group was significantly higher than that in the control group (OR = 1.66, 95% CI is 1.07-2.59). CONCLUSIONS: An increased prevalence of abnormal menstruation was found in mercury-exposed workers in China. Dysmenorrhea may be a useful biomarker for assessing female exposure to mercury occupationally. These observations suggest that further studies and preventive measures are warranted.

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Significant associations were reported between impaired semen parameters and the following chemical exposures: metals (lead, mercury)

Sheiner EK, Sheiner E, Hammel RD, Potashnik G, Carel R. Effect of occupational exposures on male fertility: literature review. Ind Health. 2003 Apr;41(2):55-62.

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Mercuric chloride produced a reduction in epididymal sperm count, sperm motility, and sperm viability, and there were no sperm-positive smears in this group.

Rao MV, Sharma PS. Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice. Reprod Toxicol. 2001 Nov;15(6):705-12.

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Dally A, Hendry B. Declining sperm count. Increasing evidence that Young's syndrome is associated with mercury. BMJ. 1996 Jul 6;313(7048):44.

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mercury(II) (EC50 = 31 microM) induced some cytotoxic effect. Owing to the cytotoxic effect of mercury(II), lactate levels dropped at concentrations above 20 microM.

Gebhardt S, Winterstein U, Schill WB, Hayatpour J. Sertoli cells as a target for reproductive hazards. Andrologia. 2000 Sep;32(4-5):239-46.

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All parameters of the semen analysis including the concentration of sperm, percentage of morphologically normal sperm, percentage of motile sperm, curvilinear velocity, straight-line velocity, average path velocity, and amplitude of lateral head displacement, were reduced in those with elevated blood mercury concentrations

Leung TY, Choy CM, Yim SF, Lam CW, Haines CJ. Whole blood mercury concentrations in sub-fertile men in Hong Kong. Aust N Z J Obstet Gynaecol. 2001 Feb;41(1):75-7.

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The study revealed a higher frequency of adverse reproductive outcomes, especially congenital anomalies, among the women exposed to inorganic mercury levels at or substantially lower than 0.6 mg/m3;

Elghany NA, Stopford W, Bunn WB, Fleming LE. Occupational exposure to inorganic mercury vapour and reproductive outcomes. Occup Med (Lond). 1997 Aug;47(6):333-6.

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the estimated median lethal concentration [LC50] and median teratogenic concentration [TC50] were 0.313microM and 0.236microM, respectively) for MeHgCl2 ; and HgCl2, with estimated LC50 and TC50 values of 0.601microM and 0.513microM, respectively.

Prati M, Gornati R, Boracchi P, Biganzoli E, Fortaner S, Pietra R, Sabbioni E, Bernardini G. A comparative study of the toxicity of mercury dichloride and methylmercury, assayed by the Frog Embryo Teratogenesis Assay--Xenopus (FETAX). Altern Lab Anim. 2002 Jan-Feb;30(1):23-32.

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The chromosome aberrations in human peripheral lymphocytes exposed to various concentrations of CH3HgCl or HgCl2 increased in a concentration-dependent manner and were significantly higher than the control.

Ogura H, Takeuchi T, Morimoto K, "A comparison of chromosome aberrations and micronucleus techniques for the assessment of the genotoxicity of mercury compounds in human blood lymphocytes. Mutat Res 1996 Jun;340(2-3):175-82.

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Clinical observations have prompted suspicions of associations between acrodynia (Pink Disease) and epididymis obstruction (de Kretser et al. 1998).

de Kretser DM, Huidobro C, Southwick GJ, Temple-Smith PD (1998) The role of the epididymis in human infertility. J Reprod Fertil Suppl 53: 271-275

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Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice.

Rao MV, Sharma PS. Reprod Toxicol. 2001 Nov;15(6):705-12.

Reproductive Endocrinology and Toxicology Division, Department of Zoology, School of Sciences, Gujarat University, 380009, Ahmedabad, India

Mercury intoxication has been associated with male reproductive toxicity in experimental animals and mercury may have the potential to produce adverse effects on fertility in men. Vitamin E may protect against toxic effects of mercury in the liver and other tissues. To investigate the protective role of vitamin E against mercuric chloride toxicity for the testis, epididymis, and vas deferens of adult male mice, animals were treated with either mercuric chloride 1.25 mg/kg/day, vitamin E 2 mg/kg/kg, or a combination of the two treatments. Control animals were treated with water. Treatments were administered by daily gavage for 45 days. An additional group of animals treated with mercuric chloride were permitted to recover for 45 days after mercuric chloride treatments. Parameters studied included serum testosterone, epididymal sperm count, motility, and morphology, epididymal and vas deferens adenosine triphosphatase (ATPase), phosphorylase, sialic acid, glycogen and protein, testicular succinate dehydrogenase (SDH), phosphatases, cholesterol, ascorbic acid, and glutathione. Fertility was evaluated by sperm positive vaginal smears after overnight cohabitation with a female. Mercuric chloride produced a reduction in epididymal sperm count, sperm motility, and sperm viability, and there were no sperm-positive smears in this group. Biochemical tests from the male reproductive organs were also altered by mercuric chloride treatment. Coadministration of vitamin E with mercuric chloride prevented the changes in sperm and biochemical parameters and was associated with control rates of sperm positive smears after cohabitation. Animals given vitamin E with mercuric chloride also had lower concentrations of mercury in the testis, epididimyis, and vas deferens. Permitting animals to recover for 45 days after mercuric chloride treatment resulted in partial recovery of sperm and biochemical parameters. Vitamin E cotreatment has a protective role against mercury-induced male reproductive toxicity.
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Mercury's widespread reproductive effects on wildlife

That mercury can affect fertility is well known since mercury has been commonly used as a spermicide in birth control products. Potential effects can again be seen from effects on wildlife. Some Florida panthers that eat birds and animals that eat fish, frogs, and turtles containing very low levels of mercury (about 1 part per million) have died from chronic mercury poisoning[5,6]. Since mercury is an estrogenic chemical and reproductive toxin, the majority of the rest cannot reproduce. The average male Florida panther has estrogen levels as high as females, due to the estrogenic properties of mercury. Similar is true regarding feminization and reproductive problems and population declines of some other animals at the top of the food chain like alligators and wading birds[5,6,7,12,29,40], and marine mammals such as polar bears, seals, beluga and orca whales(12,29,40,41). In recent years 67% of male panther cubs born have had undescended testicles, low testosterone levels, abnormal sperm, and very high estrogen levels. Recent tests show some males have estrogen levels twice as high as testosterone levels and some females have higher testosterone levels than estrogen levels(12). Levels of mercury in Florida are also sufficient to have contaminated lakes and bays in Florida to levels where fish in over half the lakes and streams tested have levels of mercury dangerous to wildlife or humans eating the fish, and where birds and panthers in South Florida are dying as a result of mercury levels in the fish(40). Panthers eat racoons and other fish predators.

5. Facemire CF, Gross TS, Guillette, LJ. Reproductive impairment in the Florida panther. Health Perspect 1995; 103 (Supp4):79-86.

6. Florida Panther Interagency Committee, Status Report:Mercury Contamination in Florida Panthers, Florida Department of Environmental Protection, Dec 1989.

7. Maretta M, Marettova E,Skrobanek P, Ledec M. Effect of mercury on the epithelium of the fowl testis. Vet Hung 1995; 43(1):153-6; & Monsees TK, Franz M, Gebhardt S, Winterstein U, Schill WB, Hayatpour J. Sertoli cells as a target for reproductive hazards. Andrologia. 2000 Sep;32(4-5):239-46; & M.Maretta et al, "Effect of mercury on the epithelium of the fowl testis", Vet Hung 1995, 43(1):153-6; &Orisakwe OE, Afonne OJ, Low-dose mercury induces testicular damage in mice that is protected against by zinc.Eur J Obstet Gynecol Reprod Biol. 2001 Mar;95(1):92-6

12. "Are Environmental Hormones Emasculating Wildlife", Science News, Volume 145 1994, p24-27

29. J.Toppari et al, NIEHS, Envir. Health Perspectives, Vol 104, Supp 4, August 1996, p741-803.

40. "Mercury found in dead Florida Bay cormorants",Tallahassee Democrat, 1-5-95; & Sepulveda MS et al, 1999, Effects of mercury on health and first-year survival of free-ranging great eggrets from southern Florida, Archives Environ Contam and Toxicol, 37:369-376; & Osowski SL, 1995, The decline of mink in Georgia, North Carolina, and S. Carolina: the Role of Contaminants, Env Contam and Toxicol, 29:418-423; & Jagoe CH, 1998, Mercury in Alligators in the Southeastern U.S., Science of the Total Envirnonment, 213:255-262, & Esley RM, Mercury levels in alligator meat in south Louisian, 1999, Bull Environ Contam Toxicol, 63: 598-603 & DeGuise S, Lagace A, Beland P; True hermaphoditism in St Lawrence Beluga Whales, Journal of Wildlife Diseases(Delphinapterus leucas), 1994, 30: 287-290.

41. Lars-Otto Reiersen et al, Rovaniemi Finland, Arctic Monitoring and Assessment
Program, The Arctic Pollution 2002 Report, (Associated Press, Oct 1, 2002); & Scientists at the Norwegian Polar Institute (NPI) in Tromso,Norway; BBC Radio 4 programme Costing The Earth, Thursday, 26 September, 2002 (By Alex Kirby BBC News Online environment correspondent)

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Studies found that very low levels of exposure to mercury cause genetic/ DNA damage[81-88] and inhibits DNA & RNA synthesis[81,85/86]; damages sperm, lowers sperm counts and reduces motility [81,88-92,5,6/88,93,95]; causes menstrual disturbances [96,97]

Reviews of recent studies have found that the incidence of abnormalities of genitourinary abnormalities in human males has increased during the past 50 years, including cryptorchidism and hypospadia[79,81,115]. The incidence of testicular cancer was found to have increased 3 to 4 fold since the 1940s. The reviews also found that studies indicate that sperm quality and quanity have decreased significantly during this period, with an average decrease in sperm density of approximately 40 % since 1940 along with increased sperm abmormalities. Mercury and other toxic metals are among the toxics that have been found in animal studies to have such effects [5-7,40,79,88,95].

A large cohort study of occupationally exposed women found an increased risk of spontaneous abortion and other pregnancy complications[101]. Women with hormonal problems seeking help at a gynecological clinic in Germany were found to have higher body burdens of heavy metals, including mercury[74,75,78], and women with idiopathic menstrual problems had higher levels of mercury[75,77,96,100]. Most women with very high levels of mercury were infertile, and after clearance of metals many were fertile again[74-78].

74. Gerhard I, Moonga B, Waldbrenner A, Runnebaum B, Tubingen Univ. Gynecological Clinic, Heidelberg. Heavy Metals and Fertility. J of Toxicology and Environmental Health, 1998; Part A, 54(8):593-611.

75. Gerhard I, Waibel S, Daniel V, Runnebaum B. Impact of heavy metals on hormonal and immunological factors in women with repeated miscarriages. Hum Reprod Update 1998; 4(3):301-9.

76. Gerhard I. Amalgam aus gynakologischer Sicht. Der Frauenarzt 1995; 36(6): 627-28.

77. Gerhard I, Runnebaum B, Schdstoffe und Fertillitatsstorungen. Schwermetalle und Mineralstoffe, Geburtshilfe Frauenheikd, 1992, 52(7):383-396; & Gerhard I, Waldbrenner P, Thuro H, Runnebaum B, [Diagnosis of heavy metal loading by the oral DMPS and chewing gum tests]. Klinisches Labor 38:404-411 (1992)

78. Gerhard I, Runnebaum. Environmental pollutants and fertility disorders. Geburtshilfe Frauenheilkd 1992; 52(7), 383-96; & Roller E et al, J Fert Reprod, 1995, 3, 31-33:&

Gerhard I. Ganzheitiche Diagnostik un Therapie bie Infertilitat. Erfahrungsheilkunde, 1993, 42(3): 100-106; & Gerhard I, Runnebaum B, The limits of hormone substitution in pollutant exposure and fertility disorders. Zentralbl Gynakol 1992; 114, 593-602.

79. T.Colborn(Ed.),Chemically Induced Alterations in Functional Development, Princeton Scientific Press,1992.

81. Khera KS, Teratogenic and genetic effects of mercury toxicity. In:The Biochemistry of Mercury in the Environment, Nriagu, J.O.(Ed) Amsterdam , Elsevier, 503-18,1979; &

John Aitken, Head- Dept. Of Biological Sciences, University of Newcastle in Australia. "Sperm on the wane", paper for Conference on Male-Mediated Developmental Toxicity. Montreal, June 22, 2001, The Gazette, June 22, 2001.

82. Babich H. The mediation of mutagenicity and clastogenicity of heavy metals by physiochemical factors. Environ Res 1985: 37;253-286.

83. Bucio L, Garcia C, Souza V, Hernandez E, Gonzalez C, Betancourt M, Gutierrez-Ruiz MC. Uptake, cellular distribution and DNA damage produced by mercuric chloride in a human fetal hepatic cell line. Mutat Res 1999; Jan 25;423(1-2):65-72.

84. Pamphlett R, Slater M, Thomas S. Oxidative damage to nucleic acids in motor neurons containing Hg. J Neurol Sci 1998; 159(2):121-6. (rats & primates)

85. O'Halloran TV. Transition metals in control of gene expression. Science 1993; 261(5122):715-25.

86. Verschaeve L, Kirsch-Volders M, Susanne C, Groetenbriel C, Haustermans R, Lecomte A, Roossels D. Genetic damage induced by occupational low level mercury exposure. Envir Res, 12:306-10,1976.

87. Ariza ME, Williams MV. Mercury mutagenesis. Biochem Mol Toxicol 1999; 13(2):107-12.

88. Lee IP, Dixon RL. Effects of mercury on spermatogenesis studied by velocity sedimentation cell separation., J Pharmacol Exp Thera 1975, 194(1);171- 181; & Ben-Ozer EY, Rosenspire AJ, et al, Mercuric chloride damages cellular DNA by a non-apoptotic mechanism. Mutat Res. 2000 Oct 10;470(1):19-27; & Ogura H, Takeuchi T, Morimoto K, "A comparison of chromosome aberrations and micronucleus techniques for the assessment of the genotoxicity of mercury compounds in human blood lymphocytes. Mutat Res 1996 Jun;340(2-3):175-82

89. Eggert-Kruse W, Effect of heavy metals on in vitro interaction between human sperm and cervical mucus. Dtsch Med Wochenschr 1992; 117(37): 1383-9(German).

90. Ernst E, Lauritsen JG. Effect of mercury on human sperm motility. Toxicol 1991; 68(6):440-4.

91. Daily A, Hendry B, Declining sperm count: evidence that Young's syndrome is associated with mercury, BMJ, 1996, 313(7048): 44; & de Kretser DM, Huidobro C, Southwick GJ, Temple-Smith PD (1998) The role of the epididymis in human infertility. J Reprod Fertil Suppl 53: 271-275

92. Ng TB, Liu WK. Toxic effect of heavy metals on cells isolated from the rat adrenal and testis. In Vitro Cell Dev Biol 1990 Jan;26(1):24-8.

93. Ivanitskaia NF, Evaluation of combined effect of mercury and ionizing radition on reproductive function of animals. Gig Sanit 1991; 12: 48-51.

94. Mohamed MK, Mottet NK. "Lazer Light Scatering Study of the Toxic Effects of Methylmercury on sperm motility". J Androl.,7(1):11-15.,1986.

95. Mohamed MK, Burbacher TM, Mottet NK, Effects of methyl mercury on testicular functions in monkeys. Toxicol 1987; 60(1):29-36;

96.Gerhard I, "Reproductive risks of heavy metals in women", in: Reproductive Toxicology, Richardson M(Ed.), VCH Weinheim, 1993,167-83.

97. Lorscheider FL, Vimy MJ, Summers AO. Mercury exposure from silver tooth fillings: emerging evidence questions a paradigm. FASEB J 1995; 9(7):504-508.

100. Schulte-Uebbing C. Umweltbedingte Frauenkranheiten. Sonntag-Verlag, Stuttgart,1996; & Umweltmedizin in der Frauenheilkunde. Arztezeitschr Naturheilkunde 35(2):9-17.

115. Giwercman A, Carlsen E, Keiding N, Skakkebaek N.E. Evidence for increasing abnormaties of the human testis: a review. Environ Health Perspect 1993; 101(Supp2): 65-71.

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III.8. Effects on Dental Staff

The enigma of parkinsonism in chronic borderline mercury intoxication, resolved by challenge with penicillamine.

Finkelstein Y, Vardi J, Kesten MM, Hod I.
Neurotoxicology. 1996 Spring;17(1):291-5.

Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.

A 47 year old female dentist suffered from hemiparkinsonism which had started eighteen months earlier and was manifested mainly by resting tremor and cogwheel rigidity. A baseline quantitative urinary mercury excretion was 46 micrograms/day. The patient was treated with chelating agent d-penicillamine for a week. Chelation therapy resulted in clinical improvement of parkinsonism and in dynamic changes in daily urinary mercury excretion with a prompt increase to 79 micrograms/day, a subsequent decline followed by increase in the mercury urinary excretion. After a week chelation therapy was stopped. During a follow-up period of five years, the neurological status remained unchanged after the initial penicillamine-induced improvement. This case may be evidence, therefore, of a rare clinical variant of elemental mercury intoxication associated with parkinsonism, in the absence of most classical neuropsychiatric signs of chronic mercurialism.

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Bittner, AC;Echeverria, D;Woods, JS;Aposhian, HV;Naleway, C;Martin, MD;Mahurin, RK
Heyer, NJ;Cianciola, M; Behavioral effects of low-level exposure to Hg-0 among dental professionals: A cross-study evaluation of psychomotor effects. Neurotoxicol. Teratol., 1998, 20(4): 429-439.
SO NEUROTOXICOLOGY AND TERATOLOGY
AB A cross-study design was used to evaluate the sensitivities of five psychomotor tasks previously used to assess preclinical effects of low-level Hg-0 (urinary less than or equal to 55 mu
g/l). Pooling dental professional subject populations from six studies conducted over the last 6 years, a larger study population was obtained with a high degree of uniformity (N =230). The five psychomotor tests were: Intentional Hand Steadiness Test (IHST); Finger Tapping; The One-Hole Test; NES Simple Reaction Time (SRT); and Hand Tremor. Multivariate
analyses were conducted following the hierarchical analysis of multiple responses (HAMR) approach. First, multiple scores of each test were combined into a single-factor (or related
summary) variable and its reliability was estimated. Second, multiple regression analyses were conducted including log- transformed [Hg-0]U levels, age, gender, and alcohol consumption in each model. Computed were both B and b(u), the magnitudes of the log-Hg-0 standardized coefficient,
respectively uncorrected and corrected for dependent variable attenuation due to unreliability. Results indicated remarkable differences in the effects of relative level of Hg-0 on
psychomotor performance. Significant associations were found for the IHST factor (B = 0.415, p < 10(-6)), followed by finger tapping, which was relatively meager and insignificant (B =0.141, p = 0.17). The IHST results hold the greatest occupational relevance for dental professionals who rely on manual dexterity in restorative dentistry. Further, this statistical approach is recommended in future studies for condensation of multiple scores into summary scores with enhanced reliabilities useful in correcting for attenuation relationships (B(u)s) with exposure levels. (C) 1998 Elsevier Science Inc.

Echeverria, D;Aposhian, HV;Woods, JS;Heyer, NJ;Aposhian, MM;Bittner, AC;Mahurin, RK
Cianciola, M, Neurobehavioral effects from exposure to dental amalgam Hg degrees: new distinctions between recent exposure and Hg body burden. Faseb J., 1998, 12(11): 971-980.

AB Potential toxicity from exposure to mercury vapor (Hg degrees) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central
nervous system (CNS) toxicity associated with handling Hg-containing amalgam materials among dental personnel with very low levels of Hg degrees exposure (i.e., urinary Hg <4 mu g/l),
applying a neurobehavioral test batter New distinctions between subtle preclinical effects on
symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 mu g/l, presents convincing new evidence of adverse behavioral effects associated with low Hg degrees exposures within the range of that received by the general population.
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Aydin, N ;Karaoglanoglu, S; Yigit, A; Keles, MS; Kirpinar, I; Seven, N
Neuropsychological effects of low mercury exposure in dental-staff in Erzurum, Turkey,

Int. Dent. J., 2003, 53(2): 85-91.

AB Objective: To carry out measurements of the Hg levels and personal exposure in Turkish dental clinics, and to evaluate possible adverse effects on the CNS in dental personnel.
Setting: Five dental clinics (1 private, 4 public) in Erzurum, Turkey. Subjects and methods: 43, Hg vapour-exposed dental staff were examined and 43 hospital employees with no known
exposure to Hg acted as the control group. Hg concentrations in plasma and urine were analysed by atomic absorption spectrophotometry. Possible effects on the central nervous system (CNS) were estimated by neuropsychological tests (Weschler Memory Scale-Revised (WMS-R) and Verbal Test of Memory Processes (VTMP)) and two self-administered questionnaires (Symptom Checklist-90-Revised (SCL-90-R) and Beck Depression Inventory (BDI)). Results: The dental staff
group had higher whole blood (B-Hg) and urine (U-Hg) Hg levels than the control group. The mean B-Hg value was 2.18nmol/l and U-Hg was 1.17 nmol/mmol creatinine. U-Hg had an inverse relationship with logical memory (in WMS-R test) and total retention score (in VTMP test), and a positive relationship with increased scores of Anxiety and Psychoticism (in SCL-90- R). Conclusion: These results may represent long-term consequences of low Hg exposure. In dentistry, to decrease toxic effects, proper Hg hygiene should be practiced by all
dental health care workers.

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Contact dermatitis in Korean dental technicians.
Lee JY, Yoo JM, Cho BK, Kim HO.
Contact Dermatitis. 2001 Jul;45(1):13-6.

Department of Dermatology, The Catholic University of Korea, Seoul, Korea.

The high risk of occupational contact dermatitis in dental personnel are well accepted throughout the world. There are few reports concerning occupational skin disease in dental personnel in Korea. The purposes of this study were to investigate the frequency, characteristics and causative factors of contact dermatitis in Korean dental technicians. Recording of personal history, physical examination and patch tests with the Korean standard series and dental screening series were performed in 49 dental technicians. Most of the subjects were exposed to a variety of compounds, including acrylics, metals, plaster, alginate, etc. 22 (44.9%) subjects had contact dermatitis, present or past, and the site involved was the hand in all 22. The most common clinical feature of hand dermatitis was itching (77.3%); scaling, fissuring and erythema were other common clinical features. Metals, including potassium dichromate (24.5%), nickel sulfate (18.4%), mercury ammonium chloride (16.3%), cobalt chloride (12.2%) and palladium chloride (10.2%), showed high positive rates in patch test results of 49 dental technicians. 7 positive reactions to the various acrylics were found in 3 subjects. In our study, the frequency and clinical features of the contact dermatitis showed a similarity to other reports, though the patch test results were somewhat different; a higher patch-positive reaction to metals and a relatively lower patch-positive reaction to acrylics than the patch test results reported in Europe.

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Harakeh, S;Sabra, N;Kassak, K;Doughan, B; Factors influencing total mercury levels among Lebanese dentists, Sci. Total Environ., 2002, 297(1-3): 153-60.

AB The aim of the current study is to examine the various factors, which contribute to high levels of mercury (Hg) in the hair of Lebanese dentists. The survey, which was carried out on ninety- nine dentists in the greater Beirut area, included a structured questionnaire designed to provide information about the parameters that influenced their occupational exposure to Hg.
These included: precautionary measures, dental fillings, work habits and lifestyle of the tested dentists. The study showed that two of the four investigated precautionary measures had a
significant effect on Hg level. The results revealed that, at the 95% confidence levels, Hg concentration in hair was significantly lower among the dentists who always used gloves
and masks. Multiple regression analysis showed that the use of masks (P=0.055) had significant effects on mercury accumulation in hair. y to evaluate CNS functions in relation to both recent exposure and Hg body burden.

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Oral mucosal diseases investigated by patch testing with a dental screening series.

Alanko K, Kanerva L, Jolanki R, Kannas L, Estlander T.
Contact Dermatitis. 1996 Apr;34(4):263-7.

Department of Dermatology, University Hospital, Helsinki, Finland.

The role of contact allergies in oral mucosal diseases was studied. The subjects were 24 patients out of 479 tested, who had oral mucosal symptoms and positive patch test reactions in a dental series during 1987-1994 at the Department of Dermatology, Helsinki University Hospital. The clinical diagnoses were oral lichen planus (LPO, 13 patients), leukoplakia (2), glossodynia, i.e., 'burning mouth syndrome' (4), stomatitis (3) and recurrent angioedema (2). All but 2 patients had allergic reactions to mercury (Hg) (12 patients), gold sodium thiosulfate (Au) (13 patients) or both. A clinical connection between oral symptoms and contact allergy was seen in 10 patients. 9 patients (7 LPO, 2 leukoplakia) had Hg allergy. In these cases, the oral lesions disappeared after the amalgam fillings had been removed. 1 patient had recurrent stomatitis and perioral eczema after dental care and 2,2-bis(4-(2-hydroxy-3-methacryloxypropoxy)phenyl)propane (BIS-GMA) allergy. Her symptoms were caused by drilling of acrylic fillings. In addition, a connection between localized stomatitis and contact allergy was considered probable in 2 cases. 1 patient had stomatitis from contact with an orthodontic device and nickel allergy. The other had stomatitis from contact with a dental gold crown and gold allergy.

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Atopic dermatitis, conjunctivitis, and hand dermatitis among Swedish dental personnel, including use of personal protective devices.

Lonnroth E, Shahnavaz H.

Department of Human Work Sciences, Lulea Technical University, Sweden.

A previous study on dental personnel in northern Sweden show that dentists had a significantly higher prevalence of self-reported and physician-diagnosed atopic dermatitis and conjunctivitis, compared to chair assistants and referents (Lonnroth & Shahnavaz 1998). Further, significantly more male dentists reported experience of hand dermatitis compared to male referents. To compare the prevalence among dental personnel working in other geographical areas of Sweden, and survey the use of personal protective equipment, a questionnaire study was conducted during 1997, which included all dentists and his/her chair assistants, working in general private and public dental care in Sweden. A total of 7384 dental personnel were included in the study, 4293 dentists (54.7% male and 45.3% female), and 3090 chair assistants. Logistic regression was used for analysing data. Results show that significantly more dentists reported symptoms of atopic dermatitis, conjunctivitis, and hand dermatitis, and had been diagnosed by a physician, compared to chair assistants.

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Adverse health reactions in skin, eyes, and respiratory tract among dental personnel in Sweden.

Lonnroth EC, Shahnavaz H.
Swed Dent J. 1998;22(1-2):33-45.

Department of Human Work Sciences, Lulea Technical University, Sweden.

Dental personnel manually handle products that contain monomers. Several studies have documented adverse health effects after exposure to such products. Gloves made of vinyl or latex are easily penetrated by monomers. Ordinary glasses, or visors, do not protect against vapour from polymer products. Dental face masks filter out about 40% of respirable particles. To survey the prevalence of asthma, atopic dermatitis, conjunctivitis, hay fever/rhinitis, and hand eczema among dental personnel, a questionnaire was distributed to all dental teams in Northern Sweden. Referents were researchers, teachers, and secretaries from the same geographical area. The response rate was 76% for dental teams, and 66% for referents. The results show a significantly higher prevalence of conjunctivitis, and atopic dermatitis among dentists, both male and female. Hypersensitivity to dental materials was reported by significantly more dental personnel than by referents.

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Contact dermatitis in Korean dental technicians.

Lee JY, Yoo JM, Cho BK, Kim HO.

Department of Dermatology, The Catholic University of Korea, Seoul, Korea.

The high risk of occupational contact dermatitis in dental personnel are well accepted throughout the world. There are few reports concerning occupational skin disease in dental personnel in Korea. The purposes of this study were to investigate the frequency, characteristics and causative factors of contact dermatitis in Korean dental technicians. Recording of personal history, physical examination and patch tests with the Korean standard series and dental screening series were performed in 49 dental technicians. Most of the subjects were exposed to a variety of compounds, including acrylics, metals, plaster, alginate, etc. 22 (44.9%) subjects had contact dermatitis, present or past, and the site involved was the hand in all 22. The most common clinical feature of hand dermatitis was itching (77.3%); scaling, fissuring and erythema were other common clinical features. Metals, including potassium dichromate (24.5%), nickel sulfate (18.4%), mercury ammonium chloride (16.3%), cobalt chloride (12.2%) and palladium chloride (10.2%), showed high positive rates in patch test results of 49 dental technicians. 7 positive reactions to the various acrylics were found in 3 subjects. In our study, the frequency and clinical features of the contact dermatitis showed a similarity to other reports, though the patch test results were somewhat different; a higher patch-positive reaction to metals and a relatively lower patch-positive reaction to acrylics than the patch test results reported in Europe.

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Epithelium-fibroblast co-culture for assessing mucosal irritancy of metals used in dentistry.

Schmalz G, Arenholt-Bindslev D, Hiller KA, Schweikl H.
Eur J Oral Sci. 1997 Feb;105(1):86-91.

Department of Operative Dentistry and Periodontology, University of Regenburg, Germany. Gottfried.Schmalz@klinik.uni-regensburg.de

No valid animal or in vitro model exists to assess the potential mucosal irritancy of dental materials. However, recently, a commercially available model system based on a recombined co-culture of human fibroblasts and human epithelial cells has been introduced for evaluating the time-dependent irritancy of cosmetic products. Cell viability and prostaglandin E2 (PGE2) release from the cells were used as markers for the irritative potential of test materials. The objective of the present study was to evaluate the suitability of this model for monitoring the irritative potential of metals and cast alloys used in dentistry. The human fibroblast-keratinocyte co-cultures were exposed to test specimens fabricated from copper, zinc, palladium, nickel, tin, cobalt, indium, a high noble cast alloy, and from a dental ceramic. Cell survival rates decreased after exposure to copper (14-25%), cobalt (60%), zinc (63%), indium (85%), nickel (87%), and the non-oxidized and oxidized high noble cast alloy (87%/90%) compared to untreated control cultures. In parallel, the PGE2 release was continuously monitored up to 24 h using a competitive displacement enzyme immunoassay. PGE2 release increased most highly in the cultures exposed to copper (6-25 fold), cobalt (7 fold), indium (4 fold), and zinc (2 fold) compared to untreated control cultures. The PGE2 determination proved to be a non-destructive method for continuous monitoring of cell reactions in the same culture. The model used seems promising for evaluating the time-dependent mucosal irritancy of dental cast alloys.
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A multicenter study of patch test reactions with dental screening series.

Kanerva L, Rantanen T, Aalto-Korte K, Estlander T, Hannuksela M, Harvima RJ, Hasan T, Horsmanheimo M, Jolanki R, Kalimo K, Lahti A, Lammintausta K, Lauerma A, Niinimaki A, Turjanmaa K, Vuorela AM.
Am J Contact Dermat. 2001 Jun;12(2):83-7.

Section of Dermatology, Finnish Institute of Occupational Health, Helsinki, Finland.

BACKGROUND: Dental products contain many allergens, and may cause problems both for patients undergoing dental treatment and for dental personnel because of occupational exposure. Individual patch test clinics may not study sufficient numbers of patients to collect reliable data on uncommon allergens. OBJECTIVE: To collect information on dental allergens based on a multicenter study. MATERIALS AND METHODS: The Finnish Contact Dermatitis Group tested more than 4,000 patients (for most allergens, 2,300 to 2,600 patients) with dental screening series. Conventional patch testing was performed. The total number and percentage of irritant (scored as irritant [IR] or doubtful [?]) and allergic (scored as +, ++, or +++) patch test reactions, respectively, were calculated, as well as the highest and lowest percentage of allergic patch test reactions recorded by the different patch test clinics. A reaction index (RI) was calculated, giving information on the irritancy of the patch test substances. RESULTS: The most frequent allergic patch test reactions were caused by nickel (14.6%), ammoniated mercury (13%), mercury (10.3%), gold (7.7%), benzoic acid (4.3%), palladium (4.2%) and cobalt (4.1%). 2-hydroxyethyl methacrylate (2.8%) provoked most of the reactions caused by (meth)acrylates. Menthol, peppermint oil, ammonium tetrachloroplatinate, and amalgam alloying metals provoked no (neither allergic nor irritant) patch test reactions. CONCLUSION: Patch testing with allergens in the dental screening series, including (meth)acrylates and mercury, needs to be performed to detect contact allergy to dental products

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Exposure to mercury vapor and impact on health in the dental profession in Sweden.

Langworth S, Sallsten G, Barregard L, Cynkier I, Lind ML, Soderman E.
J Dent Res. 1997 Jul;76(7):1397-404.

Department of Occupational Medicine, Huddinge University Hospital, Sweden.

Possible adverse effects of mercury exposure in dentistry have been discussed in several studies. The objective of the present study was to carry out detailed measurements of mercury exposure in the dental profession in Sweden, and to search for adverse health effects from such exposure. We examined 22 dentists and 22 dental nurses, working in teams, at six Swedish dental clinics. Measurements of air mercury, performed with personal, active air samplers, showed a median air Hg of 1.8 micrograms/m3 for the dentists, and 2.1 micrograms/m3 for the dental nurses. Spot measurements with a direct reading instrument displayed temporarily elevated air Hg, especially during the preparation and application of amalgam. The average concentration of mercury in whole blood (B-Hg) was 18 nmol/L, in plasma (P-Hg) 5.1 nmol/L, and in urine (U-Hg) 3.0 nmol/mmol creatinine. Possible effects on the central nervous system (CNS) were registered with three questionnaires: Q16, Eysenck Personality Inventory (EPI), and the Profile of Mood Scales (POMS). In the Q16, the number of symptoms was statistically significantly higher in the dentistry group compared with an age- and gender-matched control group (n = 44). The urinary excretion of albumin and urinary activity of the tubular enzyme N-acetyl-beta-glucose-aminidase (NAG) did not differ between the two groups. The results confirm that exposure to mercury in the dental profession in Sweden is low. The air Hg levels were mainly influenced by the method of amalgam preparation and inserting, and by the method of air evacuation during drilling and polishing.
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"Menstruation disturbances observed in dental assistants could be related to the increased levels of mercury in serum and urine. Allergy is also a frequent medical problem"

Lewczuk E, Affelska-Jercha A, Tomczyk J. [Occupational health problems in dental practice] [Article in Polish] Med Pr. 2002;53(2):161-5.

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H.V.Aposhian et al, "mobilization of Mercury in Humans by DMPS", Envir. Health Perspectives, Vol 106, Supp. 4, Aug.1998; & "Urinary Mercury after Administration DMPS", FASEB J., 6: 2472-

Epidemiologisk undersokning av fosterkador hos 1.2 milj. barn, fodda sedan 1967; Norge yrkesmed. Avd. Haukelands sykehus. Aftenposton 6 mpv 1997.

(490) Rojas M, Olivet C . Occupational exposure and health effects of metallic mercury among dentists and dental assistants: a preliminary study. Valencia, Venezuela; Acta Cient Venez 2000;51(1):32-8; & Nadorfy-Lopez E, Bello B. Skeletal muscle abnormalities associated with occupational exposure to mercury vapours. Histol Histopathol 2000 Jul;15(3):673-82.

(491) Nerudova J, Cabelkova Z, Cikrt M; Mobilization of mercury by DMPS in occupationally exposed workers. Int J Occup Med Environ Health 2000;13(2):131-46 .

(492) Glina DM, Satut BT, Andrade EM. Occupational exposure to metallic mercury in the dentist's office of a public primary health care clinic in the city of Sao Paulo. Cad Saude Publica 1997 Apr;13(2):257-267; & (b) Aydin N, Yigit A, Keles MS, Kirpinar I, Seven N. Neuropsychological effects of low mercury exposure in dental staff in Erzurum, Turkey. Int Dent J 2003 Apr;53(2):85-91.

(493) Moller AT, Spangenberg JJ. Stress and coping amongst South African dentists in private practice. J Dent Assoc S Afr 1996 Jun;51(6):347-57; & Stefansson CG, Wicks S. Health care occupations and suicide in Sweden 1961-1985. Soc Psychiatry Psychiatr Epidemiol 1991 Dec;26(6):259-64

(503) Rupp, Paffenberger, Significance to health of mercury used in dental practice, Reports of Councils and Bureaus, JADA, Vol 182, June 1971; & Rao, Hefferen, Biocompatibility of Dental Materials, Vol III,D.C. Smith and D.F. Williams, Eds., CRC Press, Boca Raton, Fl 1982, Toxicity of Mercury; & Center for Chemical Hazard Assessment, Potential Occupational Hazards: Dentistry, Syracuse Research, Contract No.210-78-0019, 1980; & Merck Manuel, 14th Edition, p1552; & Faria Md Mde A; Chronic occupational metallic mercurialism; Rev Saude Publica 2003 Feb;37(1):116-27.

(504) Gosselin, Smith, Hodge, Clincial Toxicology of Commercial Products, Williams and Wilkins Publisher, Baltimore, 5th Ed, 1984; & Katzung, MD, Basic Clinical Pharmacology, 2nd Ed.; & Thienes, Haley, Clinical Toxicology, Lea & Febeger, Philadelphia, 5th Ed, 1972.

(520) Health effects of amalgam fillings and results of replacement of amalgam filings. Over 1500 medical study references(most in Medline) and approx. 60,000 clinical cases of amalgam replacement followed by doctors. www.home.earthlink.net/~berniew1/amalg6.html

(531) Dr. Ewan Macdonald et al , Evidence dentists have higher than normal levels of mercury exposure and adverse health effects, Journal of Occupational and Environmental Medicine, May 2002; & Wesnes K., A pilot study of the effect of low level exposure to mercury on the health of dental surgeons. Occupational & Environmental Medicine. 52(12):813-7, 1995 Dec.

(541) Razagui IB, Haswell SJ; . Mercury and selenium concentrations in maternal and neonatal scalp hair: relationship to amalgam-based dental treatment received during pregnancy. Biol Trace Elem Res 2001 Jul;81(1):1-19; & Cernichiari E, Brewer R, Myers GJ, Marsh DO, Berlin M, Clarkson TW; Monitoring methyl mercury during pregnancy: maternal hair predicts fetal brain exposure. Neurotoxicology 1995 Winter;16(4):729005-10:

(545) Ritchie KA, Gilmour WH, Macdonald EB, et al, Health and neuropsychological functioning of dentists exposed to mercury. Occup Environ Med 2002 May;59(5):287-93

(562) Joshi A, Douglass CW, et al, The relationship between amalgam restorations and mercury levels in male dentists and nondental health professionals , J. Public Health Dent. 2003, 63(1): 52-60.

(563) Aydin, N ;Karaoglanoglu, S; Yigit, A; Keles, MS; Kirpinar, I; Seven, N; Neuropsychological effects of low mercury exposure in dental-staff in Erzurum, Turkey, Int. Dent. J., 2003, 53(2): 85-91.

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Behavioral effects of low-level exposure to elemental Hg among dentists.

Echeverria D, Heyer NJ, Martin MD, Naleway CA, Woods JS, Bittner AC Jr.

Battelle Center for Public Health Research and Evaluation (CPHRE), Seattle, WA 98105, USA.

Exposure thresholds for health effects associated with elemental mercury (Hg degree) exposure were examined by comparing behavioral test scores of 19 exposed (mean urinary Hg = 36 micrograms/l) with those of 20 unexposed dentists. Thirty-six micrograms Hg/l is 7 times greater than the 5 micrograms Hg/l mean level measured in a national sample of dentists. To improve the distinction between recent and cumulative effects, the study also evaluated porphyrin concentrations in urine, which are correlated with renal Hg content (a measure of cumulative body burden). Subjects provided an on-site spot urine sample, were administered a 1-h assessment consisting of a consent form, the Profile of Mood Scales, a symptom and medical questionnaire, and 6 behavioral tests: digit-span, symbol-digit substitution, simple reaction time, the ability to switch between tasks, vocabulary, and the One Hole Test. Multivariate regression techniques were used to evaluate dose-effects controlling for the effects of age, race, gender and alcohol consumption. A dose-effect was considered statistically significant below a p value of 0.05. Significant urinary Hg dose-effects were found for poor mental concentration, emotional lability, somatosensory irritation, and mood scores. Individual tests evaluating cognitive and motor function changed in the expected directions but were not significantly associated with urinary Hg. However, the pooled sum of rank scores for combinations of tests within domains were significantly associated with urinary Hg, providing evidence of subtle preclinical changes in behavior associated with Hg exposure. Coproporphyrin, one of three urinary porphyrins altered by mercury exposure, was significantly associated with deficits in digit span and simple reaction time.(ABSTRACT TRUNCATED AT 250 WORDS)

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see www.home.earthlink.net/~berniew1/dental.html

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III.9. Developmental Effects see www.home.earthlink.net/~berniew1/fetaln.html

& www.home.earthlink.net/~berniew1/kidshg.html

Amalgam and fetal exposure: references and snips from abstracts, annotation (Not done)

Many recent studies have found reproductive effects including infertility and developmental effects in the fetus and infants at much lower levels than those having significant effects on adults. As compared to adults, the fetus and newborns have been found to be much more susceptable to the effects of low levels of mercury exposure due to low body weight with higher food consumption rate per kilogram of body weight, higher gastrointestinal absorption rate, less effective renal excretion, and a less effective blood-brain barrier.

Rice, D.C., Issues in developmental neurotoxicology: interpretation and implications of the data. Can J Public Health 1998; 89(Supp1): S31-40.

& Rice DC, Barone S, Critical Periods of Vulnerability for the Developing Nervous System: Evidence from human and animal models. Environ Health Persect 2000, 108(supp 3):511-533

& Weiss B, Landrigan PJ. The developing brain and the Environment. Environmental Health Perspectives, Volume 107, Supp 3, June 2000;

& Stein J, Schettler T, Wallinga D, Valenti M. In harm's way: toxic threats to child development. J Dev Behav Pediatr 2002 Feb;23(1 Suppl):S13-22.

& National Research Council, Toxicological Effects of Methylmercury (2000), pp. 304-332: Risk Characterization and Public Health Implications, Nat'l Academy Press 2000.

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The results of the present study demonstrated that mercury vapor released from the amalgam fillings in pregnant rats was distributed to maternal and fetal organs in dose-dependent amounts of the amalgam fillings.

Takahashi Y, Tsuruta S, Arimoto M, Tanaka H, Yoshida M. Placental transfer of mercury in pregnant rats which received dental amalgam restorations. Toxicology. 2003 Mar 14;185(1-2):23-33.

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The most common source of maternal exposure to mercury vapor is amalgam fillings, while the most common sources of methyl mercury in people are amalgam and fish.

Leistevuo J et al, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6

& Kingman A, Albertini T, Brown L, National Institute of Dental Research, Mercury concentrations in urine and blood associated with amalgam exposure in the U.S. military population. Dent Res 1998; 77(3):461-71.

& Bjorkman L, Sandborgh-Englund, Ekstrand J. Mercury in Saliva and Feces after Removal of Amalgam Fillings. Toxicol And Applied Pharmacol 1997; 144:156-162.

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Both elemental mercury from amalgam and methyl mercury from amalgam and fish have been demonstrated to cause rapid transmittal through the placenta to the fetus [14,38,41,42,44-47.

14.Lutz E, Lind B, Herin P, Krakau I, Bui TH, Vahter M. Concentrations of mercury, cadmium, and lead in brain and kidney of second trimester fetuses and Infants. Journal of Trace Elements in Medicine and Biology 1996;10:61-67.

& 31. Leistevuo J et al, Dental amalgam fillings and the amount of organic mercury in human saliva. Caries Res 2001 May-Jun;35(3):163-6

& 38.Vimy MJ, Hooper DE, King WW, Lorscheider FL. Mercury from maternal silver tooth fillings: a source of neonatal exposure", Biological Trace Element Research, 56: 143-52,1997.

& 41. Oskarsson A, Schultz A, Skerfving S, Hallen IP, Ohlin B, Lagerkvist BJ. Mercury in breast milk in relation to fish consumption and amalgam. Arch Environ Health, 1996,51(3):234-41.

& 42. Drasch G, Aigner S, Roider G, Staiger F, Lipowsky G. Mercury in human colostrum and early breast milk. J Trace Elem Med Biol 1998; 12:23-27;

& 44. Yang J, Jiang Z,Wang Y, Qureshi IA, Wu XD. Maternal-fetal transfer of metallic mercury via placenta and milk. Ann Clin Lab Sci 1997; 27(2):135-141.

& 45. Sundberg J, Ersson B, Lonnerdal B, Oskarsson A. Protein binding of mercury in milk and plasma from mice and man--a comparison between methylmercury and inorganic mercury. Toxicology 1999 Oct 1;137(3):169-84.

& 46. Vahter M, Akesson A, Lind B, Bjors U, Schutz A, Berglund M, "Longitudinal study of methylmercury and inorganic mercury in blood and urine of pregnant and lactating women, as well as in umbilical cord blood", Environ Res 2000 Oct;84(2):186-94;

& G. B. Ramirez, C. V. Cruz, C. Dalisay, The Tagum Study I: Analysis and Clinical Correlates of Mercury in Maternal and Cord Blood, Breast Milk, Meconium, and Infants' Hair , PEDIATRICS Vol. 106 No. 4 October 2000, pp. 774-781.

& 47. Ramirez GB, Cruz MC, Pagulayan O, Ostrea E, Dalisay C. The Tagum study I: analysis and clinical correlates of mercury in maternal and cord blood, breast milk, meconium, and infants' hair. Pediatrics 2000 Oct;106(4):774-81.

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The fetal mercury content after maternal inhalation of mercury vapor was found to be over 20 times that for maternal exposure to an equivalent dose of inorganic mercury, and levels of mercury in the brain, heart, and major organs have been found to be higher after equal exposure levels to mercury vapor than for the other mercury forms [8].

8. Magos L, Clarkson TW, Hudson AR. The effects of dose of elemental mercury and first pass circulation time on organ distribution of inorganic mercury in rats. Biochim Biophys Acta 1989; 991(1):85-9.

Developmental, learning, and behavioral effects have been found from mercury vapor at much lower levels than for exposure to methyl mercury [49,56-58],(304). Similarly for inhibition of some essential cellular processes (333,329).

49. Newland MC, Warfvinge K, Berlin M. Behavioral consequences of in utero exposure to mercury vapor. Toxicology & Applied Pharmacology 1996; 139: 374-386

56. Leonhardt R, Pekel M, Platt B, Haas HL, Busselberg D. Voltage-activated calcium channel currents of rat DRG neurons are reduced by mercuric chloride and methylmercury. Neurotoxicology 1996 Spring;17(1):85-92

57. Monnet-Tschudi F (1998) Induction of apoptosis by compounds depends on maturation and is not associated with microglial activation. J Neurosci Res 53: 361-367

58. Fredriksson A, Dencker L, Archer T, Danielsson BR. Prenatal exposure to metallic mercury vapour and methylmercury produce interactive behavioral changes in adult rats. Neurotoxicol Teratol 1996; 18(2): 129-34.

(304) M.J.Vimy et al, "Mercury from Maternal Silver Tooth Fillings: a source of neonatal exposure", Biological Trace Element Research, 56: 143-52,1997.

(329)Candura SM, D'Agostino G, Castoldi AF, Messori E, Liuzzi M, Manzo L, Tonini M., "Effects of mercuryic chloride and methyly mercury on cholinergic neuromusular transmission in the guinea-pig illium", Pharmacol Toxicol 1997; 80(5): 218-24; &Castoldi AF, Candura SM, Costa P, Manzo L, Costa LG, "Interaction of mercury compounds with muscarinic receptor subtypes in the rat brain", Neurotoxicology 1996; 17(3-4): 735-41;

(333) A.J.Freitas et al, "Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in the rat brain", Brain Research, 1996, 738(2): 257-64; & P.R.Yallapragoda et al,"Inhibition of calcium transport by Hg salts" in rat cerebellum and cerebral cortex", J Appl toxicol, 1996, 164(4): 325-30; & E.Chavez et al, "Mitochondrial calcium release by Hg+2",J Biol Chem, 1988, 263:8, 3582-; A. Szucs et al, Cell Mol Neurobiol, 1997,17(3): 273-8; & D.Busselberg, 1995, "Calcium channels as target sites of heavy metals",Toxicol Lett, Dec;82-83:255-61

The upper level of mercury exposure recommended by the German Commission on Human Biomonitoring is 10 micrograms per liter in the blood(54), but adverse effects such as increases in blood pressure and cognitive effects have been documented as low as 1 ug/L, with impacts higher in low birthweight babies(54).

54. P.Grandjean et al, "MeHg and neurotoxicity in children", Am J Epidemiol, 1999;

& Sorensen N, et al; Prenatal mercury exposure rasises blood pressure, Epidemiology 1999, 10:370-375; & National Research Council, Toxicological Effects of Methylmercury (2000), pp. 304-332: Risk Characterization and Public Health Implications, Nat'l Academy Press 2000.

One study[120] found mercury vapor affected NGF concentration, RNA, and choline acetyltransferese in rat's forebrain at between 4 and 11 parts per billion(ppb) tissue concentration.

120. Soderstrom S, Fredriksson A, Dencker L, Ebendal T. The effect of mercury vapor on cholinergic neurons in the fetal brain. Developmental Brain Research, 1995; 85(1): 96-108.

121. Atchison WD. Effects of neurotoxicants on synaptic transmission. Neuroltoxicol Teratol

1998; 10(5):393-416.

122. Ronnback L, Hansson E. Chronic encephalopathies induced by low doses of mercury or lead. Br J Ind Med 49:233-240, 1992.

123. F. Monnet-Tschudi et al, "Comparison of the developmental effects of 2 mercury compounds on glial cells and neurons in the rat telencephalon", Brain Research, 1996, 741:52-59.

124. Larkfors L, Oskarsson A, Sundberg J, Ebendal T. Methylmercury induced alterations in the nerve growth factor level in the developing brain. Res Dev Res 1991;62(2):287- 94; & Choi BH, Lapham LW, Amin-Zaki L, Saleem T. Abnormal neuronal migration of human fetal brain. Journal of Neurophalogy 1978; 37:719-733.

125. Rice DC, Evidence of delayed neurotoxicity produced by methylmercury developmental exposure. Neurotoxicology 1996; 17(3-4): 583-96.

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Mercury from maternal "silver" tooth fillings in sheep and human breast milk. A source of neonatal exposure.

Vimy MJ, Hooper DE, King WW, Lorscheider FL. Biol Trace Elem Res. 1997 Feb;56(2):143-52.

Department of Medicine, Faculty of Medicine, University of Calgary, Alberta, Canada.

Neonatal uptake of mercury (Hg) from milk was examined in a pregnant sheep model, where radioactive mercury (Hg203)/silver tooth fillings (amalgam) were newly placed. A crossover experimental design was used in which lactating ewes nursed foster lambs. In a parallel study, the relationship between dental history and breast milk concentration of Hg was also examined in 33 lactating women. Results from the animal studies showed that, during pregnancy, a primary fetal site of amalgam Hg concentration is the liver, and, after delivery, the neonatal lamb kidney receives additional amalgam Hg from mother's milk. In lactating women with aged amalgam fillings, increased Hg excretion in breast milk and urine correlated with the number of fillings or Hg vapor concentration levels in mouth air. It was concluded that Hg originating from maternal amalgam tooth fillings transfers across the placenta to the fetus, across the mammary gland into milk ingested by the newborn, and ultimately into neonatal body tissues. Comparisons are made to the U. S. minimal risk level recently established for adult Hg exposure. These findings suggest that placement and removal of "silver" tooth fillings in pregnant and lactating humans will subject the fetus and neonate to unnecessary risk of Hg exposure.

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I-Hg levels in placenta increased with an increasing number of maternal dental amalgam fillings (p < 0.001). Despite placental accumulation (median, 1.3 microg/kg; range, 0.18-6.7 microg/kg wet weight), a substantial fraction of maternal blood I-Hg, probably as Hg(0), reached the fetus. Although MeHg transferred easily to the fetus, it also accumulated in the placenta. On average, 60% of placental Hg was in the form of MeHg. The median concentration was 1.8 microg/kg (range, 0-6.2 microg/kg wet weight), more than twice the maternal blood concentration.

Ask K, Akesson A, Berglund M, Vahter M (2002) Inorganic and methyl mercury in placentas of Swedish women. Environ Health Perspect 110: 523-526

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About 72% of the Hg in blood (n = 148) in early pregnancy was MeHg (median 0.94 microg/L, maximum 6.8 microg/L). Blood MeHg decreased during pregnancy, partly due to decreased intake of fish in accordance with recommendations to not eat certain predatory fish during pregnancy. Cord blood MeHg (median 1.4 microg/L, maximum 4.8 microg/L) was almost twice that in maternal blood in late pregnancy and was probably influenced by maternal MeHg exposure earlier and before pregnancy. Blood I-Hg (median 0.37 microg/L, maximum 4.2 microg/L) and urine T-Hg (median 1.6 microg/L, maximum 12 microg/L) in early pregnancy were highly correlated, and both were associated with the number of amalgam fillings. The concentrations decreased during lactation, probably due to excretion in milk. Cord blood I-Hg was correlated with that in maternal blood.

Vahter M, Akesson A, Lind B, Bjors U, Schutz A, Berglund M (2000) Longitudinal study of methyl and inorganic mercury in blood and urine of pregnant and lactating women, as well as in umbilical cord blood. Environ Res 84: 186-194

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The data obtained were used to construct a model of logistic regression showing statistical significance (p = 0.05) between the number of fillings and mercury levels, whereas the occlusal extension of dental repairs was more significantly correlated with metal concentrations(p<.05)

Luglie PF, Frulio A, Campus G, Chessa G, Fadda G, Dessole S (2000) Dosaggio del mercurio nel liquido amniotico umano ('Mercury dosage in human amniotic fluid'). Minerva Stomatol 49: 155-161

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There was an association between inorganic mercury in blood and milk (r = .96, p < .0001); the average level of inorganic mercury in milk was 55% of the level of inorganic mercury in blood. No significant correlations were found between the levels of any form of mercury in milk and the levels of organic mercury in blood. The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. Exposure of the infant to mercury from breast milk was calculated to range up to 0.3 microg/kg x d, of which approximately one-half was inorganic mercury. This exposure, however, corresponds to approximately one-half the tolerable daily intake for adults recommended by the World Health Organization. We concluded that efforts should be made to decrease mercury burden in fertile women.

Oskarsson A, Schultz A, Skerfving S, Hallen IP, Ohlin B, Lagerkvist BJ (1996) Total and inorganic mercury in breast milk in relation to fish consumption and amalgam in lactating women. Arch Environ Health 51: 234-241

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The lactational transfer of mercury was more efficient following administration of inorganic mercury than after administration of methylmercury, with a five times higher peak concentration in milk, higher milk:plasma concentration ratios, and 8% of the administered dose excreted in milk compared with 4% for methylmercury.

Sundberg J, Jonsson S, Karlsson MO, Hallen IP, Oskarsson A.. Kinetics of methylmercury and inorganic mercury in lactating and nonlactating mice.. Toxicol Appl Pharmacol. 1998 Aug;151(2):319-29.

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(note: many of the studies of the pharmacokinetics of mercury in milk of animals does not match the situation of exposure by someone with amalgam. The dose administered is usually inorganic HgCl or organic MeHgCl. But those with amalgam, the mercury exposure is mostly elemental mercury vapor or methyl mercury, not elemental mercury. Some mercury is converted to inorganic forms after entering cells. But test exposure of a one time dose, which results in less mercury transferred over time, also does not match the constant lower level exposure from amalgam, so the test showing saturation of the mercury carrier over time also doesn't match exposure from amalgam. The form of mercury compounds in milk is also different for mercury vapor exposure vs inorganic mercury exposure. So comparison of mercury vapor exposure vs methyl mercury exposure would be more appropriate. I have seen no effort to determine the species or compounds in milk after exposure from amalgam, although this would be an important issue- with likely considerable as mercury/amino acid compounds and some methylmercury. And I've seen no effort to determine how much of the methyl mercury in milk comes from amalgam vs fish. For some, more of the methyl mercury likely comes from amalgam than from fish. Also, from other animal studies such as whales, it has been found that the exposure from milk at first involves accumulated mercury from the mother's body burden, but the mother's body burden goes down significantly and levels in milk over time as more is transferred into the calf.

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The primary objective was to determine whether environmental pollutants can be detected in meconium.. A total of 426 infants were studied. The exposure rate (based on meconium analysis) and the median concentration of the pollutants in the positive samples were as follows: mercury (83.9%; 3.17 ng/ml)

Enrique MO, Morales V, Ngoumgna E, Prescilla R, Tan E, Hernandez E, Ramirez GB, Cifra HL, Manlapaz ML. Prevalence of fetal exposure to environmental toxins as determined by meconium analysis. Neurotoxicology. 2002 Sep;23(3):329-39.

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Influence on foetal development

The risk of influence on foetal development was pointed out in the 1997 risk analysis. This is not contradicted by more recent results that may suggest an elevated risk, among women exposed to mercury in the course of their work, of giving birth to babies who are small for their gestational age. In addition, there are experiments on animals indicating that one expected effect of exposure to low doses of mercury vapour is inhibition of brain development. In these experiments, this inhibition resulted in reduced cognitive and motor capacity. Such inhibition of brain development falls within the normal range in the population.

These effects in animal experiments resemble those observed after exposure to methyl mercury. However, the dose of mercury that yields the effect has been only about one-tenth of the dose of mercury that exerts an effect following exposure to methyl mercury. Only through epidemiological studies using batteries of neuropsychological tests and possibly neurophysiological survey methods can these effects be demonstrated.

The risk of inhibition of brain development during the foetal stage and early childhood is obvious. This hazard is a contraindication for amalgam fillings in children and women of fertile age, until a quantification of the risk prompts a different assessment.

Berlin M. (1999). Mercury in dental fillings -- an environmental medicine risk assessment. A literature and knowledge summary. In Amalgam and Health. Edited by Novakova V. pp 369. Swedish Council for Planning and Coordination of Research (FRN), Stockholm

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IV. 1. Oral Effects of Amalgam

First is a list of references on oral effects of amalgam. Then abstracts for each article is included(some abstracts snipped).

larger review with much more documentation at:

www.myflcv.com/periodon.html

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1. Certosimo AJ, O'Connor RP. Oral electricity. Gen Dent. 1996 Jul-Aug;44(4):324-6.

2. Schmidt F, Mannsaker. [Mercury and creatinine in urine of employees exposed to magnetic fields. A study of a group electrolysis-operators in Norzink A/S in Odda] [Article in Norwegian] Tidsskr Nor Laegeforen. 1997 Jan 20;117(2):199-202.

3. Rose MD, Costello JP. The tarnished history of a posterior restoration. Br Dent J. 1998 Nov 14;185(9):436.

4. Forsell M, Larsson B, Ljungqvist A, Carlmark B, Johansson O. Mercury content in amalgam tattoos of human oral mucosa and its relation to local tissue reactions. Eur J Oral Sci. 1998 Feb;106(1):582-7.

5. Kissel SO, Hanratty JJ. Periodontal treatment of an amalgam tattoo. Compend Contin Educ Dent. 2002 Oct;23(10):930-2, 934, 936.

6. Nadarajah V, Neiders ME, Aguirre A, Cohen RE. J Toxicol Environ Health. Localized cellular inflammatory responses to subcutaneously implanted dental mercury. 1996 Oct 11;49(2):113-25.

7. Rusch-Behrend GD, Gutmann JL. Management of diffuse tissue argyria subsequent to endodontic therapy: report of a case. Quintessence Int. 1995 Aug;26(8):553-7.

8. Weaver T, Auclair PL, Taybos GM. An amalgam tattoo causing local and systemic disease?

Oral Surg Oral Med Oral Pathol. 1987 Jan;63(1):137-40.

(note: the last 2 represent extremely widespread and common effects that are well known and commonly treated, but I'm not familiar with recent journal articles regarding amalgam tattoos.)

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Oral electricity.
Certosimo AJ, O'Connor RP. Gen Dent. 1996 Jul-Aug;44(4):324-6.
National Naval Dental Center, Naval Dental School, Bethesda, Maryland, USA.

"Oral electricity," "electrogalvanism," or "galvanic currents" has long been recognized as a potential source of oral pain and discomfort. This phenomenon of oral galvanism results from the difference in electrical potential between dissimilar restorative metals located in the mouth. In this case report, the literature is reviewed, and an interesting case study'is presented. The patient's clinical presentation, and the duration and constancy of the oral symptoms

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[Mercury and creatinine in urine of employees exposed to magnetic fields. A study of a group electrolysis-operators in Norzink A/S in Odda] [Article in Norwegian]

Schmidt F, Mannsaker.
Tidsskr Nor Laegeforen. 1997 Jan 20;117(2):199-202.

The results described are based on a study of 26 male cell house employees. They were exposed to a combination of static magnetic fields (3-10 mT) and low frequency oscillating magnetic fields of variable frequency and strength for eight hours a day over a period of four weeks. Every fifth week was spent off work. Urine samples collected at the end of the four weeks of exposure were compared with samples collected at the end of the week off work. The results show that the cell house workers excreted significantly more mercury in their urine after exposure to magnetic fields (p = 0.01). The mercury/creatinine ratio was also significantly higher after exposure (p < 0.01). These results support findings by Schmidt in a study from 1992 when the levels of mercury and creatinine in the urine of cell house workers were compared with the levels in office personnel.

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The tarnished history of a posterior restoration.

Rose MD, Costello JP. Br Dent J. 1998 Nov 14;185(9):436.

Eastman Dental Institute, London.
Galvanic corrosion is an electrochemical reaction between dissimilar metals that has the potential to cause unpleasant and even painful biological effects intra-orally. A case is presented where a full gold crown underwent galvanic change after being placed in contact with an amalgam restoration.
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Mercury content in amalgam tattoos of human oral mucosa and its relation to local tissue reactions.

Forsell M, Larsson B, Ljungqvist A, Carlmark B, Johansson O.
Eur J Oral Sci. 1998 Feb;106(1):582-7.

Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

Mucosal biopsies from 48 patients with and 9 without amalgam tattoos were analysed with respect to their mercury content, distribution of mercury in the tissue, and histological tissue reactions. The distribution of mercury was assessed by autometallography (AMG), a silver amplification technique. The mercury content was determined by energy dispersive X-ray fluorescence (EDXRF), a multielemental analysis. Mercury was observed in connective tissue where it was confined to fibroblasts and macrophages, in vessel walls and in structures with the histological character of nerve fibres. A correlation was found between the histopathological tissue reaction, the type of mercury deposition, the intensity of the AMG reaction, and the mercury content. Mercury was also found in patients with amalgam dental fillings but without amalgam tattoos.

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Periodontal treatment of an amalgam tattoo.

Kissel SO, Hanratty JJ. Compend Contin Educ Dent. 2002 Oct;23(10):930-2, 934, 936.

The amalgam tattoo can often result in an unsightly cosmetic appearance, especially in the maxillary anterior region. The predominant treatment for an amalgam tattoo is the free gingival graft, which also results in a poor cosmetic appearance.

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Localized cellular inflammatory responses to subcutaneously implanted dental mercury.

Nadarajah V, Neiders ME, Aguirre A, Cohen RE. J Toxicol Environ Health. 1996 Oct 11;49(2):113-25.

Department of Oral Diagnostic Sciences, School of Dental Medicine, State University of New York at Buffalo 14214,

Previous reports have demonstrated mercury accumulation and toxicity in oral tissues following exposure to mercury vapor from dental amalgam restorations. In the present study, inflammatory responses to subcutaneously administered mercury were assessed histopathologically and immunocytochemically in a rat model system. A panel of six well-characterized monoclonal antibodies specific for monocytes, macrophage subsets, T and B lymphocytes, and major histocompatibility complex (MHC) class II (la) determinants was used to quantitate alterations in mononuclear cell subsets in situ at time intervals from 2 d to 8 wk. The results revealed acute inflammatory cell infiltration at 2 and 3 d, followed by chronic inflammation that persisted after 8 wk. The numbers of monocytes, resident macrophage subsets, and mononuclear cells expressing la antigen were significantly different from control tissues at 1-2 wk. The numbers of resident macrophages remained significantly higher even after 8 wk. These data showed that in situ mercury accumulation can lead to altered expression of MHC class II determinants with persistent chronic inflammation and shifts in mononuclear cell subpopulations.

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Management of diffuse tissue argyria subsequent to endodontic therapy: report of a case.

Rusch-Behrend GD, Gutmann JL. Quintessence Int. 1995 Aug;26(8):553-7.

Department of Restorative Sciences, Baylor College of Dentistry, Dallas, Texas 75246

A case of severe mucogingival argyria secondary to leakage around and corrosion of silver cone root canal obturations and apical amalgam restorations is presented. Following removal of the silver points and re-treatment of the root canals, periradicular surgery was performed to remove the amalgam root-end restorations and reduce the amount of dispersed metallic particles in the subcutaneous tissues. Subsequent free gingival grafting created an esthetically pleasing and biologically acceptable result.
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An amalgam tattoo causing local and systemic disease?
Oral Surg Oral Med Oral Pathol. 1987 Jan;63(1):137-40.
Weaver T, Auclair PL, Taybos GM.

Amalgam tattoos are common oral lesions. The case presented here involved a 33-year-old woman who had had an amalgam tattoo for 2 years and complained of localized soreness and occasional swelling as well as systemic symptoms of weight loss, fatigue, sinusitis, and headaches. After excisional biopsy of the lesion, the patient's complaints ceased dramatically. It is suggested that alterations in healing due to the presence of amalgam particles led to systemic as well as local disease.

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2. Lou Gerhig's Disease(ALS) see www.myflcv.com/~berniew1/als.html

3. Chronic Fatigue Syndrome(CFS) see www.myflcv.com/cfsfm.html

4. Fibromyalgia(FMS) (same 3.)

5. Alzheimer's Disease see www.myflcv.com/alzhg.html

6. Rheumetoid Arthritis (same as 3.)

7. Multiple Sclerosis(MS) see www.myflcv.com/ms.html

8. Parkinson's Disease see www.myflcv.com/parknew.html

9. Lupus (same as 3.)

10. Degenerative Eye Conditions see www.myflcv.com/eyehg.html

11. Epilepsy see www.healingartscenter.com/Library/articles/art10.htm

12. Allergies

Allergies

That allergies to metals can cause physical symptoms is well known from experience with patch testing for allergies. Allergy diagnostics with epicutaneous tests (patch testing) can sometimes, besides skin reactions, provoke systemic effects with such symptoms as headache, vertigo, fatigue and general malaise (Kunkeler et al. 2000; Inerot and Möller 2000).

A group of 65 patients who had all reacted with intensified subjective symptoms in conjunction with amalgam removal, were subjected to provocation experiments by means of patch testing.

The tests were carried out blind, with a concentration of roughly 10 mg of metallic mercury, 4 mg phenylmercuric acetate and mercury-free substances. For a week after the skin application, the patients had to keep a log according to a questionnaire on their symptoms. Some reacted with increased symptoms of substances containing mercury, and were described as 'mercury-intolerant'. The patients who did not react were described as 'mercury-tolerant'

(Marcusson 1996).

Neutrophils from 14 intolerant and 14 tolerant patients and 14 controls were tested. The cells were exposed to HgCl₂ and compared in terms of the release of superoxide. A statistically significant difference between tolerant and intolerant patients was observed. There was a correlation between the activity of superoxide dismutase (SOD) in lymphocytes and the symptom score, and also between superoxide formation and the symptom score for the mercury-exposed patients. The results indicate that the oxidative metabolism and, in particular, superoxide dismutase may be perturbed in mercury-intolerant patients.

(Marcusson et al. 2000).

The peripheral lymphocytes of 10 patients referred to as mercury intolerant and 9 patients referred to as tolerant with regard to presence or absence of psychosomatic symptoms when percutaneously exposed to low patch test doses of mercury were stimulated in vitro with four metal salts. In addition, cells from 7 subjects with no anamnestic mercury intolerance or allergy to metals as well as free from dental alloys were included as controls. Lymphocyte transformation test was done by in vitro challenge with palladium chloride and seven concentrations of mercuric chloride. Stimulation with palladium chloride and mercuric chloride showed a difference between the combined mercury-intolerant and -tolerant patients on one hand and the controls on the other, but there was no significant difference between the two patient groups. (Cederbrant , Marcusson, 2000)

Marcusson JA (1996) Psychological and somatic subjective symptoms as a result of dermatological patch testing with metallic and phenyl mercuric acetate. Toxicol Lett 84: 113-122

Marcusson JA, Carlmark B, Jarstrand C (2000) Mercury intolerance in relation to superoxide dismutase, glutathione peroxidase, catalase, and the nitroblue tetrazolium responses. Environ Res 83: 123-128

Cederbrant K, Gunnarsson LG, Marcusson JA. Mercury intolerance and lymphocyte transformation test with nickel sulfate, palladium chloride, mercuric chloride, and gold sodium thiosulfate.. Environ Res. 2000 Oct;84(2):140-4.

Kunkeler L, Bikkers SCE, Bezemer PD, Bruynzeel DP (2000) (Un)usual effects of patch testing. Br J Dermatol 143: 582-586

Inerot A, Möller H (2000) Symptoms and signs reported during patch testing. American Journal of Contact Dermatitis 11: 49-52

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A 65 year old patient had a large accumulation of oral copper and chronic allergy to copper that appeared to be related to copper from amalgam fillings.

Gerhardsson L, Bjorkner B, Karlsteen M, Schutz A. Copper allergy from dental copper amalgam? Sci Total Environ. 2002 May 6;290(1-3):41-6.

see www.myflcv.com/immunere.html

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IV. 2. ALS

Documentation that mercury from amalgam causes Lou Gehrig's Disease(ALS).

(snipped from a bigger paper with many references prior to 1996, which were mostly deleted) (Over 200 peer-reviewed references at end of summary of case, which document that mercury causes the conditions seen in ALS with the mechanisms of causality)

I. Introduction.

ALS is a systemic motor neuron disease that affects the corticospinal and corticobulbar tracts, ventral horn motor neurons, and motor cranial nerve nuclei(405). Approximately 10 percent of ALS cases are of the familial type that has been linked to a mutation of the copper/zinc super oxide dismustase gene(Cu/Zn SOD). The majority of ALS cases are of the sporadic type. Based on studies of groups of monozygous twins, animal studies, and ALS patient case studies, the majority of ALS cases do not appear to be genetic but rather have primarily environmental related causes(405,97,416,423,etc.). Some of the mechanisms of neural damage found in ALS include increased free radical generation/oxidative damage, impaired electron transport, disrupted calcium channel function, neurotoxicity, oxidative damage to mitochondrial DNA/ inhibition of the mitochondrial respiratory chain, and generalized disruption of metabolism of neuroexciotoxic amino acids like glutamate, aspartate, NAAG. The mechanisms by which exposure to mercury and other neurotoxic substances cause all of this will be documented.

The main factors determining whether chronic conditions are induced by metals appear to be exposure and genetic susceptibility, which determines individuals immune sensitivity and ability to detoxify metals(405,375). Very low levels of exposure have been found to seriously affect relatively large groups of individuals who are immune sensitive to toxic metals, or have an inability to detoxify metals due to such as deficient sulfoxidation or metallothionein function or other inhibited enzymatic processes related to detoxification or excretion of metals. Those with the genetic allele ApoE4 protein in the blood have been found to detox metals poorly and to be much more susceptible to chronic neurological conditions than those with types ApoE2 or E3(437).

Some of the toxic exposures which have been found to be a factor in ALS other than mercury include lead, pyretherins, agricultural chemicals, Lyme disease, failed root canaled teeth, and smoking(references on these have been removed from paper). All have been demonstrated to cause the some of the mechanisms of damage listed above seen in ALS and since such exposures are common as is exposure to mercury, such exposures appear to synergistically cause the types of damage seen in ALS.

This paper will demonstrate that mercury is the most common of toxic substances which are documented to accumulate through chronic exposure in the neurons affected by ALS and which have been documented to cause all of the conditions and symptoms seen in ALS. It will also be noted that chronic infections such as mycoplasma,echo-7 enterovirus, and candida albicans often affect those with chronic immune deficiencies such as ALS patients and need to be dealt with in treatment. Some studies have also found persons with chronic exposure to electromagnetic fields(EMF) to have higher levels of mercury exposure and excretion(28) and higher likelihood of getting chronic conditions like ALS(526).

II. Documentation of High Common Exposures and Accumulation of Mercury in Motor Neurons

Daily mercury exposures to those with amalgam dental fillings commonly exceed the Government health guideline for mercury, due to mercury's negative vapor pressure and galvanic action with other metals in the mouth(documented in another submittal).

Mercury has been found to accumulate preferentially in the primary motor function related areas involved in ALS- such as the brain stem, cerebellum, rhombencephalon, dorsal root ganglia, and anterior horn motor neurons, which enervate the skeletal muscles(48,291,327,329,442).

Mercury, with exposure either to vapor or organic mercury tends to accumulate in the glial cells in a similar pattern, and the pattern of deposition is the same as that seen from morphological changes(327,287). Mercury has been found to be taken up into neurons of the brain and CNS without having to cross the blood-brain barrier, since mercury has been found to be taken up and transported along nerve axons as well through calcium and sodium channels(329).

III. Effects of Exposure to Mercury and Toxic Metals

A direct mechanism involving mercury's inhibition of cellular enzymatic processes by binding with the hydroxyl radical(SH) in amino acids appears to be a major part of the connection to allergic/immune reactive conditions such as autism, schizophrenia, eczema, psoriasis, and allergies(181), as well as to autoimmune conditions such as ALS, Lupus, Alzheimer's(AD), Scleroderma(468), Chronic Fatigue(CFS), Fibromyalgia(FM), etc. (405,375). For example mercury has been found to strongly inhibit the activity of dipeptyl peptidase (DPP IV) which is required in the digestion of the milk protein casein(411,412) as well as of xanthine oxidase(439) Additional cellular level enzymatic effects of mercury's binding with proteins include blockage of sulfur oxidation processes (33,114,194,412), effects on the cytochrome-C energy processes (43,84,232,338), along with mercury's adverse effects on cellular mineral levels of calcium, magnesium, copper, zinc, and lithium (43,96,119,333,430,432,489,507). And along with these blockages of cellular enzymatic processes, mercury has been found to cause additional neurological and immune system effects in many through immune/ autoimmune reactions (314,375,405) A recent study gives a comprehensive review of studies finding a connection between ALS, toxic metals, and autoimmunity(405).

Oxidative stress and reactive oxygen species(ROS) have been implicated as major factors in neurological disorders including ALS, motor neuron disease(MND), CFS, FM, Parkinson's(PD), Multiple Sclerosis(MS), and Alzheimer's(AD) (13,56,84,98,145,207,442-444,453, 462,496). Mercury forms conjugates with thiol compounds such as glutathione and cysteine and causes depletion of glutathione, which is necessary to mitigate reactive damage. One study found that insertion of amalgam fillings or nickel dental materials causes a suppression of the number of T-lymphocytes(270), and impairs the T-4/T-8 ratio. Low T4/T8 ratio has been found to be a factor in autoimmune conditions. Mercury induced lipid peroxidation has been found to be a major factor in mercury's neurotoxicity, along with leading to decreased levels of glutathione peroxidation and superoxide dismustase(SOD)(13,254,490,494-496). Only a few micrograms of mercury severely disturb cellular function and inhibits nerve growth(175,226,255,305). Metalloprotein(MT) have a major role in regulation of cellular copper and zinc metabolism, metals transport and detoxification, free radical scavenging, and protection against inflammation (114,442,). Mercury inhibits sulfur ligands in MT and in the case of intestinal cell membranes inactivates MT that normally bind cuprous ions(477,114), thus allowing buildup of copper to toxic levels in many and malfunction of the Zn/Cu SOD function. Mercury also causes displacement of zinc in MT and SOD, which has been shown to be a factor in neurotoxicity and neuronal diseases

(405,517). Exposure to mercury results in changes in Metalloprotein compounds that have genetic effects, having both structural and catalytic effects on gene expression

( 114,241,296,442,477,495,517). Some of the processes affected by such MT control of genes include cellular respiration, metabolism, enzymatic processes, metal-specific homeostasis, and adrenal stress response systems. Significant physiological changes occur when metal ion concentrations exceed threshold levels. Such MT formation also appears to have a relation to autoimmune reactions in significant numbers of people (114, 368,369,375,442). Of a population of over 3000 tested by the immune lymphocyte reactivity test(MELISA,375), 22% tested positive for inorganic mercury and 8% for methyl mercury, but much higher percentages tested positive for autoimmune condition patients. In the MELISA laboratory, 12 out of 13 ALS patients tested showed positive immune reactivity lymphocyte responses to metals in vitro [60c], indicating metals reactivity a likely major factor in their condition. A recent study assessed the possible causes of high ALS rates in Guam and similar areas and the recent decline in this conditions. One of the studies conclusions was that a likely major factor for the high ALS rates in Guam and similar areas in the past was chronic dietary deficiency since birth in Ca, Mg and Zn induced excessive absorption of divalent metal cations such as mercury which accelerates oxidant-mediated neuronal degenerations in a genetically susceptible population(466).

Programmed cell death(apoptosis) is documented to the a major factor in degenerative

neurological conditions like ALS, Alzheimer's, MS, Parkinson's, etc. Some of the factors documented to be involved in apoptosis of neurons and immune cells include inducement of the inflamatory cytokine Tumor Necrosis Factor-alpha(TNFa) (126), reactive oxygen species and oxidative stress(13,43a,56a,296b,495), reduced glutathione levels(56,126a,111a), liver enzyme effects and inhibition of protein kinase C and cytochrome P450(43,84,260), nitric oxide and peroxynitrite toxicity (43a,521,524), excitotoxicity and lipid peroxidation(490,496), excess free cysteine levels (56d,111a,33,330),excess glutamate toxicity(13b, 416), excess dopamine toxicity (56d,13a), beta-amyloid generation(462), increased calcium influx toxicity (296b,333,416,432,462c,507) and DNA fragmentation(296,42,114,142) and mitochondrial membrane dysfunction (56de, 416).

TNFa(tumor necrosis factor-alpha) is a cytokine that controls a wide range of immune

cell response in mammals, including cell death(apoptosis). This process is involved in inflamatory and degenerative neurological conditions like ALS, MS, Parkinson's, rheumatoid arthritis, etc. Cell signaling mechanisms like sphingolipids are part of the control mechansim for the TNFa apoptosis mechanism(126a). Gluthathione is an amino acid that is a normal cellular mechanism for controlling apoptosis. When glutathione is depleted in the brain, reactive oxidative species increased, and CNS and cell signaling mechinsisms are disrupted by toxic exposures such as mercury, neuronal cell apoptosis results and neurological damage. Mercury has been shown to induce TNFa and deplete glutathione, causing inflamatory effects and cellular apoptosis in neuronal and immune cells(126b,126c).

Na(+),K(+)-ATPase is a transmembrane protein that transports sodium and potassium ions across cell membranes during an activity cycle that uses the energy released by ATP hydrolysis. Mercury is documented to inhibit Na(+),K(+)-ATPase function at very low levels of exposure(288ab). Studies have found that in ALS cases there was an elevation in plasma serum digoxin and a reduction in serum magnesium and RBC membrane Na(+)-K+ ATPase activity (263). The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in ALS, while the concentration of serum lipid peroxidation products and nitric oxide increased. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction. It is documented in this paper that mercury is a cause of most of these conditions seen in ALS (13a,111,288,442,521b,43,56,263,etc.)

Mercury blocks the immune function of magnesium and zinc (198,427,43,38), whose deficiencies are known to cause significant neurological effects(461,463,430). The low Zn levels result in deficient CuZnSuperoxide dismustase (CuZnSOD), which in turn leads to increased levels of superoxide due to toxic metal exposure. This is in addition to mercury's effect on metallothionein and copper homeostasis as previously discussed(477). Copper is an essential trace metal which plays a fundamental role in the biochemistry of the nervous system (489,495,463,464). Several chronic neurological conditions involving copper metabolic disorders are well documented like Wilson's Disease and Menkes Disease. Mutations in the copper/zinc enzyme superoxide dismustase(SOD) have been shown to be a major factor in the motor neuron degeneration in conditions like familial ALS. Exposures to toxic metals such as mercury and cadmium have been found to cause such effects, and similar effects on Cu/Zn SOD have been found to be a factor in other conditions such as autism, Alzheimer's, Parkinson's, and non-familial ALS (489,490,495,469,111). This condition can result in zinc deficient SOD and oxidative damage involving nitric oxide, peroxynitrite, and lipid peroxidation(490,495,496,489,524), which have been found to affect glutamate mediated excitability and apoptosis of nerve cells and effects on mitochondria (119c,412,416,495,496,502,519,524). These effects can be reduced by zinc supplementation (495,517,430), as well as supplementation with antioxidants and nitric oxide-suppressing agents and peroxynitrite scavengers such as Vit C, Vit E, lipoic acid, Coenzyme Q10, carnosine, gingko biloba, N-acetyl cysteine,melatonin, etc.(444,494,495,469,470,521,524). Ceruloplasmin in plasma can be similarly affected by copper metabolism disfunction, like SOD function, and is often a factor in neurodegeneration(489).

Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALS) have been attributed to several different mechanisms, including increased intracellular calcium (333,496,507), glutamate dysregulation and excitotoxicity(119c,412,416,496,502), oxidative stress and free radical damage(13,43,56,442,490), nitric oxide related toxicity caused by peroxynitrite(524), mitochondrial damage/dysfunction(519), neurofilament aggregation and dysfunction of transport mechanisms(507), and autoimmunity(313,314,369,405,513). These alterations and effects are not mutually exclusive but rather are synergistic, and increased calcium and altered calcium homeostasis appears to be a common denominator. Mercury forms strong bonds with the-SH groups of proteins causing alteration of the transport of calcium (333,43,96,254,329,432,496) and causes mitochondrial release of calcium (43,329,333,432,496,519). This results in a rapid and sustained elevation in intracellular levels of calcium (333,496). Calcium plays a major role in the extreme neurotoxicity of mercury and methyl mercury. Both inhibit cellular calcium ATPase and calcium uptake by brain microsomes at very low levels of exposure (270,288,329,333,432,56,). Protein Kinase C (PKC) regulates intracellular and extra cellular signals across neuronal membranes, and both forms of mercury inhibit PKC at micromolar levels, as well as inhibiting phorbal ester binding(43,432). They also block or inhibit calcium L-channel currents in the brain in an irreversible and concentration dependent manner. Mercury vapor or inorganic mercury exposure affects the posterior cingulate cortex and causes major neurological effects with sufficient exposure (428,453). Metallic mercury is much more potent than methyl mercury in such actions, with 50 % inhibition in animal studies at 13 ppb(333,329). Mercury is seen to be a factor in all of these known mechanisms of neural degeneration seen n ALS and other motor neuron conditions.

Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression and neurotransmitter release in neurons(432,496,43,114). Mercury alters calcium homeostasis and calcium levels in the brain and affects gene expression and neurotransmitter release through its effects on calcium, etc. Mercury inhibits sodium and potassium (N,K)ATPase in dose dependent manner and inhibits dopamine and noreprenephrine uptake by synaptosomes and nerve impulse transfer(288,270,56,43). Mercury also interrupts the cytochrome oxidase system, blocking the ATP energy function (43,84), lowering immune growth factor IGF-I levels and impairing astrocyte function(119,152,497). Astrocytes are common cells in the CNS involved in the feeding and detox of nerve cells. Increases in inflammatory cytokines such as caused by toxic metals trigger increased free radical activity and damage to astrocyte and astrocyte function(152). IGF-I protects against brain and neuronal pathologies like ALS, MS, and Fibromyalgia by protecting the astrocytes from this destructive process.

Mercury exposure also degrades the immune system resulting in more susceptibility to viral, bacterial, or parasitic effects along with candida albicans which are often present in those with chronic conditions and require treatment (404,469,470). Four such commonly found in ALS patients are mycoplasma AND echo-7 enterovirus(469,470), candida albicans(404), and parasites. Mercury from amalgam interferes with production of cytokines that activate macrophage and neutrophils, disabling early control of viruses or other pathogens and leading to enhanced infection(131). While the others are also being commonly found, mycoplasma has been found in 85% of ALS patients by clinics treating such conditions(470). Mycoplasma appears to be a cofactor with mercury in the majority of cases and shifts the immune T cell balance toward inflammatory cytokines(470). Treatment of these chronic infections are required and documented to cause improvement in such patients(470).

Exposure to mercury vapor and methyl mercury is well documented to commonly cause

conditions involving tremor, with populations exposed to mercury experiencing tremor levels on average proportional to exposure level (250).

Mercury lymphocyte reactivity and effects on amino acids such as glutamate in the CNS induce CFS type symptoms including profound tiredness, musculoskeletal pain, sleep disturbances, gastrointestinal and neurological problems along with other CFS symptoms and Fibromyalgia (346,368,369,375,496). Mercury has been found to be a common cause of Fibromyalgia (346,369) , which based on a Swedish survey occurs in about 12% of women over 35 and 5.5% of men(368). ALS patients have been found to have a generalized deficiency in metabolism of the neuroexcitotoxic amino acids like glutamate, aspartate, NAAG, etc.

(416). Glutamate is the most abundant amino acid in the body and in the CNS acts as excitory neurotransmitter (346,412,416,438,496,119c), which also causes inflow of calcium. Astrocytes, a type of cell in the brain and CNS with the task of keeping clean the area around nerve cells, have a function of neutralizing excess glutamate by transforming it to glutamic acid. If astrocytes are not able to rapidly neutralize excess glutamate, then a buildup of glutamate and calcium occurs, causing swelling and neurotoxic effects(119,152,333,496,524). Mercury and other toxic metals inhibit astrocyte function in the brain and CNS(119,152), causing increased glutamate and calcium related neurotoxicity(119,152,333,226,496) which are responsible for much of the Fibromyalgia symptoms and a factor in neural degeneration in MS and ALS. This is also a factor in conditions such as CFS, Parkinson's, and ALS(346,416,496,524). Animal studies have confirmed that increased levels of glutamate(or aspartate, another amino acid excitory neurotransmitter) cause increased sensitivity to pain , as well as higher body temperature- both found in CFS/Fibromyalgia. Mercury and increased glutamate activate free radical forming processes like xanthine oxidase which produce oxygen radicals and oxidative neurological damage(346,142,13). Nitric oxide related toxicity caused by peroxynitrite formed by the reaction of NO with superoxide anions, which results in nitration of tyrosine residues in neurofilaments and manganese Superoxide Dimustase(SOD) has been found to cause inhibition of the mitochondrial respiratory chain, inhibition of the glutamate transporter, and glutamate-induced neurotoxicity involved in ALS(524,521).

In addition to the documentation showing the mechanisms by which mercury causes the conditions and symptoms seen in ALS and other neurodegenerative diseases, many studies of patients with major neurological or degenerative diseases have found direct evidence mercury and amalgam fillings play a major role in development of conditions such as such as ALS (92,97,207,325,327,416,423,442,469,470,520,35).

Medical studies and doctors treating chronic conditions like Fibromyalgia and Chronic Fatigue have found that supplements which cause a decrease in glutamate or protect against its effects have a positive effect on Fibromyalgia and other chronic neurologic conditions. Some that have been found to be effective include CoQ10(444), ginkgo biloba and pycnogenol(494a), NAC(494a), Vit B6, methyl cobalamine(B12), L-carnitine, choline, ginseng, vitamins C and E, nicotine(494), and omega 3 fatty acids(fish and flaxseed oil)(417,495e). Such supplements including N-acetylcysteine(NAC), Vitamins E and C, zinc, and creatinine have been found to offer significant protection against cell apoptosis and neurodegeneration in neurological conditions such as ALS(13c,56a,517,524,564,494).

In a study of the brains of persons dying of ALS, spherical and crescent-shaped introneuronal inclusions(SCI) were distributed in association with each other among the parahippocampal gyrus, dentate gyrus of the hippocampus and amygdala, but not any non-motor-associated brain regions(522). The occurrence of SCI in both the second and third layers of the parahippocampal gyrus and amygdala was significantly correlated to the presence of dementia in ALS cases. Mercury has been found to accumulate in these areas of the brain and to cause adverse behavioral effects in animal studies and humans(66,287,305).

Another neurological effect of mercury that occurs at very low levels is inhibition of nerve growth factors, for which deficiencies result in nerve degeneration. Only a few micrograms of mercury severely disturb cellular function and inhibits nerve growth (175,226,255,305,149). Prenatal or neonatal exposures have been found to have life long effects on nerve function and susceptibility to toxic effects. Prenatal mercury vapor exposure that results in levels of only 4 parts per billion in newborn rat brains was found to cause decreases in nerve growth factor and other effects(305). This is a level that is common in the population with several amalgam fillings or other exposures(see submission on exposure levels). Insulin-like-growth factor I (IGF-I) are positively correlated with growth hormone levels and have been found to be the best easily measured marker for levels of growth hormone, but males have been found more responsive to this factor than women(497). IGF-I controls the survival of spinal motor neurons affected in ALS during development as well as later in life(497,498). IGF-I and insulin levels have been found to be reduced in ALS patients with evidence this is a factor in ALS(497,498). Several clinical trials have found IGF-I treatment is effective at reducing the damage and slowing the progression of ALS and Alzheimer's with no medically important adverse effects(498). It has also been found that in chronically ill patients the levels of pituitary and thyroid hormones that control many bodily processes are low, and that supplementing both thyrotropin-releasing hormone and growth control hormone is more effective at increasing all of these hormone levels in the patient(499).

Clinical tests of patients with ALS, MND, Parkinson's, Alzheimer's, Lupus(SLE), and rheumatoid arthritis have found that the patients generally have elevated plasma cysteine to sulphate ratios, with the average being 500% higher than controls(330,331,56,84), and in general being poor sulphur oxidizers. This means that these patients have blocked enzymatic processes for converting the basic cellular fuel cysteine to sulfates and glutathione, and thus insufficient sulfates available to carry out necessary bodily processes. Mercury has been shown to diminish and block sulphur oxidation and thus reducing glutathione levels which is the part of this process involved in detoxifying and excretion of toxics like mercury(33). Glutathione is produced through the sulphur oxidation side of this process. Low levels of available glutathione have been shown to increase mercury retention and increase toxic effects(111), while high levels of free cysteine have been demonstrated to make toxicity due to inorganic mercury more severe(333,194,56,33b). The deficiency in conjugation and detoxification of sulfur based toxins in the liver results in toxic metabolites and progressive nerve damage over time (331). Mercury has also been found to play a part in inducing intolerance and neuronal problems through blockage of the P-450 enzymatic process(84,33b). Patients with some of these conditions have found that bathing in Epsom Salts (magnesium sulfate) offers temporary relief for some of their symptoms by providing sulfates that avoid the blocked metabolic pathway. A more definitive test such as MELISA for immune reactivity to toxics is available by sending blood to a European lab(87).

In one subtype of ALS, damaged, blocked, or faulty enzymatic superoxide dimustase (SOD) processes appear to be a major factor in cell apoptosis involved in the condition(443). Mercury is known to damage or inhibit SOD activity(441,33,111).

Total dental revision(TDR) which includes replacing amalgam fillings, extracting root canaled teeth, and treating cavitations has been found to offer significant health improvements to many with ALS or other autoimmune conditions(200,369,375,293,437,469). IGF-1 treatments have also been found to alleviate some of the symptoms of ALS(424). Medical studies and doctors treating fibromyalgia have found that supplements which cause a decrease in glutamate or protect against its effects have a positive effect on fibromyalgia. Some that have been found to be effective in treating metals related autoimmune conditions include Vit B6, CoenzymeQ10, methyl cobalamine(B12), L-carnitine, choline, ginseng, Ginkgo biloba, vitamins C and E, nicotine, and omega 3 fatty acids(fish and flaxseed oil)(417,444,469).

One dentist with severe symptoms similar to ALS improved after treatment for mercury poisoning(246), and others treated for mercury poisoning or using TDR have also recovered or significantly improved (97,405,406,469-470,).The Edelson Clinic in Atlanta which treats ALS patients reports similar experience(406), and the Perlmutter Clinic has also had success with treatment of ALS and other degenerative neurological conditions(469).

Zinc is a mercury and copper antagonist and can be used to lower copper levels and protect against mercury damage(517,564). Lipoic acid has been found to have protective effects against cerebral ischemic-reperfusion, excitotoxic amino acid(glutamate) brain injury, mitochondrial dysfunction, diabetic neuropathy(494). Other antioxidants such as carnosine(495a), Coenzyme Q10,Vitamins C & E, gingko biloba, and pycnogenol have also been found protective against degenerative neurological conditions(494,495e, 444).

Another supplement that appears useful in conditions involving muscle function degeneration is creatine(502). In the motor cortex of the ALS group the N-acetylaspartate (NAA)/creatine (Cr(t)) metabolite ratio was lower than in our control group, indicating NAA loss. Upon creatine supplementation we observed in the that creatine supplementation causes an increase in the diminished NAA levels in ALS motor cortex as well as an increase of choline levels in both ALS and control motor cortices. This indicates an improvement in function of the pathological ALS skeletal muscles related to changes of mitochondrial respiratory chain which appears to affect motor neuron survival.

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see www.myflcv.com/als.html

IV. 3. CFS & FMS

Documentation that mercury is a common cause and synergistic factor in CFS, FMS, Lupus, Scleraderma, atopic conditions, and other autoimmune conditions

Intro

Chronic fatigue syndrome(CFS) is characterized by fatigue, neurologic symptoms including headaches, brain fog, mood disorders, and motor dysfunction. Spect scans of those with CFS have found that the majority have over 5 times more areas of regional brain damage and reduced blood flow in the cerebral cortex area of the brain than controls.

Schwartz RB, Garada BM, Komaroff AL, Gleit M, Holman BL. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MRI and SPECT. Am J Roentgenol, 1994, 162(4):935-41;

& Spect Imaging: comparison of findings in patients with CFS, AIDA dementia complex, and major unipolar depression, Am J Roentgenol 1994, 162(4): 943-51;

& Ichiso M, Salit IE, Abbey SE. Assessment of regional cerebral perfusion by SPECT in CFS. Nucl Med Commun 1992; 13:767-72. (just included for background)

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The majority with CFS studied were also found to have increased Th2 inflamatory cytokine activity and a blunted DHEA response curve to I.V. ATCH indicative of hypothalamic/adrenal deficiency such as relative glucocorticoid deficiency

Patarca-Monero R, Klimas NG, Fletcher MA. Immunotherapy of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2001, 8(1): 3-37;

& DeBecker P, De Meirleir K, Joos E, Velkeniers B. DHEA response to I.V. ACTH in patients with CFS. Horm Metab Res 1999, 31(1): 18-21. (more background on the condition)

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CFS and Fibromyalgia patients have also been found to commonly have abnormal enzymatic processes that affect the sodium-potassium ATPase energy channels, which appears to be a major factor in the condition and for which mercury is a known cause.

De Meirleir K, Bisbal C, Campine I, De Becker, et al. A 37 kDa 1-5A binding proein as a potential biochemical marker for CFS. Am J Med 2000, 108(2): 99-105;

& Suhadolnik RJ, Peterson DL, Obrien K, et al, Biochemical evidence for a novel low molecular weight 2-5A-dependent Rnase L in CFS. J Interferon Cytokine Res, 1997, 17(7): 377-85;

& Chaudhuri A, Watson WS, Pearn J, Behan PO. The symptoms of chronic fatigue syndrome are related to abnormal ion channel function. Med Hypotheses 2000 Jan;54(1):59-63

& Knapp LT; Klann E. Superoxide-induced stimulation of protein kinase C via thiol modification and modulation of zinc content. J Biol Chem 2000 May 22;

& B.Rajanna et al, "Modulation of protein kinase C by heavy metals", Toxicol Lett, 1995, 81(2-3):197-203:

& A.Badou et al, "HgCl2-induced IL-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels", J Biol Chem. 1997 Dec 19;272(51):32411-8;

& D.B.Veprintsev, 1996, Institute for Biological Instrumentation, Russian Academy of Sciences, Pb2+ and Hg2+ binding to alpha-lactalbumin".Biochem Mol Biol Int 1996 Aug;39(6):1255-65

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This also has been found to result in inflamatory processes that cause muscle tissue damage and result in higher levels of urinary excretion of creatine , choline, and glycine in CFS, and higher levels of excretion of choline, taurine, citrate, and trimethyl amine oxide in FM.

Richards SCM, Bell J, Cheung, YL, Cleare A, Scott DL. Muscle metabolites detected in urine in FM and CFS suggest ongoing muscle damage. Conference Proceedings of the British Scociety of Rheumatologists, April

2001, Scotland, Abstract 382; http://freespace,virgin.net/david.axford/me_nb_o4.htm.

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The main factors determining whether chronic conditions are induced by metals appear to be exposure and genetic susceptability, which determines individuals immune sensitivity and ability to detoxify metals.

J Stejskal, V Stejskal. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999. www.melisa.org

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Mercury (especially mercury vapor) rapidly crosses the blood brain barrier and is stored in

brain, homonal organs, heart, liver, and kidneys.

Takahashi Y, Tsuruta S, Hasegawa J, Kameyama Y, Yoshida M. Release of mercury from dental amalgam fillings in pregnant rats and distribution of mercury in maternal and fetal tissues. Toxicology 2001 Jun 21;163(2-3):115-26

& J.A.Weiner et al,"The relationship between mercury concentration in human organs and predictor variables", Sci Tot Environ, 138(1-3):101-115,1993;

& Cornett CR, Ehmann WD, Wekstein DR, Markesbery WR. Trace elements in Alzheimer's disease pituitary glands. Biol Trace Elem Res. 1998 Apr-May;62(1-2):107-14.

& Omura Y, Shimotsuura Y, Fukuoka A, Fukuoka H, Nomoto T. Significant mercury deposits in internal organs following the removal of dental amalgam. Acupunct Electrother Res. 1996 Apr-Jun;21(2):133-60.

& World Health Organization(WHO),1991, Environmental Health Criteria 118, Inorganic Mercury, WHO, Geneva, Switzerland.

& Falnoga I, Tusek-Znidaric M, Horvat M, Stegnar P. Mercury, selenium, and cadmium in human autopsy samples from Idrija residents and mercury mine workers. Environ Res. 2000 Nov;84(3):211-8

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A direct mechinism involving mercury's inhibition of cellular enzymatic processes by binding with the hydroxyl radical(SH) in amino acids appears to be a major part of the connection to allergic/immune reactive conditions such as lupus and schleraderma; and atopic conditions such as eczema and psorisis.

Clinical tests of patients with chronic neurological conditions, Lupus(SLE), and rheumatoid arthritis have found that the patients generally have elevated plasma cysteine to sulphate ratios, with the average being 500% higher than controls, and in general being poor sulphur oxidizers. This means that these patients have insufficient sulfates available to carry out necessary bodily processes. Mercury has been shown to diminish and block sulphur oxidation and thus reducing glutathione levels which is the part of this process involved in detoxifying and excretion of toxics like mercury. Glutathione is produced through the sulphur oxidation side of this process. Low levels of available glutathione have been shown to increase mercury retention and increase toxic effects, while high levels of free cysteine have been demonstrated to make toxicity due to inorganic mercury more severe. Mercury has also been found to play a part in inducing intolerance and neuronal problems through blockage of the P-450 liver enzymatic process.

Wilkinson LJ, Waring RH. Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production. Toxicol In Vitro. 2002 Aug;16(4):481-3;

& C.Gordon et al, "Abnormal sulphur oxidation in systemic lupus erythrmatosus(SLE)", Lancet, 1992,339:8784,25-

& Overzet K, Gensler TJ, Kim SJ, Geiger ME, van Venrooij WJ, Pollard KM, Anderson P, Utz PJ. Small nucleolar RNP Scleroderma autoantigens associate with phosphorylated serine/arginine splicing factors during apoptosis. Arthritis Rheum 2000 Jun;43(6):1327-36

& Alberti A, Pirrone P, Elia M, Waring RH, Romano C. Sulphation deficit in "low-functioning" autistic children. Biol Psychiatry 1999, 46(3):420-4.

& Parronchi P, Brugnolo F, Sampognaro S, Maggi E. Genetic and Environmental Factors Contributing to the Onset of Allergic Disorders. Int Arch Allergy Immunol 2000 Jan;121(1):2-9.

& Markovich et al, "Heavy metals (Hg,Cd) inhibit the activity of the liver and kidney sulfate transporter Sat-1", Toxicol Appl Pharmacol, 1999,154(2):181-7;

& S.A. McFadden, "Xenobiotic metabolism and adverse environmental response: sulfur-dependent detox pathways",Toxicology, 1996, 111(1-3):43-65;

& Ionescu G. Schwermetallbelastung bei atopischer Dermatitis und Psoriasis. Biol Med 1996; 2:65-68.

& A.G.Riedl et al, Neurodegenerative Disease Research Center, King's College, UK, "P450 and hemeoxygenase enzymes in the basal ganglia and their role's in Parkinson's disease", Adv Neurol, 1999; 80:271-86;

& Lu SC, "Regulation of hepatic glutathione synthesis: current concepts and controversies"; FASEB J, 1999, 13(10):1169-83

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Mercury induced autoimmunity in animals and humans has been found to be associated with mercury's expression of major histocompatibility complex(MHC) class II genes. Mercury and other toxic metals also form inorganic compounds with OH, NH2, CL, in addition to the SH radical and thus inhibits many cellular enzyme processes, coenzymes, hormones, and blood cells. Mercury vapor or Inorganic mercury have been shown in animal studies to induce autoimmune reactions and disease through effects on immune system T cells. Chronic immune activation is common in CFS and FMS, with increase in activated CD8+ cytotoxic T-cells and decreased NK cells. One study found that insertion of amalgam fillings or nickel dental materials causes a supression of the number of T-lympocytes, and impairs the T-4/T-8 ratio. Low T4/T8 ratio has been found to be a factor in lupus, anemia, MS, eczema, inflamatory bowel disease, and glomerulonephritis.

M.A.Miller et al, "Mercuric chloride induces apoptosis in human T lymphocytes", Toxicol Appl Pharmacol, 153(2):250-7 1998;

& Rossi AD,Viviani B, Vahter M. Inorganic mercury modifies Ca2+ signals, triggers apoptosis, and potentiates NMDA toxicit in cerebral granule neurons. Cell Death and Differentiation 1997; 4(4):317-24.

& Goering PL, Thomas D, Rojko JL, Lucas AD. Mercuric chloride-induced apoptosis is dependent on protein synthesis. Toxicol Lett 1999; 105(3): 183-95;

& Bagenstose LM, Salgame P, Monestier M.. Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans., Immunol Res, 1999,20(1): 67-78;

& Kubicka-Muranyi M, Kremer J, Rottmann N, Lubben B, Albers R, Bloksma N, Luhrmann R, Gleichmann E. Murine systemic autoimmune disease induced by mercuric chloride: T helper cells reacting to self proteins. Int Arch Allergy Immunol. 1996 Jan;109(1):11-20.

& El-Fawai HA, Waterman SJ, De Feo A, Shamy MY. Neuroimmunotoxicology: Humoral Assesment of Neurotoxicity and Autoimmune Mechinisms. Contact Dermatitis 1999; 41(1): 60-1.

& Hu H; Moller G; Abedi-Valugerdi M. Mechanism of mercury-induced autoimmunity: both T helper 1- and T helper 2-type responses are involved. Immunology 1999 Mar;96(3):348-57;

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Mercury has been found to impair conversion of thyroid T4 hormone to the active T3 form as well as causing autoimmune thyroiditis common to such patients. In general, immune activation from toxic metals such as mercury resulting in cytokine release and abnormalities of the hypothalamus-pituitary-adrenal(HPA) axis can cause changes in the brain, hypocortisolism, fatigue, and severe psycholgical symtoms such as profound fatigue, muscosketal pain, sleep disturbances, gastrointestinal and neurological problems as are seen in CFS, fibromyalgia, and autoimmune thyroidititis. Such hypersensitivity has been found most common in those with genetic predisposition to heavy metal sensitivity, such as found more frequently in patients with human lymphocyte antingens (HLA-DRA) . A significant portions of the population appear to fall in this category.

Very low levels of exposure have been found to seriously affect relatively large groups of individuals who are immune sensitive to toxic metals, or have an inability to detoxify metals due to such as deficient sulfoxidation or metallothionein function or other inhibited enzymatic processes related to detoxification or excretion of metals. For those with chronic conditions, fatigue regardless of the underlying disease is primarily associated with hypersensitivity to inorganic and organic mercury, nickel, and gold. When tested for immune reactivity using a test like the blood lymphocyte immune reactivity test(MELISA) to determine the cause, the majority with mercury sensitivity recover when amalgam is replaced and system mercury levels are reduced. (similar for other sensitivities)

Stejskal VD, Forsbeck M, Cederbrant KE, Asteman O. l, "Mercury-specific Lymphocytes: an indication of mercury allergy in man", J. Of Clinical Immunology, 1996, Vol 16(1);31-40.

& Sterzl I, Prochazkova J, Stejaskal VDM et al, Mercury and nickel allergy: risk facotrs in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228.

& Stejskal VDM, Danersund A, Lindvall A. Metal-specific memory lympocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters 1999.

& Sterzl I, Fucikova T, Zamrazil V. The fatigue syndrome in autoimmune thyroiditis with Polyglanular activation of autoimmunity. Vnitrni Lekarstvi 1998; 44: 456-60;

& Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31

& J Stejskal, V Stejskal. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999.

& Saito K. Analysis of a genetic factor of metal allergy-polymorphism of HLA-DR-DO gene. Kokubyo Gakkai Zasschi 1996; 63: 53-69;

& Prochazkova J, Ivaskova E, Bartova J, Stejskal VDM. Immunogentic findings in patients with altered tolerance to heavy metals. Eur J Human Genet 1998; 6: 175.

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Mercury exposure through dental fillings appears to be a major factor in chronic fatigue syndrome(CFS) through its effects on ATP and immune system(lymphocute reactivity, neutraphil activity, effects on T-cells and B-cells) as well as its promotion of growth of candida albicans in the body and the methylation of inorganic mercury by candida and intestional bacteria to the extremely toxic methyl mercury form, which like mercury vapor crosses the blood-brain barrier, and also damages and weakens the immune system .

Previous references and:

Pollard KM, Pearson Dl, Hultman P. Lupus-prone mice as model to study xenobiotic-induced autoimmunity. Envriron Health Perspect 1999; 107(Suppl 5): 729-735..

& S. Yannai et al, "Transformations of inorganic mercury by candida albicans and saccharomyces cerevisiae", Applied Envir Microbiology,1991, 7:245-247;

& K.Lohmann et al, "Multiple Chemical Sensitivity Disorder in patients with neuroltoxic illnesses", Gesundheitswesen, 1996, 58(6):322-31.

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Mercury lymphocyte reactivity, effects on glutamate in the CNS, and mercury induced hypothyroidism induce CFS type symptoms including profound tiredness, musculoskeletal pain, sleep distubances, gastrointestinal and neurological problems along with other CFS symptoms and fibromyalgia. Mercury has been found to be a common cause of fibromyalgia. Glutamate is the most abundant amino acid in the body and in the CNS acts as excitory neurotransmitter, which also causes inflow of calcium. Astrocytes, a type of cell in the brain and CNS with the task of keeping clean the area around nerve cells and facilitating neurotransmission, have a function of neutralizing excess glutamate by transforming it to glutamic acid. If astrocytes are not able to rapidly neutralize excess glutamate, then a buildup of glutamate and calcium occurs, causing swelling and neurotoxic effects . Mercury and other toxic metals inhibit astrocyte function in the brain and CNS, causing increased glutamate and calcium related neurotoxicity which are responsible for much of the fibromylgia symptoms. This is also a factor in conditions such as CFS, Parkinson's, and ALS. Animal studies have confirmed that increased levels of glutamate(or aspartate, another amino acid excitory neurotransmitter) cause increased sensitivity to pain , as well as higher body temperature- both found in CFS/fibromyalgia. Mercury and increased glutamate activate free radical forming processes like xanthine oxidase which produce oxygen radicals and oxidative neurological damage.

S.Hussain et al, "Mercuric chloride-induced reactive oxygen species and its effect on antioxidant enzymes in different regions of rat brain",J Environ Sci Health B 1997 ; 32(3):395-409;

& S.Tan et al, "Oxidative stress induces programmed cell death in nueronal cells", J Neurochem, 1998, 71(1):95-105.

& P.Bulat, "Activity of Gpx and SOD in workers occupationally exposed to mercury", Arch Occup Environ Health, 1998, Sept, 71 Suppl:S37-9;

& A.J.Freitas et al, "Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in the rat brain", Brain Research, 1996, 738(2): 257-64;

& P.R.Yallapragoda et al,"Inhibition of calcium transport by Hg salts" in rat cerebellum and

cerebral cortex", J Appl toxicol, 1996, 164(4): 325-30;

& Ariza ME; Bijur GN; Williams MV. Lead and mercury mutagenesis: role of H2O2, superoxide dismutase, and xanthine oxidase. Environ Mol Mutagen 1998;31(4):352-61

& Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphoctes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999; 20: 289-298.

& Hanson S, Fibromyalgia, glutamate, and mercury. Heavy Metal Bulletin, Issue 4, 1999, p3-6.

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Hisatome I, Kurata Y, et al; Block of sodium channels by divalent mercury: role of specific cysteinyl residues in the P-loop region. Biophys J. 2000 Sep;79(3):1336-45; & Bhattacharya S, Sen S et al, Specific binding of inorganic mercury to Na(+)-K(+)-ATPase in rat liver plasma membrane and signal transduction. Biometals. 1997 Jul;10(3):157-62; & Wagner CA, Waldegger S,et al; Heavy metals inhibit Pi-induced currents through human brush-border NaPi-3 cotransporter in Xenopus oocytes.. Am J Physiol. 1996 Oct;271(4 Pt 2):F926-30

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Studies have found that in CFS, Myalgic, Lupus, and Rheumetoid Arthritis cases there was an a reduction in serum magnesium and RBC membrane Na(+)-K+ ATPase activity and elevation in plasma serum digoxin (263). The activity of some of the free-radical scavenging enzymes, concentration of glutathione, decreased significantly in these conditions, while the concentration of serum lipid peroxidation products and nitric oxide increased. The inhibition of Na+-K+ ATPase can thus result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction. It is documented in this paper that mercury is a cause of most of these conditions.

Kumar AR, Kurup PA. Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders. J Assoc Physicians India. 2002 Mar;50:400-6;

& Kurup RK, Kurup PA. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. Int J Neurosci. 2003 May;113(5):683-701,

& (c) Kurup RK, Kurup PA. Hypothalamic digoxin, hemispheric dominance, and neuroimmune integration. Int J Neurosci. 2002 Apr;112(4):441-62;

& (d) Kurup RK, Kurup PA, Hypothalamic digoxin and hemispheric chemical dominance--relation to the pathogenesis of senile osteoporosis, degenerative osteoarthritis, and spondylosis. Int J Neurosci. 2003 Mar;113(3):341-59.

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Mercury from amalgam interferes with production of cytokines that activate macrophage and neutraphils, disabling early control of viruses and leading to enhanced infection. Animal studies have confirmed that mercury increases effects of the herpes simplex virus type 2 for example. Mercury damages the immune system and in those with chronic conditons has been found to commonly facilitate infestation by pathogens such as viruses, harmful bacteria, mycoplasma, candida, and parasites. The majority of those tested who have CFS or FMS have been found to have infections of mycoplasma, Human Herpes Virus-6, Cytomeglivirus, or bacterial infections such as intracellular chlamydia.. Clinics treating these conditions commonly find such pathogens to be a factor in the condition. Mercury detoxification and treatment of these pathogens results in significant improvement in the majority of those treated. Of one group of 86 patients with CFS symptoms, 78% reported significant health improvements after replacement of amalgam fillings within a relatively short period, and the MELISA immune reactivity test found significant reduction in lymphocyte reactivity compared to pre removal tests.

Christensen MM, Ellermann-Eriksen S, Mogensen SC. Influence of mercury chloride on resistance to generalized infection with herpes simplex virus type 2 in mice. Toxicology 1996, 114(1): 57-66;

& Y.Omura et al, Heart Disease Research Foundation, NY,NY, "Role of mercury in resistant infections and recovery after Hg detox with cilantro", Acupuncture & Electro-Therapeutics Research, 20(3):195-229, 1995;

& M. E. Godfrey, Candida, Dysbiosis and Amalgam. J. Adv. Med. vol 9 no 2 (1996);

& Romani L, Immunity to Candida Albicans: Th1,Th2 cells and beyond. Curr Opin Microbiol 1999, 2(4):363-7

& Dr. G. Nicholson, Institute for Molecular Medicine, New Treatments for Chronic Infections Found in Fibromyalgia Syndrome, Chronic Fatigue Syndrome, Rheumatoid Arthritis, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Gulf War Illnesses, www.immed.org/reports/autoimmune_illness/rep1.html

& De Meirleir K, Bisbal C, Campine I, De Becker, et al. A 37 kDa 1-5A binding protein as a potential biochemical marker for CFS. Am J Med 2000, 108(2): 99-105

& Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphoctes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999; 20: 289-298.

& Stejskal VDM, Danersund A, Lindvall A.( MELISA), Metal-specific memory lympocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters 1999.

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Many thousands are documented(in another submission) to have recovered from all of these immune related conditions caused by mercury after amalgam replacement.

(see also: www.myflcv.com/hgremove.html)

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(extra abstracts)

Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica.

Cutolo M, Foppiani L, Minuto F.
J Endocrinol Invest. 2002;25(10 Suppl):19-23.

University of Genova, Genova, Italy. mcutolo@unige.it

Stressful/inflammatory conditions activate the immune system and subsequently the hypothalamic-pituitary-adrenal (HPA) axis through the central and peripheral production of cytokines such as IL-6 and TNF-alpha. A relative adrenal hypofunction, as evidenced by inappropriately normal F levels and reduced DHEAS levels, has been recently claimed to play a causative role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR). Thus, we evaluated baseline levels of adrenal androgens, IL-6 and IL-12 together with HPA axis challenge by ovine CRH and low-dose ACTH in premenopausal RA women and aged PMR women. In addition, adrenal steroids, IL-6, and acute-phase reactant levels were measured at baseline and during 12 months of glucocorticoid tapering regimen in a cohort of PMR patients. Reduced DHEAS levels (p<0.05) associated to increased (p<0.05) IL-6 and IL-12 levels were found in RA patients as compared to controls (C). Irrespective of the inflammatory condition, basal and stimulated cortisol levels in RA were similar to C, whereas DHEA secretion after ACTH testing was significantly (p<0.01) reduced. During HPA challenge, F responses in PMR patients proved inadequate in the setting of the inflammatory status, confirmed by increased IL-6 levels. In addition, these patients showed significantly (p<0.05) increased 17-hydroxyprogesterone (17-OHP) responses after ACTH testing as compared to C. The longitudinal study in PMR patients showed that glucocorticoid therapy leads to a stable reduction of IL-6 and of acute-phase reactant levels, which persist even after glucocorticoid tapering. Our data show an inadequate adrenal secretion in RA and PMR, both characterized by increased levels of HPA axis-stimulating cytokines. The reduced basal levels of DHEAS in RA might be ascribed to a reduced biosynthesis as consequence of a cytokine-induced impairment of P450 17.20-lyase activity. In PMR, the ACTH-induced enhanced 17-OHP levels suggest a partial age- and cytokine-induced impairment of the P450 21 beta-hydroxylase, which eventually leads to inadequate glucocorticoid production. The clinical and biochemical improvement observed after glucocorticoid therapy in patient with RA and PMR, might thus be attributed to a direct dampening of pro-inflammatory factors as well as to the restoration of the steroid milieu. Given its multifaceted properties, including the ability to counteract the negative side effects of glucocorticoids, the therapeutical administration of DHEA might be considered in these pathologies, provided its safety is proved.
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The role of neuroendocrine system in the pathogenesis of rheumatic diseases (minireview).

Imrich R.
Endocr Regul. 2002 Jun;36(2):95-106.

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Units of Rheumatology and Clinical Chemistry, Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden. sigridur.valtysdottir@medicin.uu.se

OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in women with primary Sjogren's syndrome (pSS). METHODS: In 10 women with pSS and 10 age matched female controls, we evaluated serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, growth hormone, sex hormone binding globulin, cortisol, and adrenocorticotropin hormone (ACTH), in both basal condition and after stimulation with corticotropin releasing hormone, thyrotropin releasing hormone, and luteinizing hormone releasing hormone intravenously. Patients had not previously been treated with glucocorticoids. RESULTS: Patients with pSS had significantly lower basal mean DHEA-S values compared with healthy controls (2.4 +/- 0.4 vs 3.9 +/- 0.3 mumol/l; p < 0.05) and significantly lower DHEA-S values after stimulation. The cortisol/DHEA-S ratio in the patient group was higher than in controls (171 +/- 39 vs 76 +/- 5; p < 0.05). A correlation was found between basal ACTH and DHEA-S values in the patients (r = 0.650; p = 0.05). No correlation was seen between disease activity or age and the serum concentration of DHEA-S. The levels of other hormones both at baseline and after stimulation were similar in patients and controls. CONCLUSION: The results show that women with pSS have intact cortisol synthesis but decreased serum concentrations of DHEA-S and increased cortisol/DHEA-S ratio compared with healthy controls. The findings may reflect a constitutional or disease mediated influence on adrenal steroid synthesis. The thyroid axis and gonadotropin secretion were similar in patients and controls.

[Autoimmune fatigue syndrome and fibromyalgia syndrome]

[Article in Japanese]

Itoh Y, Igarashi T, Tatsuma N, Imai T, Yoshida J, Tsuchiya M, Murakami M, Fukunaga Y.
Nippon Ika Daigaku Zasshi. 1999 Aug;66(4):239-44.

Department of Pediatrics, Nippon Medical School, Tokyo, Japan.

We have encounted two patients with fibromyalgia (FM) initially diagnosed as having autoimmune fatigue syndrome (AIFS). To investigate the relationship between AIFS and FM, the distribution of the tender points in patients with AIFS was assessed according to the ACR criteria for FM. It was revealed that AIFS patients had 5.6 tender points on averages. Patients with headaches, digestive problems, or difficulty going to school had more tender points than patients without. Patients with ANA titers < 1: 160 had more tender points than patients with ANA > or = 1: 160. Anti-Sa negative patients had more tender points than positive patients. These results suggest a relationship between AIFS and FM in terms of the pathophysiologic mechanisms of the numerous tender points. In other words, ANA-positive FM patients could be one form of AIFS, as well as ANA-positive chronic fatigue syndrome patients. Thus, autoimmunity could explain the controversial disease entities of FM and/or CFS.

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IV. 5. Alzheimer's

Alzheimer's Disease and mercury.

The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Maccioni RB, Munoz JP, Barbeito L.. Arch Med Res. 2001 Sep-Oct;32(5):367-81.

Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, Faculty of Sciences, University of Chile, Santiago, Chile. rmaccion@uchile.cl

"Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death. Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the beta-amyloid peptide (Abeta), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). Experiments with hippocampal cells in culture have indicated a relationship between fibrillary amyloid and the cascade of molecular signals that trigger tau hyperphosphorylations. Two main protein kinases have been shown to be involved in anomalous tau phosphorylations: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3beta. Cdk5 plays a critical role in brain development and is associated with neurogenesis as revealed by studies in brain cells in culture and neuroblastoma cells. Deregulation of this protein kinase as induced by extracellular amyloid loading results in tau hyperphosphorylations, thus triggering a sequence of molecular events that lead to neuronal degeneration. Inhibitors of Cdk5 and GSK3beta and antisense oligonucleotides exert protection against neuronal death. On the other hand, there is cumulative evidence from studies in cultured brain cells and on brains that oxidative stress constitutes a main factor in the modification of normal signaling pathways in neuronal cells, leading to biochemical and structural abnormalities and neurodegeneration as related to the pathogenesis of Alzheimer's disease."

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Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain. Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL. Neurotoxicology. 1997;18(2):315-24

Department of Chemistry, University of Kentucky, Lexington 40506-0055, USA

"Hg2+ interacts with brain tubulin and disassembles microtubules that maintain neurite structure. Since it is well known that Hg vapor (Hg0) is continuously released from "silver" amalgam tooth fillings and is absorbed into brain, rats were exposed to Hg0 4h/day for 0, 2, 7, 14 and 28 d at 250 or 300 micrograms Hg/m3 air, concentrations present in mouth air of some humans with many amalgam fillings. Average rat brain Hg concentrations increased significantly (11-47 fold) with duration of Hg0 exposure. By 14 d Hg0 exposure, photoaffinity labelling on the beta-subunit of the tubulin dimer with [alpha 32P] 8N3 GTP in brain homogenates was decreased 41-74%, upon analysis of SDS-PAGE autoradiograms. The identical neurochemical lesion of similar or greater magnitude is evident in Alzheimer brain homogenates from approximately 80% of patients, when compared to human age-matched neurological controls. Total tubulin protein levels remained relatively unchanged between Hg0 exposed rat brains and controls, and between Alzheimer brains and controls. Since the rate of tubulin polymerization is dependent upon binding of GTP to tubulin dimers, we conclude that chronic inhalation of low-level Hg0 can inhibit polymerization of brain tubulin essential for formation of microtubules."

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Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Leong CC, Syed NI, Lorscheider FL. Neuroreport. 2001 Mar 26;12(4):733-7.

Faculty of Medicine, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.

"Inhalation of mercury vapor (Hg0) inhibits binding of GTP to rat brain tubulin, thereby inhibiting tubulin polymerization into microtubules. A similar molecular lesion has also been observed in 80% of brains from patients with Alzheimer disease (AD) compared to age-matched controls. However the precise site and mode of action of Hg ions remain illusive. Therefore, the present study examined whether Hg ions could affect membrane dynamics of neurite growth cone morphology and behavior. Since tubulin is a highly conserved cytoskeletal protein in both vertebrates and invertebrates, we hypothesized that growth cones from animal species could be highly susceptible to Hg ions. To test this possibility, the identified, large Pedal A (PeA) neurons from the central ring ganglia of the snail Lymnoea stagnalis were cultured for 48 h in 2 ml brain conditioned medium (CM). Following neurite outgrowth, metal chloride solution (2 microl) of Hg, Al, Pb, Cd, or Mn (10(-7) M) was pressure applied directly onto individual growth cones. Time-lapse images with inverted microscopy were acquired prior to, during, and after the metal ion exposure. We demonstrate that Hg ions markedly disrupted membrane structure and linear growth rates of imaged neurites in 77% of all nerve growth cones. When growth cones were stained with antibodies specific for both tubulin and actin, it was the tubulin/microtubule structure that disintegrated following Hg exposure. Moreover, some denuded neurites were also observed to form neurofibrillary aggregates. In contrast, growth cone exposure to other metal ions did not effect growth cone morphology, nor was their motility rate compromised. To determine the growth suppressive effects of Hg ions on neuronal sprouting, cells were cultured either in the presence or absence of Hg ions. We found that in the presence of Hg ions, neuronal somata failed to sprout, whereas other metalic ions did not effect growth patterns of cultured PeA cells. We conclude that this visual evidence and previous biochemical data strongly implicate Hg as a potential etiological factor in neurodegeneration."

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TNFa(tumor necrosis factor-alpha) is a cytokine that controls a wide range of immune cell response in mammals, including cell death(apoptosis). This process is involved in degenerative neurological conditions like MS, ALS, Parkinson's, etc. Cell signaling mechanisms like sphingolipids are part of the control mechansim for the TNFa apoptosis mechanism. Gluthathione is an amino acid that is a normal cellular mechanism for controlling apoptosis. When glutathione is depleted in the brain and CNS and cell signaling mechinsisms are disrupted by toxic exposures such as mercury, apoptosis results and neurological damage. The following are a sampling from peer-reviewed studies regarding this process.

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Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases.
Singh I, Pahan K, Khan M, Singh AK. J Biol Chem. 1998 Aug 7;273(32):20354-62.

Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA. singhi@musc.edu

The present study underlines the importance of reactive oxygen species in cytokine-mediated degradation of sphingomyelin (SM) to ceramide. Treatment of rat primary astrocytes with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta led to marked alteration in cellular redox (decrease in intracellular GSH) and rapid degradation of SM to ceramide. Interestingly, pretreatment of astrocytes with N-acetylcysteine (NAC), an antioxidant and efficient thiol source for glutathione, prevented cytokine-induced decrease in GSH and degradation of sphingomyelin to ceramide, whereas treatment of astrocytes with diamide, a thiol-depleting agent, alone caused degradation of SM to ceramide. Moreover, potent activation of SM hydrolysis and ceramide generation were observed by direct addition of an oxidant like hydrogen peroxide or a prooxidant like aminotriazole. Similar to NAC, pyrrolidinedithiocarbamate, another antioxidant, was also found to be a potent inhibitor of cytokine-induced degradation of SM to ceramide indicating that cytokine-induced hydrolysis of sphingomyelin is redox-sensitive. Besides astrocytes, NAC also blocked cytokine-mediated ceramide production in rat primary oligodendrocytes, microglia, and C6 glial cells. Inhibition of TNF-alpha- and diamide-mediated depletion of GSH, elevation of ceramide level, and DNA fragmentation (apoptosis) in primary oligodendrocytes by NAC, and observed depletion of GSH, elevation of ceramide level, and apoptosis in banked human brains from patients with neuroinflammatory diseases (e.g. X-adrenoleukodystrophy and multiple sclerosis) suggest that the intracellular level of GSH may play a critical role in the regulation of cytokine-induced generation of ceramide leading to apoptosis of brain cells in these diseases.
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Inhibition of phosphatidylinositol 3-kinase induces nitric-oxide synthase in lipopolysaccharide- or cytokine-stimulated C6 glial cells.
Pahan K, Raymond JR, Singh I. J. Biol. Chem. 274: 7528-7536, 1999.

Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

Nitric oxide (NO) produced by inducible nitric-oxide synthase (iNOS) in different cells including brain cells in response to proinflammatory cytokines plays an important role in the pathophysiology of demyelinating and neurodegenerative diseases. The present study underlines the importance of phosphatidylinositol 3-kinase (PI 3-kinase) in the expression of iNOS in C6 glial cells and rat primary astrocytes. Bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) was unable to induce the expression of iNOS and the production of NO in rat C6 glial cells. Similarly, wortmannin and LY294002, compounds that inhibit PI 3-kinase, were also unable to induce the expression of iNOS and the production of NO. However, a combination of wortmannin or LY294002 with LPS or IL-1beta induced the expression of iNOS and the production of NO in C6 glial cells. Consistent with the induction of iNOS, wortmannin also induced iNOS promoter-derived chloramphenicol acetyltransferase activity in LPS- or IL-1beta-treated C6 glial cells. The expression of iNOS by LPS in C6 glial cells expressing a dominant-negative mutant of p85alpha, the regulatory subunit of PI 3-kinase, further supports the conclusion that inhibition of PI 3-kinase provides a necessary signal for the induction of iNOS. Next we examined the effect of wortmannin on the activation of mitogen-activated protein (MAP) kinase and nuclear factor NF-kappaB in LPS- or IL-1beta-stimulated C6 glial cells. In contrast to the inability of LPS and IL-1beta alone to induce the expression of iNOS, both LPS and IL-1beta individually stimulated MAP kinase activity and induced DNA binding and transcriptional activity of NF-kappaB. Wortmannin alone was unable to activate MAP kinase and NF-kappaB. Moreover, wortmannin had no effect on LPS- or IL-1beta-mediated activation of MAP kinase and NF-kappaB, suggesting that wortmannin induced the expression of iNOS in LPS- or IL-1beta-stimulated C6 glial cells without modulating the activation of MAP kinase and NF-kappaB. Similar to C6 glial cells, wortmannin also stimulated LPS-mediated expression of iNOS and production of NO in astrocytes without affecting the LPS-mediated activation of NF-kappaB. Taken together, the results from specific chemical inhibitors and dominant-negative mutant expression studies demonstrate that apart from the activation of NF-kappaB, inhibition of PI 3-kinase is also necessary for the expression of iNOS and production of NO.
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Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death.
Xu J, Yeh CH, Chen S, He L, Sensi SL, Canzoniero LM, Choi DW, Hsu CY.
J Biol Chem. 1998 Jun 26;273(26):16521-6.
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Cytokines, including tumor necrosis factor-alpha (TNF-alpha), may elicit cytotoxic response through the sphingomyelin-ceramide signal transduction pathway by activation of sphingomyelinases and the subsequent release of ceramide: the universal lipid second messenger. Treatment of bovine cerebral endothelial cells (BCECs) with TNF-alpha for 16 h followed by cycloheximide (CHX) for 6 h resulted in an increase in ceramide accumulation, DNA fragmentation, and cell death. Application of a cell permeable ceramide analogue C2 ceramide, but not the biologically inactive C2 dihydroceramide, also induced DNA laddering and BCEC death in a concentration- and time-dependent manner. TNF-alpha/CHX-mediated ceramide production apparently is not a result of sphingomyelin hydrolysis because sphingomyelin content does not decrease in this death paradigm. In addition, an acidic sphingomyelinase inhibitor, desipramine, had no effect on TNF-alpha/CHX-induced cell death. However, addition of fumonisin B1, a selective ceramide synthase inhibitor, attenuated TNF-alpha/CHX-induced intracellular ceramide elevation and BCEC death. Together, these findings suggest that ceramide plays at least a partial role in this paradigm of BCEC death. Our results show, for the first time, that ceramide derived from de novo synthesis is an alternative mechanism to sphingomyelin hydrolysis in the BCEC death process initiated by TNF-alpha/CHX.
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Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death.
Dbaibo GS, El-Assaad W, Krikorian A, Liu B, Diab K, Idriss NZ, El-Sabban M, Driscoll TA, Perry DK, Hannun YA. FEBS Lett. 2001 Aug 10;503(1):7-12.

Department of Pediatrics, American University of Beirut, Lebanon. gdbaibo@aub.edu.lb

Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor alpha. When cells were pre-treated with glutathione, a proposed cellular regulator of neutral sphingomyelinase, inhibition of ceramide accumulation at early time points was achieved with attenuation of cell death. Inhibition of both pathways achieved near-complete inhibition of ceramide accumulation and cell death indicating that both pathways of ceramide generation are stimulated. This illustrates the complexity of ceramide generation in cytokine action.
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Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death.
Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA.
J Biol Chem. 1998 May 1;273(18):11313-20.

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Tumor necrosis factor-alpha (TNFalpha)-induced cell death involves a diverse array of mediators and regulators including proteases, reactive oxygen species, the sphingolipid ceramide, and Bcl-2. It is not known, however, if and how these components are connected. We have previously reported that GSH inhibits, in vitro, the neutral magnesium-dependent sphingomyelinase (N-SMase) from Molt-4 leukemia cells. In this study, GSH was found to reversibly inhibit the N-SMase from human mammary carcinoma MCF7 cells. Treatment of MCF7 cells with TNFalpha induced a marked decrease in the level of cellular GSH, which was accompanied by hydrolysis of sphingomyelin and generation of ceramide. Pretreatment of cells with GSH, GSH-methylester, or N-acetylcysteine, a precursor of GSH biosynthesis, inhibited the TNFalpha-induced sphingomyelin hydrolysis and ceramide generation as well as cell death. Furthermore, no significant changes in GSH levels were observed in MCF7 cells treated with either bacterial SMase or ceramide, and GSH did not protect cells from death induced by ceramide. Taken together, these results show that GSH depletion occurs upstream of activation of N-SMase in the TNFalpha signaling pathway. TNFalpha has been shown to activate at least two groups of caspases involved in the initiation and "execution" phases of apoptosis. Therefore, additional studies were conducted to determine the relationship of GSH and the death proteases. Evidence is provided to demonstrate that depletion of GSH is dependent on activity of interleukin-1beta-converting enzyme-like proteases but is upstream of the site of action of Bcl-2 and of the execution phase caspases. Taken together, these studies demonstrate a critical role for GSH in TNFalpha action and in connecting major components in the pathways leading to cell death.
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Hisatome I, Kurata Y, et al; Block of sodium channels by divalent mercury: role of specific cysteinyl residues in the P-loop region. Biophys J. 2000 Sep;79(3):1336-45;

& Bhattacharya S, Sen S et al, Specific binding of inorganic mercury to Na(+)-K(+)-ATPase in rat liver plasma membrane and signal transduction. Biometals. 1997 Jul;10(3):157-62;

& Anner BM, Moosmayer M, Imesch E. Mercury blocks Na-K-ATPase by a ligand-dependent and reversible mechanism. Am J Physiol. 1992 May;262(5 Pt 2):F830-6.

& Wagner CA, Waldegger S,et al; Heavy metals inhibit Pi-induced currents through human brush-border NaPi-3 cotransporter in Xenopus oocytes.. Am J Physiol. 1996 Oct;271(4 Pt 2):F926-30;

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Studies have found that in Alzheimer's cases there was a reduction in serum magnesium and RBC membrane Na(+)-K+ ATPase activity and an elevation in plasma serum digoxin (263). The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's, while the concentration of serum lipid peroxidation products and nitric oxide increased. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction. It is documented in this paper that mercury is a cause of most of these conditions seen in Alzheimer's .

Kumar AR, Kurup PA. Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders. J Assoc Physicians India. 2002 Mar;50:400-6;

& Kurup RK, Kurup PA. Hypothalamic digoxin, hemispheric chemical dominance, and Alzheimer's disease. Int J Neurosci. 2003 Mar;113(3):361-81.

Kumar SV, Maitra S, Bhattacharya S. In vitro binding of inorganic mercury to the plasma membrane of rat platelet affects Na+-K+-Atpase activity and platelet aggregation. Biometals. 2002 Mar;15(1):51-7.

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(Reactive oxygen species(ROS) and oxidative stress damage to neuronal cells by mercury)

Mercuric chloride-induced reactive oxygen species and its effect on antioxidant enzymes in different regions of rat brain.

Hussain S, Rodgers DA, Duhart HM, Ali SF. J Environ Sci Health B. 1997 May;32(3):395-409

Neurochemistry Laboratory, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA.

The present study was undertaken to determine if in vitro exposure to mercuric chloride produces reactive oxygen species (ROS) in the synaptosomes prepared from various regions of rat brain. The effects of in vivo exposure to mercury on antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in different regions of rat brain were also investigated. Adult male Sprague-Dawley (CD) rats were dosed with 0, 1, 2.0 or 4.0 mg HgCl2/kg body weight, for 7 days. One week after the last dose, animals were sacrificed by decapitation, their brains were removed and dissected and frozen in dry ice prior to measuring the activities of these enzymes. The results demonstrated that in vitro exposure to mercury produced a concentration-dependent increase of ROS in different regions of the rat brain. In vivo exposure to mercury produced a significant decrease of total SOD, Cu, Zn-SOD and Mn-SOD activities in the cerebellum of rats treated with different doses of mercury. SOD activity did not vary significantly in cerebral cortex and brain stem. GPx activity declined in a dose-dependent manner in the cerebellum with a significant reduction in animals receiving the 4 mg HgCl2/kg body weight. The activity of GPx increased in the brain stem while unchanged in the cerebral cortex. The results demonstrate that inorganic mercury decreased SOD activity significantly in the cerebellum while GPx activity was affected in both cerebellum and brain stem. Therefore, it can be concluded that oxidative stress may contribute to the development of neurodegenerative disorders caused by mercury intoxication.
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Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells.

Tan S, Wood M, Maher P.
J Neurochem. 1998 Jul;71(1):95-105

The Scripps Research Institute, La Jolla, California 92037, USA.

Oxidative stress is implicated in a number of neurological disorders including stroke, Parkinson's disease, and Alzheimer's disease. To study the effects of oxidative stress on neuronal cells, we have used an immortalized mouse hippocampal cell line (HT-22) that is particularly sensitive to glutamate. In these cells, glutamate competes for cystine uptake, leading to a reduction in glutathione and, ultimately, cell death. As it has been reported that protein kinase C activation inhibits glutamate toxicity in these cells and is also associated with the inhibition of apoptosis in other cell types, we asked if glutamate toxicity was via apoptosis. Morphologically, glutamate-treated cells underwent plasma membrane blebbing and cell shrinkage, but no DNA fragmentation was observed. At the ultrastructural level, there was damage to mitochondria and other organelles although the nuclei remained intact. Protein and RNA synthesis inhibitors as well as certain protease inhibitors protected the cells from glutamate toxicity. Both the macromolecular synthesis inhibitors and the protease inhibitors had to be added relatively soon after the addition of glutamate, suggesting that protein synthesis and protease activation are early and distinct steps in the cell death pathway. Thus, the oxidative stress brought about by treatment with glutamate initiates a series of events that lead to a form of cell death distinct from either necrosis or apoptosis.
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Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death.

Bains JS, Shaw CA. Brain Res Brain Res Rev. 1997 Dec;25(3):335-58.

Department of Ophthalmology, The University of British Columbia, Vancouver, Canada. jbains@unixg.ubc.ca

Oxidative stress has been implicated in both normal aging and in various neurodegenerative disorders and may be a common mechanism underlying various forms of cell death including necrosis, apoptosis, and excitotoxicity. In this review, we develop the hypothesis that oxidative stress-mediated neuronal loss may be initiated by a decline in the antioxidant molecule glutathione (GSH). GSH plays multiple roles in the nervous system including free radical scavenger, redox modulator of ionotropic receptor activity, and possible neurotransmitter. GSH depletion can enhance oxidative stress and may also increase the levels of excitotoxic molecules; both types of action can initiate cell death in distinct neuronal populations. Evidence for a role of oxidative stress and diminished GSH status is presented for Lou Gehrig's disease (ALS), Parkinson's disease, and Alzheimer's disease. Potential links to the Guamanian variant of these diseases (ALS-PD complex) are discussed. In context to the above, we provide a GSH-depletion model of neurodegenerative disorders, suggest experimental verifications of this model, and propose potential therapeutic approaches for preventing or halting these diseases.

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Mercury and oxidative stress, mitochondrial damage, etc.

Activity of glutathione peroxidase and superoxide dismutase in workers occupationally exposed to mercury.

Bulat P, Dujic I, Potkonjak B, Vidakovic A.

Institute of Occupational Health Dr Dragomir Karajovic, Belgrade, Yugoslavia.

According to previous research the lipid peroxidation process has a significant role in mercury toxicity. Since glutathione peroxidase (GPX) and superoxide dismutase (SOD) play a significant role in erythrocyte antioxidative defence, it is very important to determine their activity in occupationally exposed workers. The aim of this study was to assess the activity of antioxidative enzymes in the erythrocytes of workers occupationally exposed to mercury. We compared a group of 42 workers exposed to elemental mercury in a chloralkali plant (Hg group). The control group (C group) consisted of 75 subjects employed in lime production who had never been exposed to mercury or any toxic substance. The GPX activities in erythrocytes were significantly lower in the Hg group than in the control group (Hg group, 9.05 +/- 7.52 IU/gHb; C group 15.54 +/- 4.85 IU/gHb; p < 0.001). Also, SOD activity in the erythrocytes of workers occupationally exposed to mercury was significantly lower than in the control group (Hg group, 1280.7 +/- 132.3 IU/gHb; C group, 1377.9 +/- 207.5 IU/gHb; p < 0.006). The concentrations of mercury in blood were significantly higher in the Hg group compared to the control group (Hg group, 0.179 +/- 0.040 micromol/l; C group, 0.023 +/- 0.011 micromol/l; p < 0.001). On the basis of previous results, it can be concluded that occupational exposure to elemental mercury leads to increased lipid peroxidation in erythrocytes. Also, it can be postulated that this exposure leads to decreased activity of GPX and SOD in erythrocytes

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Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells.

Olivieri G, Brack C, Muller-Spahn F, Stahelin HB, Herrmann M, Renard P, Brockhaus M, Hock C. J Neurochem. 2000 Jan;74(1):231-6.

Neurobiology Laboratory, Psychiatric University Hospital, Basel, Switzerland. Olivieri@ubaclu.unibas.ch

Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p<0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD.

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The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion.

Olivieri G, Novakovic M, Savaskan E, Meier F, Baysang G, Brockhaus M, Muller-Spahn F.
Neuroscience. 2002;113(4):849-55.

Neurobiology Laboratory, Psychiatric University Hospital, CH-4025 Basel, Switzerland.

gianfranco.olivieri@pharma.novartis.com

The role of estrogen as a neurotrophic/neuroprotective agent in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is increasingly being shown. In this study we examine the neuroprotective effects of beta-estradiol on SHSY5Y neuroblastoma cells which have been exposed to the heavy metals cobalt and mercury. The results show that cobalt and mercury are able to induce oxidative stress and cell cytotoxicity and increase the secretion of beta-amyloid 1-40 and 1-42. These deleterious effects are reversed by the pretreatment of cells with beta-estradiol. It is further shown that beta-estradiol exerts its neuroprotective action through mechanisms which reduce oxidative stress and reduce beta-amyloid secretion. Pre-treatment of the cells with alpha-estradiol did not alleviate the toxic effects of the heavy metals. Our results are significant as they contribute to a better understanding of the mode of action of estrogen with relevance to its use in the treatment of neurodegenerative disorders

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Increased blood mercury levels in patients with Alzheimer's disease.

Hock C, Drasch G, Golombowski S, Muller-Spahn F, Willershausen-Zonnchen B, Schwarz P, Hock U, Growdon JH, Nitsch RM.
J Neural Transm. 1998;105(1):59-68.

Department of Psychiatry, University of Basel, Switzerland.

Alzheimer's disease (AD) is a common neurodegenerative disorder that leads to dementia and death. In addition to several genetic parameters, various environmental factors may influence the risk of getting AD. In order to test whether blood levels of the heavy metal mercury are increased in AD, we measured blood mercury concentrations in AD patients (n = 33), and compared them to age-matched control patients with major depression (MD) (n = 45), as well as to an additional control group of patients with various non-psychiatric disorders (n = 65). Blood mercury levels were more than two-fold higher in AD patients as compared to both control groups (p = 0.0005, and p = 0.0000, respectively). In early onset AD patients (n = 13), blood mercury levels were almost three-fold higher as compared to controls (p = 0.0002, and p = 0.0000, respectively). These increases were unrelated to the patients' dental status. Linear regression analysis of blood mercury concentrations and CSF levels of amyloid beta-peptide (A beta) revealed a significant correlation of these measures in AD patients (n = 15, r = 0.7440, p = 0.0015, Pearson type of correlation). These results demonstrate elevated blood levels of mercury in AD, and they suggest that this increase of mercury levels is associated with high CSF levels of A beta, whereas tau levels were unrelated. Possible explanations of increased blood mercury levels in AD include yet unidentified environmental sources or release from brain tissue with the advance in neuronal death.

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Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain.

Cornett CR, Markesbery WR, Ehmann WD.

Department of Chemistry, University of Kentucky, Lexington 40506-0055, USA.

Four elements that have been implicated in free-radical-induced oxidative stress in Alzheimer's disease (AD) were measured by instrumental neutron activation analysis (INAA) in seven brain regions from 58 AD patients and 21 control subjects. A statistically significant elevation of iron and zinc was observed in multiple regions of AD brain, compared with controls. Mercury was elevated in AD in most regions studied, but the high variability of mercury levels in both AD and control subjects prevented the AD-control difference from reaching significance. Selenium, a protective agent against mercury toxicity, was significantly elevated only in AD amygdala. The elevation of iron and zinc in AD brain has the potential of augmenting neuron degeneration through free radical processes.
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HgCl2-induced interleukin-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels.

Badou A, Savignac M, Moreau M, Leclerc C, Pasquier R, Druet P, Pelletier L.
J Biol Chem. 1997 Dec 19;272(51):32411-8.

INSERM Unite 28, Institut Federatif de Recherche 30, Hopital Purpan Place du Dr. Baylac, Toulouse 31059 cedex, France. Abdellah.Badou@purpan.inserm.fr

Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
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(Mercury inhibits sulfur metabolism resulting in neurologic and metabolic damage)

Heavy metals mercury, cadmium, and chromium inhibit the activity of the mammalian liver and kidney sulfate transporter sat-1.

Markovich D, James KM.

Department of Physiology and Pharmacology, University of Queensland, Brisbane, Queensland, 4072, Australia. danielm@plpk.uq.edu.au

Heavy metal intoxication leads to defects in cellular uptake mechanisms in the mammalian liver and kidney. We have studied the effects of several heavy metals, including mercury, lead, cadmium, and chromium (at concentrations of 1 to 1000 microM), on the activity of the mammalian sulfate transporter sat-1(2) in Xenopus oocytes. sat-1 encodes a sulfate/bicarbonate anion exchanger expressed in the rat liver and kidney. Mercury (10 microM) strongly inhibited sat-1 transport by reducing Vmax by eightfold but not its Km for inorganic sulfate (Si). Lead (up to 1 mM) was unable to significantly inhibit sat-1 transporter activity. Cadmium (500 microM) showed weak inhibition of sat-1 transport by decreasing only sat-1 Vmax. Chromium (100 microM) strongly inhibited sat-1 transport by reducing Km for Si by sevenfold, most probably by binding to the Si site, due to the strong structural similarity between the CrO2-4 and SO2-4 substrates. This study presents the first characterization of heavy metal inhibition of the hepatic and renal sulfate/bicarbonate transporter sat-1, through various mechanisms, which may lead to sulfaturia following heavy metal intoxication.

Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways.

McFadden SA.

Proper bodily response to environmental toxicants presumably requires proper function of the xenobiotic (foreign chemical) detoxification pathways. Links between phenotypic variations in xenobiotic metabolism and adverse environmental response have long been sought. Metabolism of the drug S-carboxymethyl-L-cysteine (SCMC) is polymorphous in the population, having a bimodal distribution of metabolites, 2.5% of the general population are thought to be nonmetabolizers. The researchers developing this data feel this implies a polymorphism in sulfoxidation of the amino acid cysteine to sulfate. While this interpretation is somewhat controversial, these metabolic differences reflected may have significant effects. Additionally, a significant number of individuals with environmental intolerance or chronic disease have impaired sulfation of phenolic xenobiotics. This impairment is demonstrated with the probe drug acetaminophen and is presumably due to starvation of the sulfotransferases for sulfate substrate. Reduced metabolism of SCMC has been found with increased frequency in individuals with several degenerative neurological and immunological conditions and drug intolerances, including Alzheimer's disease, Parkinson's disease, motor neuron disease, rheumatoid arthritis, and delayed food sensitivity. Impaired sulfation has been found in many of these conditions, and preliminary data suggests that it may be important in multiple chemical sensitivities and diet responsive autism. In addition, impaired sulfation may be relevant to intolerance of phenol, tyramine, and phenylic food constituents, and it may be a factor in the success of the Feingold diet. These studies indicate the need for the development of genetic and functional tests of xenobiotic metabolism as tools for further research in epidemiology and risk assessment.

Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production.

Wilkinson LJ, Waring RH.
Toxicol In Vitro. 2002 Aug;16(4):481-3.

School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.

Cysteine dioxygenase (CDO) is the initial and rate-limiting enzyme involved in the oxidative degradation of cysteine to inorganic sulphate. It is believed to be the major source of sulphate in vivo. Inflammatory conditions such as rheumatoid arthritis have been linked with high plasma cysteine:sulphate ratios in patients. The cytokines tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) have been shown to inhibit the expression of CDO in neuronal (TE671) and hepatic (Chang) human cell lines at nanomolar concentrations. Cytokine release may therefore modulate sulphate production and hence regulate formation of sulphated biocomponents.
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Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42.

Medina S, Martinez M, Hernanz A. Free Radic Res. 2002 Nov;36(11):1179-84.

Department of Clinical Biochemistry, Hospital Universitario La Paz, Castellana 261, 28046, Madrid, Spain.

Several substances related to the neurodegenerative diseases of Alzheimer and Parkinson, such as hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, have been shown to induce apoptosis in tumoral cell lines and rat neurons but not in human neurons. Moreover, the role of mitochondria (membrane potential) during neuronal apoptosis is still a matter of debate. We present here, for the first time, in cultured human cortical neurons that the DNA fragmentation induced by these substances was preceded by a decrease of the mitochondrial membrane potential. We have also examined the antiapoptotic effect of the antioxidants glutathione, N-acetyl-cysteine and ascorbic acid. All these antioxidants inhibited the apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, since they were able to inhibit completely the mitochondrial membrane potential depolarization and the DNA fragmentation.
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Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress.

Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea TB.
J Neurochem. 2001 Jul;78(2):249-53.

Center for Cellular Neurobiology and Neurodegeneration Research and Department of Biochemistry, University of Massachusetts-Lowell, Lowell, Massachusetts 01854, USA.

The cause of neuronal degeneration in Alzheimer's disease (AD) has not been completely clarified, but has been variously attributed to increases in cytosolic calcium and increased generation of reactive oxygen species (ROS). The beta-amyloid fragment (Abeta) of the amyloid precursor protein induces calcium influx, ROS and apoptosis. Homocysteine (HC), a neurotoxic amino acid that accumulates in neurological disorders including AD, also induces calcium influx and oxidative stress, which has been shown to enhance neuronal excitotoxicity, leading to apoptosis. We examined the possibility that HC may augment Abeta neurotoxicity. HC potentiated the Abeta-induced increase in cytosolic calcium and apoptosis in differentiated SH-SY-5Y human neuroblastoma cells. The antioxidant vitamin E and the glutathione precursor N-acetyl-L-cysteine blocked apoptosis following cotreatment with HC and Abeta, indicating that apoptosis is associated with oxidative stress. These findings underscore that moderate accumulation of excitotoxins at concentrations that alone do not appear to initiate adverse events may enhance the effects of other factors known to cause neurodegeneration such as Abeta.

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(see neurolgical effects of mercury in neurodegenrative diseases- separately submitted)

Sulfate metabolism is abnormal in patients with rheumatoid arthritis. Confirmation by in vivo biochemical findings.

Bradley H, Gough A, Sokhi RS, Hassell A, Waring R, Emery P.
J Rheumatol. 1994 Jul;21(7):1192-6.

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EMF causes increased mercury exposure in those with amalgam and neurological effects.

(38) F.Schmidt et al, "Mercury in urine of employees exposed to magnetic fields", Tidsskr Nor Laegeforen, 1997, 117(2): 199-202;

& Sheppard AR and EisenbudM., Biological Effects of electric and magnetic fields of extremely low frequency. New York university press. 1977; & Ortendahl T W, Hogstedt P, Holland RP, "Mercury vapor release from dental amalgam in vitro caused by magnetic fields generated by CRT's", Swed Dent J 1991 p 31 Abstract ;

& (d)Omura, Yoshiaki; Abnormal Deposits of Al, Pb, and Hg in the Brain, Particularly in the Hippocampus, as One of the Main Causes of Decreased Cerebral Acetylcholine, Electromagnetic Field Hypersensitivity, Pre-Alzheimer's Disease, and Autism in Children; Acupuncture & Electro-Therapeutics Research, 2000, Vol. 25 Issue 3/4, p230, 3p

(39) Savitz DA; Checkoway H; Loomis DP. Magnetic field exposure and neurodegenerative disease mortality among electric utility workers. Epidemiology 1998 Jul;9(4):398-404;

& Savitz DA; Loomis DP; Tse CK. Electrical occupations and neurodegenerative disease: analysis of U.S. mortality data.Arch Environ Health 1998 Jan-Feb;53(1):71-4; & Johansen C; Olsen JH. Mortality from amyotrophic lateral sclerosis, other chronic disorders, and electric shocks among utility workers.Am J Epidemiol 1998 Aug 15;148(4):362-8; & Davanipour Z; Sobel E; Bowman JD; Qian Z; Will AD. Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields. Bioelectromagnetics 1997;18(1):28-35.

(40) Sobel E; Dunn M; Davanipour Z; Qian Z; Chui HC. Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure. Neurology 1996 ;47(6):1477-81;

& Sobel E, Davanipour Z. Electromagnetic field exposure may cause increased production of amyloid beta and eventually lead to Alzheimer's disease. Neurology. 1996 Dec;47(6):1594-600;

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(full reference and abstracts for most of these sent in paper on Parkinson's)

More documentation(see above) that mercury causes oxidative stress and induces inflamatory cytokines and is highly neurotoxic through affects on calcium homeostasis.

(43) A.Badou et al, "HgCl2-induced IL-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels", 1997 Dec 19;272(51):32411-8

& D.B.Veprintsev, 1996, Institute for Biological Instrumentation, Russian Academy of Sciences, Pb2+ and Hg2+ binding to alpha-lactalbumin".Biochem Mol Biol Int 1996 Aug;39(6):1255-65

& Knapp LT; Klann E. Superoxide-induced stimulation of protein kinase C via thiol modification and modulation of zinc content. J Biol Chem 2000 May 22;

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Documentation Alzheimer's is caused by oxidative stress and neuron cell apoptosis

(56) X.M.Shen et al, Neurolbehavioral effects of NAC conjugates of dopamine: possible relevance for Parkinson's Disease", Chem Res Toxicol, 1996, 9(7):1117-26;

& Chem Res Toxicol, 1998, 11(7):824-37;

& A.Nicole et al, "Direct evidence for glutathione as mediator of apoptsosis in neuronal cells", Biomed Pharmacother, 1998; 52(9):349-55;

& J.P.Spencer et al, "Cysteine & GSH in PD", mechinsms involving ROS", J Neurochem, 1998, 71(5):2112-22:

& P.Jenner,"Oxidative mechanisms in PD", Mov Disord, 1998; 13(Supp1):24-34;

& D. Offen et al, "Use of thiols in treatment of PD", Exp Neurol, 1996,141(1):32-9;

& A.D.Owen et al, Ann NY Acad Sci, 1996, 786:217-33;

& JJ Heales et al, Neurochem Res, 1996, 21(1):35-39.

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Mercury levels in patients with Alzheimer's

(one doesn't have to have more than those without Alz, part susceptability)

(66) Hock et al, "Increased blood mercury levels in Alzheimer's patients", Neural. Transm. 1998, 105:59-68 & Cornett et al, "Imbalances of trace elements related to oxidative damage in Alzheimer's diseased brain", Neurotoxicolgy,1998, 19:339-345.

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More neurological effects of Mercury

(111) D.Quig, Doctors Data Lab,"Cysteine metabolism and metal toxicity", Altern Med Rev, 1998;3:4, p262-270,

&D.Jay, "Glutathione inhibits SOD activity of Hg", Arch Inst cardiol Mex, 1998,68(6):457-61

; & Pocernich CB, Cardin AL, Racine CL, Lauderback CM, Allan Butterfield D. Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease. Neurochem Int 2001 Aug;39(2):141-9;

(114) M.Aschner et al, "Metallothioein induction in fetal rat brain by in utero exposure to elemental mercury

vapor", Brain Research, 1997, dec 5, 778(1):222-32;

& Boot JH. Effects of SH-blocking compounds on the energy metablolism in isolated rat hepatocytes. Cell Struct Funct 1995; 20(3): 233-8.

(122) B.Ono et al, "Reduced tyrosine uptake in strains sensitive to inorganic mercury", Genet, 1987,11(5):399-

(166) H.Basun et al, J Neural Transm Park Dis Dement Sect, "Metals in plasma and cerebrospinal fluid in normal

aging and Alzheimer's disease",1991,3(4):231-58.

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Mixed metals in amalgam cause galvanic currents that transport mercury into the body and cause adverse effects.

(192) J. Bergdahl, A.J.Certosimo et al, National Naval Dental Center, "Oral Electricity", Gen Dent, 1996, 44(4):324-6;

Mercury effects on liver and kidneys

(194) Lu SC, FASEB J, 1999, 13(10):1169-83, "Regulation of hepatic glutathione synthesis: current concepts and controversies";

& R.B. Parsons, J Hepatol, 1998, 29(4):595-602;

& R.K.Zalups et al,"Nephrotoxicity of inorganic mercury co-administered with L-cysteine", Toxicology, 1996, 109(1): 15-29.

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Mercury causes lesions seen in Alzheimer's

(207) "Mercury Vapor Inhaltion Inhibits Binding of GTP ...-Similarity to Lesions in Alzheimers Diseased Brains", Neurotoxicology 1997, 18(2)::315-24; & Met Ions Biol Syst, 1997, 34:461-,

Health standards for mercury and summary of adverse health effects

(217) Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, Toxicological Profile for Mercury , 1999;

& Apr 19,1999 Media Advisory, New MRLs for toxic substances, MRL:elemental mercury vapor/inhalation/chronic & MRL: methy mercury/ oral/acute; & http://www.atsdr.cdc.gov/mrls.html

(276) ATSDR/EPA Priority List for 1999: Top 20 Hazardous Substances, Agency for Toxic Substances and Disease Registry,U.S. Department of Health and Human Services, http://www.atsdr.cdc.gov/99list.html;

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Mercury causes autoimmunity and autoimmune conditions

(234) P.E. Bigazzi, "Autoimmunity and Heavy Metals", Lupus, 1994; 3: 449-453; & Pollard KM, Pearson Dl, Hultman P. Lupus-prone mice as model to study xenobiotic-induced autoimmunity. Envriron Health Perspect 1999; 107(Suppl 5): 729-735;

& Nielsen JB; Hultman P. Experimental studies on genetically determined susceptibility to mercury-induced autoimmune response. Ren Fail 1999 May-Jul;21(3-4):343-8;

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(257) I. Smith et al, "Pteridines and mono-amines: relevance to neurological damage", Postgrad Med J, 62(724): 113-123, 1986; & A.D.Kay et al, "Cerebrospinal fluid biopterin is decreased in Alzheimer's disease", Arch Neurol, 43(10): 996-9, Oct 1986;

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Good review paper regarding mercury connection to Alzheimer's

(258) Ely, J.T.A., Mercury Induced Alzheimer's Disease: Accelerating Incicdence?, Bull Environ Contam Toxicol,

2001, 67: 800-6.

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Lithium protects against mercury induced neurotoxicity

(280)S.Nonaka et al, Nat. Inst. of Mental Health, Bethesda Md., "Lithium treatment protects neurons in CNS from glutamate induced excitibility and calcium influx", Neurobiology, Vol 95(5):2642-2647, Mar 3, 1998;

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Sulfur metabolism blocked in chronic neurological conditions; that mercury causes shown elsewhere

(330)Wilkinson LJ, Waring RH. Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production. Toxicol In Vitro. 2002 Aug;16(4):481-3;

(331) A.Pean et al, "Pathways of cysteine metabolism in MND/ALS", J neurol Sci, 1994, 124, Suppl:59-61.

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Mercury disrupts calcium homeostasis

(333) A.J.Freitas et al, "Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in the rat brain", Brain Research, 1996, 738(2): 257-64;

& P.R.Yallapragoda et al,"Inhibition of calcium transport by Hg salts" in rat cerebellum and cerebral cortex", J Appl toxicol, 1996, 164(4): 325-30;

& Szucs A, Angiello C, Salanki J, Carperter D; Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons.Cell Mol Neurobiol, 1997,17(3): 273-8;

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Mercury and fibromyalgia

(346) Clauw DJ, "The pathogenesis of chronic pain and fatigue syndroms: fibromyalgia" Med Hypothesis, 1995, 44:369-78; & Hanson S, Fibromyalgia, glutamate, and mercury. Heavy Metal Bulletin, Issue 4, 1999,

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Mercury causes chronic autoimmune conditions

(368) Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphoctes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999. www.melisa.org

(405) Jenny Stejskal, Vera Stejskal. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999.

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Neurological effects of mercury

(372) Atchison WD. Effects of neurotoxicants on synaptic transmission. Neuroltoxicol Teratol 1998, 10(5):393- 416;

& Sidransky H, Verney E, Influence of lead acetate and selected metal salts on tryptophan binding to rat hepatic nuclei. Toxicol Pathol 1999, 27(4):441-7;

(424) Munch G; Gerlach M; Sian J; Wong A; Riederer P. Advanced glycation end products in neurodegeneration: more than early markers of oxidative stress? Ann Neurol 1998 Sep;44(3 Suppl 1):S85-8.

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Mercury induces autoimmune condition

(425) Hu H; Abedi-Valugerdi M; Moller G. Pretreatment of lymphocytes with mercury in vitro induces a response in T cells from genetically determined low-responders and a shift of the interleukin profile. Immunology 1997 Feb;90(2):198-204;

& Hu H; Moller G; Abedi-Valugerdi M. Major histocompatibility complex class II antigens are required for both cytokine production and proliferation induced by mercuric chloride in vitro. J Autoimmun 1997 Oct;10(5):441-6;

& Hu H; Moller G; Abedi-Valugerdi M. Mechanism of mercury-induced autoimmunity: both T helper 1- and T helper 2-type responses are involved. Immunology 1999 Mar;96(3):348-57.

(426) Hultman P, Nielsen JB. The effect of toxicokinetics on murine mercury-induced autoimmunity. Environ Res 1998, 77(2): 141-8.

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Major factors in susceptability to mercury(affects ability to excrete/detox mercury)

(437) Amer. College of Medical Genetics Working Group on ApoE and Alzheimer's, JAMA, 1995,274:1627-29

442) Kasarskis EJ(MD), Metallothionein in ALS Motor Neurons(IRB #91-22026), FEDRIP DATABASE, NATIONAL TECHNICAL INFORMATION SERVICE(NTIS), ID: FEDRIP/1999/07802766.

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(443) Troy CM, Shelanski ML. Down-regulation of copper/zinc superoxide dismutase causes apototic dealth in PC12 neuronal cells. Proc. National Acad Sci, USA, 1994, 91(14):6384-7;

& Rothstein JD, Dristol LA, Hosier B, Brown RH, Kunci RW. Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Proc Nat Acad Sci,USA, 1994, 91(10):4155-9.

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Autoimmune conditions(with mercury a factor in most) a leading cause of death

(450) Dr. S J Walsh and L M Rau, University of Connecticut Health Center, "Autoimmune Disease Overlooked as a Leading Cause of Death in Women. Am J Public Health 2000;90:1463-1466.

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Mercury causes apoptosis(nerve cell death)

(462) Olivieri G; Brack C; Muller-Spahn F; Stahelin HB; Herrmann M; Renard P; Brockhaus M; Hock C. Mercury induced cell cytotoxicity and oxidative stress and increased beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem 2000 Jan;74(1):231-6;

& Leong,CW, Syed,NI, Lorscheider,FL; "Retrograde Degeneration of Neurite Membrane Structural Integrity of Nerve Growth Cones Following In Vitro Exposure to Mercury", NeuroReport, 12(4): 7333-737,2001.

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Treatment clinic with success

(469)BrainRecovery.com, the book, by David Perlmutter MD; Perlmutter Health Center, Naples, Florida, www.perlhealth.com/about.htm

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aluminum can cause Alzheimer's

(470) V Rondeau, D Commenges, H Jacqmin-Gadda and JF Dartigues, . Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study. American Journal of Epidemiology, Vol 152, Issue 1 59-66 ??

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several flu shots give much higher likelihood of Alzheimer's- mercury

(475) Hugh Fudenberg, MD, paper: NVIC International Vaccine Conference, Arlington, VA September, 1997. (http://members.aol.com/nitrf) (Mercury from flu shots big factor in Alzheimer's)

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A Mechanism by which mercury caues Alzheimer's

(488) Huang X; Cuajungco MP et al; Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 1999 Dec 24;274(52):37111-6

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(489) Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis 1999 Aug;6(4):221-30;

& © Estevez AG,Beckman JS et al, Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismustase. Science 1999 Dec 24;286(5449):2498-500;

& (d) Cookson MR, Shaw PJ. Oxidative stress and motor neurons disease. Brain Pathol 1999 Jan;9(1):165-86.

& (477) Lars Landner and Lennart Lindestrom. Swedish Environmental Research Group(MFG), Copper in society and the Environment, 2nd revised edition. 1999.

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(494) (a)Kobayashi MS, Han D, Packer L. Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res 2000 Feb;32(2):115-24(PMID: 10653482;

& Bridi R, Crossetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res 2001 Aug;15(5):449-51;

& Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997;22(1-2):359-78(PMID: 8958163);

& (b)Whiteman M, Tritschler H, Halliwell B. Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase inactivation by oxidized and reduced lipoic acid. FEBS Lett 1996 Jan 22;379(1):74- 6(PMID: 8566234);

& © "Decreased phagocytosis of myelin by macrophages with ALA. Journal of Neuroimmunology 1998, 92:67- 75; & (d) & Z.Gregus et al, "Effect of lipoic acid on biliary excretion of glutathione and metals", Toxicol APPl Pharmacol, 1992, 114(1):88-96;

& (e) Li Y, Liu L, Barger SW, Mrak RE, Griffin WS. Vitamin E suppression of microglial activation is neuroprotective. J Neurosci Res 2001 Oct 15;66(2):163-70

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copper (note amalgam is largest source of excess copper in most)

(495) Kang JH, Eum WS. Enhanced oxidative damage by the familial amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismustase mutants. Biochem Biophys Acta 2000 Dec 15;1524(2-3):162-70;

& (b) JH, Eum WS. Enhanced oxidative damage by the familial amyotrophic lateral sclerosis- associated Cu,Zn-superoxide dismustase mutants. Biochem Biophys Acta 2000 Dec 15; 1524(2-3): 162-70;

&(d) Wong PC, Gitlin JD; et al, Copper chaperone for superoxide dismustase is essential to activate mammalian Cu/Zn superoxide dismustase. Proc Natl Acad Sci U S A 2000 Mar 14;97(6):2886-91;

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(496) Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999 Mar;81(3):163-221;

& Urushitani M, Shimohama S. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J Neurosci Res 2001 Mar 1;63(5):377-87;

& Cookson MR, Shaw PJ. Oxidative stress and motor neurons disease. Brain Pathol 1999 Jan;9(1):165-86

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For more detailed review, see www.myflcv.com/alzhg.html

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IV. 7. Multiple Sclerosis

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Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases.

Singh I, Pahan K, Khan M, Singh AK. J Biol Chem. 1998 Aug 7;273(32):20354-62.

Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA. singhi@musc.edu

The present study underlines the importance of reactive oxygen species in cytokine-mediated degradation of sphingomyelin (SM) to ceramide. Treatment of rat primary astrocytes with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta led to marked alteration in cellular redox (decrease in intracellular GSH) and rapid degradation of SM to ceramide. Interestingly, pretreatment of astrocytes with N-acetylcysteine (NAC), an antioxidant and efficient thiol source for glutathione, prevented cytokine-induced decrease in GSH and degradation of sphingomyelin to ceramide, whereas treatment of astrocytes with diamide, a thiol-depleting agent, alone caused degradation of SM to ceramide. Moreover, potent activation of SM hydrolysis and ceramide generation were observed by direct addition of an oxidant like hydrogen peroxide or a prooxidant like aminotriazole. Similar to NAC, pyrrolidinedithiocarbamate, another antioxidant, was also found to be a potent inhibitor of cytokine-induced degradation of SM to ceramide indicating that cytokine-induced hydrolysis of sphingomyelin is redox-sensitive. Besides astrocytes, NAC also blocked cytokine-mediated ceramide production in rat primary oligodendrocytes, microglia, and C6 glial cells. Inhibition of TNF-alpha- and diamide-mediated depletion of GSH, elevation of ceramide level, and DNA fragmentation (apoptosis) in primary oligodendrocytes by NAC, and observed depletion of GSH, elevation of ceramide level, and apoptosis in banked human brains from patients with neuroinflammatory diseases (e.g. X-adrenoleukodystrophy and multiple sclerosis) suggest that the intracellular level of GSH may play a critical role in the regulation of cytokine-induced generation of ceramide leading to apoptosis of brain cells in these diseases.
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Inhibition of phosphatidylinositol 3-kinase induces nitric-oxide synthase in lipopolysaccharide- or cytokine-stimulated C6 glial cells.

Pahan K, Raymond JR, Singh I.
J. Biol. Chem. 274: 7528-7536, 1999.

Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

Nitric oxide (NO) produced by inducible nitric-oxide synthase (iNOS) in different cells including brain cells in response to proinflammatory cytokines plays an important role in the pathophysiology of demyelinating and neurodegenerative diseases. The present study underlines the importance of phosphatidylinositol 3-kinase (PI 3-kinase) in the expression of iNOS in C6 glial cells and rat primary astrocytes. Bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) was unable to induce the expression of iNOS and the production of NO in rat C6 glial cells. Similarly, wortmannin and LY294002, compounds that inhibit PI 3-kinase, were also unable to induce the expression of iNOS and the production of NO. However, a combination of wortmannin or LY294002 with LPS or IL-1beta induced the expression of iNOS and the production of NO in C6 glial cells. Consistent with the induction of iNOS, wortmannin also induced iNOS promoter-derived chloramphenicol acetyltransferase activity in LPS- or IL-1beta-treated C6 glial cells. The expression of iNOS by LPS in C6 glial cells expressing a dominant-negative mutant of p85alpha, the regulatory subunit of PI 3-kinase, further supports the conclusion that inhibition of PI 3-kinase provides a necessary signal for the induction of iNOS. Next we examined the effect of wortmannin on the activation of mitogen-activated protein (MAP) kinase and nuclear factor NF-kappaB in LPS- or IL-1beta-stimulated C6 glial cells. In contrast to the inability of LPS and IL-1beta alone to induce the expression of iNOS, both LPS and IL-1beta individually stimulated MAP kinase activity and induced DNA binding and transcriptional activity of NF-kappaB. Wortmannin alone was unable to activate MAP kinase and NF-kappaB. Moreover, wortmannin had no effect on LPS- or IL-1beta-mediated activation of MAP kinase and NF-kappaB, suggesting that wortmannin induced the expression of iNOS in LPS- or IL-1beta-stimulated C6 glial cells without modulating the activation of MAP kinase and NF-kappaB. Similar to C6 glial cells, wortmannin also stimulated LPS-mediated expression of iNOS and production of NO in astrocytes without affecting the LPS-mediated activation of NF-kappaB. Taken together, the results from specific chemical inhibitors and dominant-negative mutant expression studies demonstrate that apart from the activation of NF-kappaB, inhibition of PI 3-kinase is also necessary for the expression of iNOS and production of NO.

Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Cytokines, including tumor necrosis factor-alpha (TNF-alpha), may elicit cytotoxic response through the sphingomyelin-ceramide signal transduction pathway by activation of sphingomyelinases and the subsequent release of ceramide: the universal lipid second messenger. Treatment of bovine cerebral endothelial cells (BCECs) with TNF-alpha for 16 h followed by cycloheximide (CHX) for 6 h resulted in an increase in ceramide accumulation, DNA fragmentation, and cell death. Application of a cell permeable ceramide analogue C2 ceramide, but not the biologically inactive C2 dihydroceramide, also induced DNA laddering and BCEC death in a concentration- and time-dependent manner. TNF-alpha/CHX-mediated ceramide production apparently is not a result of sphingomyelin hydrolysis because sphingomyelin content does not decrease in this death paradigm. In addition, an acidic sphingomyelinase inhibitor, desipramine, had no effect on TNF-alpha/CHX-induced cell death. However, addition of fumonisin B1, a selective ceramide synthase inhibitor, attenuated TNF-alpha/CHX-induced intracellular ceramide elevation and BCEC death. Together, these findings suggest that ceramide plays at least a partial role in this paradigm of BCEC death. Our results show, for the first time, that ceramide derived from de novo synthesis is an alternative mechanism to sphingomyelin hydrolysis in the BCEC death process initiated by TNF-alpha/CHX.
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Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death.

Dbaibo GS, El-Assaad W, Krikorian A, Liu B, Diab K, Idriss NZ, El-Sabban M, Driscoll TA, Perry DK, Hannun YA. FEBS Lett. 2001 Aug 10;503(1):7-12.

Department of Pediatrics, American University of Beirut, Lebanon. gdbaibo@aub.edu.lb

Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor alpha. When cells were pre-treated with glutathione, a proposed cellular regulator of neutral sphingomyelinase, inhibition of ceramide accumulation at early time points was achieved with attenuation of cell death. Inhibition of both pathways achieved near-complete inhibition of ceramide accumulation and cell death indicating that both pathways of ceramide generation are stimulated. This illustrates the complexity of ceramide generation in cytokine action.
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Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death.

Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA.
J Biol Chem. 1998 May 1;273(18):11313-20.

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Tumor necrosis factor-alpha (TNFalpha)-induced cell death involves a diverse array of mediators and regulators including proteases, reactive oxygen species, the sphingolipid ceramide, and Bcl-2. It is not known, however, if and how these components are connected. We have previously reported that GSH inhibits, in vitro, the neutral magnesium-dependent sphingomyelinase (N-SMase) from Molt-4 leukemia cells. In this study, GSH was found to reversibly inhibit the N-SMase from human mammary carcinoma MCF7 cells. Treatment of MCF7 cells with TNFalpha induced a marked decrease in the level of cellular GSH, which was accompanied by hydrolysis of sphingomyelin and generation of ceramide. Pretreatment of cells with GSH, GSH-methylester, or N-acetylcysteine, a precursor of GSH biosynthesis, inhibited the TNFalpha-induced sphingomyelin hydrolysis and ceramide generation as well as cell death. Furthermore, no significant changes in GSH levels were observed in MCF7 cells treated with either bacterial SMase or ceramide, and GSH did not protect cells from death induced by ceramide. Taken together, these results show that GSH depletion occurs upstream of activation of N-SMase in the TNFalpha signaling pathway. TNFalpha has been shown to activate at least two groups of caspases involved in the initiation and "execution" phases of apoptosis. Therefore, additional studies were conducted to determine the relationship of GSH and the death proteases. Evidence is provided to demonstrate that depletion of GSH is dependent on activity of interleukin-1beta-converting enzyme-like proteases but is upstream of the site of action of Bcl-2 and of the execution phase caspases. Taken together, these studies demonstrate a critical role for GSH in TNFalpha action and in connecting major components in the pathways leading to cell death.
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.Sublethal, 2-week exposures of dental material components alter TNF-alpha secretion of THP-1 monocytes.

Noda M, Wataha JC, Lockwood PE, Volkmann KR, Kaga M, Sano H.
Dent Mater. 2003 Mar;19(2):101-5.

Department of Oral Health Sciences, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan. nodam@den.hokudai.ac.jp

OBJECTIVES: The aim of this study was to investigate the hypothesis that dental material components alter cytokine secretion from monocytes if applied for several weeks at sublethal doses. The results in this study suggest that sublethal, 2-week exposures of inorganic mercury may alter TNF-alpha secretion from THP-1 monocytes when the cells are challenged. These alterations may influence the biological response of tissues to materials in an inflammatory intraoral environment.
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Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: differential modulation of NF-kappaB and p38 MAPK signaling pathways.

Kim SH, Johnson VJ, Sharma RP. Nitric Oxide. 2002 Aug;7(1):67-74.

Department of Physiology and Pharmacology, Interdisciplinary Program of Toxicology, The University of Georgia, Athens, GA 30602-7389, USA.

Mercury is well known to adversely affect the immune system; however, little is known regarding its molecular mechanisms. Macrophages are major producers of nitric oxide (NO) and this signaling molecule is important in the regulation of immune responses. The present study was designed to determine the impact of mercury on NO and cytokine production and to investigate the signaling pathways involved. The murine macrophage cell line J774A.1 was used to study the effects of low-dose inorganic mercury on the production of NO and proinflammatory cytokines. Cells were treated with mercury in the presence or absence of lipopolysaccharide (LPS). Mercury (5-20 microM) dose-dependently decreased the production of NO in LPS-stimulated cells. Concomitant decreases in the expression of inducible nitric oxide synthase (iNOS) mRNA and protein were detected. Treatment of J774A.1 cells with mercury alone did not affect the production of NO nor the expression of iNOS mRNA or protein. Interestingly, mercury alone stimulated the expression of tumor necrosis factor alpha (TNFalpha), and increased LPS-induced TNFalpha and interleukin-6 mRNA expression. Mercury inhibited LPS-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) but had no effect alone. In contrast, mercury activated p38 mitogen-activated protein kinase (p38 MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. These results indicate that mercury suppresses NO synthesis by inhibition of the NF-kappaB pathway and modulates cytokine expression by p38 MAPK activation in J774A.1 macrophage cells.

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Hisatome I, Kurata Y, et al; Block of sodium channels by divalent mercury: role of specific cysteinyl residues in the P-loop region. Biophys J. 2000 Sep;79(3):1336-45;

& Bhattacharya S, Sen S et al, Specific binding of inorganic mercury to Na(+)-K(+)-ATPase in rat liver plasma membrane and signal transduction. Biometals. 1997 Jul;10(3):157-62;

& Anner BM, Moosmayer M, Imesch E. Mercury blocks Na-K-ATPase by a ligand-dependent and reversible mechanism. Am J Physiol. 1992 May;262(5 Pt 2):F830-6.

& Wagner CA, Waldegger S,et al; Heavy metals inhibit Pi-induced currents through human brush-border NaPi-3 cotransporter in Xenopus oocytes.. Am J Physiol. 1996 Oct;271(4 Pt 2):F926-30

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Studies have found that in Ms cases there was a reduction in serum magnesium and RBC membrane Na(+)-K+ ATPase activity and an elevation in plasma serum digoxin. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Ms, while the concentration of serum lipid peroxidation products and nitric oxide increased. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction.

Kumar AR, Kurup PA. Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders. J Assoc Physicians India. 2002 Mar;50:400-6; & Kumar AR, Kurup PA. Membrane Na+ K+ ATPase inhibition related dyslipidemia and insulin resistance in neuropsychiatric disorders. Indian J Physiol Pharmacol. 2001 Jul;45(3):296-304.

It is documented in this paper that mercury is a cause of most of these conditions seen in MS . *****************************************************************************

Cerebrospinal fluid protein changes in multiple sclerosis after dental amalgam removal.

Huggins HA, Levy TE.
Altern Med Rev. 1998 Aug;3(4):295-300.

Center for Progressive Medicine, Puerto Vallarta, Mexico.

A relationship between multiple sclerosis (MS) and dental silver-mercury fillings has been suggested by some investigators, but never proven. This study documents objective biochemical changes following the removal of these fillings along with other dental materials, utilizing a new health care model of multidisciplinary planning and treatment. The dramatic changes in photolabeling of cerebrospinal fluid (CSF) proteins following these dental interventions suggest CSF photolabeling may serve as an objective biomarker for monitoring MS. The clear-cut character of these changes should also encourage more research to better define this possible association between dental mercury and MS.

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Dental amalgam and multiple sclerosis: a case-control study in Montreal, Canada.

Bangsi D, Ghadirian P, Ducic S, Morisset R, Ciccocioppo S, McMullen E, Krewski D.
Int J Epidemiol. 1998 Aug;27(4):667-71.

Epidemiology Research Unit, Research Center, Hotel-Dieu Pavilion, CHUM, Montreal, Quebec, Canada.

BACKGROUND: The aetiology of multiple sclerosis (MS) remains poorly understood. Dental amalgams containing mercury have recently been suggested as a possible risk factor for MS. METHODS: In a case-control study conducted between 1991 and 1994, we interviewed a total of 143 MS patients and 128 controls, to obtain information on socio-demographic characteristics and the number of dental amalgams and the time since installation based on dentists' records. RESULTS: Neither the number nor the duration of exposure to amalgams supported an increased risk of MS. After adjustment for age, sex, smoking, and education those who had more than 15 fillings had an odds ratio (OR) of 2.57 (95% CI: 0.78-8.54) compared to those who had none; for individuals whose first amalgam was inserted more than 15 years prior to the study, we found an OR of 1.34 (95% CI: 0.38-4.72). CONCLUSIONS: Although a suggestive elevated risk was found for those individuals with a large number of dental amalgams, and for a long period of time, the difference between cases and controls was not statistically significant.
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Evidence that mercury from silver dental fillings may be an etiological factor in multiple sclerosis.

Siblerud RL, Kienholz E.
Sci Total Environ. 1994 Mar 15;142(3):191-205.

Rocky Mountain Research Institute, Inc., Fort Collins, CO 80524.

This paper investigates the hypothesis that mercury from silver dental fillings (amalgam) may be related to multiple sclerosis (MS). It compares blood findings between MS subjects who had their amalgams removed to MS subjects with amalgams. MS subjects with amalgams were found to have significantly lower levels of red blood cells, hemoglobin and hematocrit compared to MS subjects with amalgam removal. Thyroxine levels were also significantly lower in the MS amalgam group and they had significantly lower levels of total T Lymphocytes and T-8 (CD8) suppressor cells. The MS amalgam group had significantly higher blood urea nitrogen and lower serum IgG. Hair mercury was significantly higher in the MS subjects compared to the non-MS control group. A health questionnaire found that MS subjects with amalgams had significantly more (33.7%) exacerbations during the past 12 months compared to the MS volunteers with amalgam removal. The paper also examines epidemiological correlations between dental caries and MS; as well as how mercury could be causing the pathological and physiological changes found in multiple sclerosis.

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(Mercury inhibits sulfur metabolism resulting in neurologic and metabolic damage)

(reactive oxygen species(ROS) and oxidative stress damage to neuronal cells by mercury)

Mercuric chloride-induced reactive oxygen species and its effect on antioxidant enzymes in different regions of rat brain.

Hussain S, Rodgers DA, Duhart HM, Ali SF.

J Environ Sci Health B. 1997 May;32(3):395-409.

Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells.

Tan S, Wood M, Maher P.
J Neurochem. 1998 Jul;71(1):95-105

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Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death.

Bains JS, Shaw CA. Brain Res Brain Res Rev. 1997 Dec;25(3):335-58.

Peroxynitrite-induced tyrosine nitration and inhibition of protein kinase C.

Knapp LT, Kanterewicz BI, Hayes EL, Klann E.
Biochem Biophys Res Commun. 2001 Aug 31;286(4):764-

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

"Protein kinase C (PKC) is an important intracellular signaling molecule whose activity is essential for a number of aspects of neuronal function including synaptic plasticity. Collectively, our findings support the hypothesis that peroxynitrite inhibits PKC activity via tyrosine nitration in neurons.

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Department of Clinical Biochemistry, Hospital Universitario La Paz, Castellana 261, 28046, Madrid, Spain.

"Several substances related to the neurodegenerative diseases of Alzheimer and Parkinson, such as hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, have been shown to induce apoptosis in tumoral cell lines and rat neurons" We present here, in cultured human cortical neurons, that the DNA fragmentation induced by these substances was preceded by a decrease of the mitochondrial membrane potential. We have also examined the antiapoptotic effect of the antioxidants glutathione, N-acetyl-cysteine and ascorbic acid. All these antioxidants inhibited the apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, since they were able to inhibit completely the mitochondrial membrane potential depolarization and the DNA fragmentation.
***Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease.

Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D.
Free Radic Biol Med. 2002 Jun 1;32(11):1076-83.

Spectroscopy Laboratory, Lancaster University, Lancaster, UK.

"The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of many different neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the beta-amyloid peptide (A(beta)) accumulates mainly extracellularly at the center of senile plaques, whereas, in PD, the alpha-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. Our results suggest that hydrogen peroxide accumulates during the incubation of A(beta) or alpha-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates."
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Cellular and mitochondrial changes in glutamate-induced HT4 neuronal cell death.

Tirosh O, Sen CK, Roy S, Packer L. Neuroscience. 2000;97(3):531-41.

Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.

Elevated levels of extracellular glutamate are neurotoxic. The cytotoxic property of extracellular glutamate is known to mediate two primary mechanisms, excitotoxicity and excitotoxicity-independent processes. The results of this study demonstrated that mitochondrial dysfunction was a key event in the excitotoxicity-independent component of neuronal cell death. Reactive oxygen species accumulation and glutathione depletion were prominent in glutamate-treated cells; however, these events were not direct mediators of cell death.
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Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders.

Kumar AR, Kurup PA. J Assoc Physicians India. 2002 Mar;50:400-6.

Medical College Hospital, Trivandrum.

OBJECTIVES: The study was conducted to assess the role of hypothalamic digoxin in neuropsychiatric and systemic disorders. A hypothesis regarding the central role of hypothalamic digoxin in neuroimmunoendocrine integration is proposed. RESULTS: Inhibition of RBC membrane Na+-K+ ATPase activity was observed in most cases along with increase in the levels of serum digoxin and decrease in the level of serum Mg++. CONCLUSION: The decreased Na+-K+ ATPase activity can be due to increased digoxin, which is a potent inhibitor of this enzyme. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction, 5) immune dysfunction and oncogenesis. The mechanism of how increased intracellular calcium and decreased magnesium can contribute to the above effects is discussed.

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Antibodies from ALS patients inhibit dopamine release mediated by L-type calcium channels.

Offen D, Halevi S, Orion D, Mosberg R, Stern-Goldberg H, Melamed E, Atlas D.
Neurology. 1998 Oct;51(4):1100-3. Department of Neurology, Rabin Medical Center-Beilinson Campus, Sackler School of Medicine, Tel-Aviv University, Petah-Tikva, Israel.

"CONCLUSIONS: These results confirm the presence of antibodies against the L-type calcium channel in the majority of sera from ALS patients, supporting their role in the pathogenesis of ALS."
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J Stejskal, V Stejskal. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999.

Autoimmunity to mercury is often found in conditions like ALS, MS, etc.

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[Apoptosis of astroglial cells] [Article in Japanese]

Matsuda T, Takuma K, Lee E, Kimura Y, Fujita T, Baba A.
Nippon Yakurigaku Zasshi. 1998 Oct;112 Suppl 1:24P-

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.

Astrocytes, the most abundant glial cell type in the brain, are considered to have physiological and pathological roles in neuronal activities. These findings suggest that astrocytes are one of the targets for ROS and the oxidative stress-induced delayed death of astrocytes is at least due to apoptosis.

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Direct evidence for glutathione as mediator of apoptosis in neuronal cells.

Nicole A, Santiard-Baron D, Ceballos-Picot I. Biomed Pharmacother. 1998;52(9):349-55.

CNRS URA 1335, Hopital Necker-Enfants Malades, Paris, France.

Recent evidence has focused attention on the role of oxidative stress in various acute and chronic neurodegenerative diseases. Particularly, a decrease in the level of the powerful antioxidant glutathione (GSH) and death of dopaminergic neurons in substantia nigra are prominent features in Parkinson's disease. These results suggested that redox desequilibrium induced by GSH depletion may serve as a general trigger for apoptosis in neuronal cells, and are consistent with the hypothesis that GSH depletion contribute to neuronal death in Parkinson's disease.
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Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease.

Offen D, Ziv I, Sternin H, Melamed E, Hochman A. Exp Neurol. 1996 Sep;141(1):32-9.

Department of Neurology, Beilinson Medical Center, Petah-Tiqva, Israel.

We have recently shown that dopamine (DA) can trigger apoptosis, an active program of cellular self-destruction, in various neuronal cultures and proposed that inappropriate activation of apoptosis by DA and or its oxidation products may initiate nigral cell loss in Parkinson's disease (PD). Since DA toxicity may be mediated via generation of oxygen-free radical species, we examined whether DA-induced cell death in PC12 cells may be inhibited by antioxidants. Our data indicate that the thiol family of antioxidants, but not vitamins C and E, are highly effective in rescuing cells from DA-induced apoptosis. Further study of the mechanisms underlying the unique protective capacity of thiol antioxidants may lead to the development of new neuroprotective therapeutic strategies for PD.
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Neurotoxicity from glutathione depletion is dependent on extracellular trace copper.

White AR, Cappai R. J Neurosci Res. 2003 Mar 15;71(6):889-97.

Department of Pathology, The University of Melbourne, and The Mental Health Research Institute, Parkville, Victoria, Australia. tony.white@ic.ac.uk

Glutathione (GSH) is an important antioxidant, and its depletion in neurons has been implicated in several neurodegenerative disorders. Aberrant copper metabolism is also implicated in neurodegeneration and may result in the generation of toxic free radicals. These studies demonstrate a critical role for extracellular trace copper in neuronal cell death caused by GSH depletion and may have important implications for the understanding of toxic processes in neurodegenerative diseases.
(note amalgam is the largest source of copper exposure in many)

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Mercury, oxidative damage, etc.

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Activity of glutathione peroxidase and superoxide dismutase in workers occupationally exposed to mercury.

Bulat P, Dujic I, Potkonjak B, Vidakovic A.

Int Arch Occup Environ Health. 1998 Sep;71 Suppl:S37-9
Institute of Occupational Health Dr Dragomir Karajovic, Belgrade, Yugoslavia.

According to previous research the lipid peroxidation process has a significant role in mercury toxicity. Since glutathione peroxidase (GPX) and superoxide dismutase (SOD) play a significant role in erythrocyte antioxidative defence, it is very important to determine their activity in occupationally exposed workers. The aim of this study was to assess the activity of antioxidative enzymes in the erythrocytes of workers occupationally exposed to mercury. We compared a group of 42 workers exposed to elemental mercury in a chloralkali plant (Hg group). The control group (C group) consisted of 75 subjects employed in lime production who had never been exposed to mercury or any toxic substance. The GPX activities in erythrocytes were significantly lower in the Hg group than in the control group (Hg group, 9.05 +/- 7.52 IU/gHb; C group 15.54 +/- 4.85 IU/gHb; p < 0.001). Also, SOD activity in the erythrocytes of workers occupationally exposed to mercury was significantly lower than in the control group (Hg group, 1280.7 +/- 132.3 IU/gHb; C group, 1377.9 +/- 207.5 IU/gHb; p < 0.006). The concentrations of mercury in blood were significantly higher in the Hg group compared to the control group (Hg group, 0.179 +/- 0.040 micromol/l; C group, 0.023 +/- 0.011 micromol/l; p < 0.001). On the basis of previous results, it can be concluded that occupational exposure to elemental mercury leads to increased lipid peroxidation in erythrocytes. Also, it can be postulated that this exposure leads to decreased activity of GPX and SOD in erythrocytes

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Mercuric chloride induces apoptosis via a mitochondrial-dependent pathway in human leukemia cells.

Araragi S, Kondoh M, Kawase M, Saito S, Higashimoto M, Sato M.
Toxicology. 2003 Feb 14;184(1):1-9.

Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.

"Mercurial compounds modulate immunologic functions by inducing cytotoxicity. These results suggest that the activation of caspase-3 was involved in HgCl(2)-induced apoptosis. The release of cytochrome c (Cyt c) from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was also observed in HgCl(2)-treated HL-60 cells. Moreover, the release of Cyt c from mitochondria was observed in HgCl(2)-treated mitochondria isolated from mice liver, and this was followed by mitochondrial permeability transition (PT). The PT was inhibited by cyclosporin A (CsA), a potent inhibitor of PT. CsA also suppressed the occurrence of DNA fragmentation induced by HgCl(2) treatment in HL-60 cells. Taken together, these findings indicate that HgCl(2) is a potent inducer of apoptosis via Cyt c release from the mitochondria in HL-60 cells."
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Sublethal, 2-week exposures of dental material components alter TNF-alpha secretion of THP-1 monocytes.

Noda M, Wataha JC, Lockwood PE, Volkmann KR, Kaga M, Sano H.
Dent Mater. 2003 Mar;19(2):101-5.

Cysteine metabolism and metal toxicity.

Quig D. Altern Med Rev. 1998 Aug;3(4):262-70.

Doctor's Data, Inc., West Chicago, IL, USA. dquig@doctorsdata.com

Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.
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Comparative studies on the toxicity of mercury, cadmium, and copper toward the isolated perfused rat liver.

Strubelt O, Kremer J, Tilse A, Keogh J, Pentz R, Younes M.
J Toxicol Environ Health. 1996 Feb 23;47(3):267-83.

Institut fur Toxikologie, Medizinische Universitat zu Lubeck, Germany.

The toxic effects of cadmium, mercury, and copper were compared over the over range 0.01, 0.03, and 0.1 mM using the isolated perfused rat liver preparation. All metals caused similar changes in various parameters used to describe general toxicity. Thus reductions in oxygen consumption, perfusion flow, and biliary secretion were found, while lactate dehydrogenase release into the perfusate, as well as liver weight, increased also in a dose-dependent fashion. Each metal caused similar magnitudes of changes and exerted similar potency. Measurement of other parameters indicating more specific injury revealed a number of differences. Although all metals reduced hepatic ATP concentration, mercury and cadmium were more potent than copper in this respect. Cadmium was the most potent at decreasing reduced glutathione levels. Mercury was most effective at increasing tissue calcium content, while copper was less so, and cadmium ineffective. Only copper significantly increased tissue malondialdehyde (MDA) content, while all metals increased its release into perfusate. Furthermore, whereas cadmium seemed the most potent metal in increasing MDA release, it was least efficacious, while copper was the most. Antioxidants such as superoxide dismutase, catalase, and Trolox C only reduced cadmium's influence on MDA in perfusate; however, they did not affect cadmium's ability to alter most other parameters of vitality. Albumin reversed the toxic effects of copper and mercury, but not cadmium. While metal-induced reductions in perfusion flow accounted for some of the toxic effects of the metals investigated, the results as a whole supported the suggestion that all metals exerted toxicity at the mitochondria, since ATP levels were reduced in a manner that could not be reproduced by perfusion flow reduction alone. Lipid peroxidation appears to play little role in determining toxicity induced by any of these metals. Furthermore, albumin may play an important physiological role in preventing hepatic injury that might otherwise be induced through acute metal intoxication.
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Effects of selenium and mercury on the enzymatic activities and lipid peroxidation in brain, liver, and blood of rats.

El-Demerdash FM.
J Environ Sci Health B. 2001 Jul;36(4):489-99.

Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Egypt.

Recent studies have reported on the toxicity and related oxidative stress of selenium and mercury. The present study compares the effects of Se as sodium selenite (Na2SeO3) and Hg as mercuric chloride (HgCl2) separately and in combination. Rats received repeated oral doses of Se (0.5 micromol/ml), Hg (0.5 micromol/ml), or Se in combination with Hg (0.5 micromol/ml of each) for 5 consecutive days. Rat serum, brain and liver samples were collected for biochemical assays. The following biochemical alterations occurred in response to Hg treatment: protein content (brain and liver), acetylcholinesterase (AChE) (brain and serum), acid and alkaline (AcP and AlP) phosphatases (plasma and liver) and glutathione S-transferase (GST) (plasma and liver) activities were significantly (P<0.05) decreased, while lactate dehydrogenase (LDH) (plasma, brain and liver), aspartate and alanine aminotransferase (AST, ALT) (serum and liver) activities were significantly increased. Thiobarbituric acid reactive substances (TBARS) was significantly increased in brain and liver. Effect of Se alone included decreased AcP, AlP and GST (serum and liver) activities. However, LDH (serum, brain and liver) and AST (liver) and TBARS (brain and liver) increased. Selenium in combination with Hg partially or totally alleviated the toxic effects of Hg on different studied enzymes. It is concluded that Se could be able to antagonize the toxic effects of mercury

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Department of Physiology and Pharmacology, Interdisciplinary Program of Toxicology, The University of Georgia, Athens, GA 30602-7389, USA.

Mercury is well known to adversely affect the immune system; however, little is known regarding its molecular mechanisms. Macrophages are major producers of nitric oxide (NO) and this signaling molecule is important in the regulation of immune responses. The present study was designed to determine the impact of mercury on NO and cytokine production and to investigate the signaling pathways involved. The murine macrophage cell line J774A.1 was used to study the effects of low-dose inorganic mercury on the production of NO and proinflammatory cytokines. Cells were treated with mercury in the presence or absence of lipopolysaccharide (LPS). Mercury (5-20 microM) dose-dependently decreased the production of NO in LPS-stimulated cells. Concomitant decreases in the expression of inducible nitric oxide synthase (iNOS) mRNA and protein were detected. Treatment of J774A.1 cells with mercury alone did not affect the production of NO nor the expression of iNOS mRNA or protein. Interestingly, mercury alone stimulated the expression of tumor necrosis factor alpha (TNFalpha), and increased LPS-induced TNFalpha and interleukin-6 mRNA expression. Mercury inhibited LPS-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) but had no effect alone. In contrast, mercury activated p38 mitogen-activated protein kinase (p38 MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. These results indicate that mercury suppresses NO synthesis by inhibition of the NF-kappaB pathway and modulates cytokine expression by p38 MAPK activation in J774A.1 macrophage cells.

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Role of reactive oxygen species and glutathione in inorganic mercury-induced injury in human glioma cells.

Lee YW, Ha MS, Kim YK. Neurochem Res. 2001 Nov;26(11):1187-93.

Department of Neurosurgery, College of Medicine, Pusan National University, Korea.

The present study was undertaken to examine the role of reactive oxygen species (ROS) and glutathione (GSH) in glia cells using human glioma cell line A172 cells. HgCl2 caused the loss of cell viability in a dose-dependent manner. HgCl2-induced loss of cell viability was not affected by H2O2 scavengers catalase and pyruvate, a superoxide scavenger superoxide dismutase, a peroxynitrite scavenger uric acid, and an inhibitor of nitric oxide N(G)-nitro-arginine Methyl ester. HgCl2 did not cause changes in DCF fluorescence, an H2O2-sensitive fluorescent dye. The loss of cell viability was significantly prevented by the hydroxyl radical scavengers dimethylthiourea and thiourea, but it was not affected by antioxidants DPPD and Trlox. HgCl2-induced loss of cell viability was accompanied by a significant reduction in GSH content. The GSH depletion was almost completely prevented by thiols dithiothreitol and GSH, whereas the loss of viability was partially prevented by these agents. Incubation of cells with 0.2 mM buthionine sulfoximine for 24 hr, a selective inhibitor of gamma-glutamylcysteine synthetase, resulted in 56% reduction in GSH content without any change in cell viability. HgCl2 resulted in 34% reduction in GSH content, which was accompanied by 59% loss of cell viability. These results suggest that HgCl2-induced cell death is not associated with generation of H2O2 and ROS-induced lipid peroxidation. In addition, these data suggest that the depletion of endogenous GSH itself may not play a critical role in the HgCl2-induced cytotoxicity in human glioma cells.
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INSERM Unite 28, Institut Federatif de Recherche 30, Hopital Purpan Place du Dr. Baylac, Toulouse 31059 cedex, France. Abdellah.Badou@purpan.inserm.fr

Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
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Pb2+ and Hg2+ binding to alpha-lactalbumin.

Veprintsev DB, Permyakov EA, Kalinichenko LP, Berliner LJ.
Biochem Mol Biol Int. 1996 Aug;39(6):1255-65.

Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow, Russia.

Interactions of human alpha-lactalbumin with Pb2+ and Hg2+ were studied by intrinsic protein fluorescence. Lead ions bind to the strong Ca2+ binding site of alpha-lactalbumin (association constant Kass approximately 2 x 10(6) M-1) with concomitant spectral changes which are similar to those induced by the binding of Ca2+. Pb2+ also binds to the strong Zn2+ site with Kass approximately 10(5) M-1 and some secondary binding site(s) (which probably contain histidine residues) with apparent Kass approximately 10(4) M-1, causing pronounced aggregation of the protein. Mercury ions bind to alpha-lactalbumin at the primary Zn2+ sites with Kass approximately (1-4) x 10(4) M-1, although the stoichiometry of the binding depends on the conformational state of the protein. Secondary Hg2+ binding sites were suggested to contain histidines, while the strong Hg2+ site contains carboxylates in the coordination sphere and seems to coincide with the strong Zn2+ site. The binding of both Pb2+ and Hg2+ decreases the thermal stability of the Ca(2+)-loaded protein and in some conditions causes pronounced protein aggregation.
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Neurobiology Laboratory, Psychiatric University Hospital, CH-4025 Basel, Switzerland. gianfranco.olivieri@pharma.novartis.com

The role of estrogen as a neurotrophic/neuroprotective agent in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is increasingly being shown. In this study we examine the neuroprotective effects of beta-estradiol on SHSY5Y neuroblastoma cells which have been exposed to the heavy metals cobalt and mercury. The results show that cobalt and mercury are able to induce oxidative stress and cell cytotoxicity and increase the secretion of beta-amyloid 1-40 and 1-42. These deleterious effects are reversed by the pretreatment of cells with beta-estradiol. It is further shown that beta-estradiol exerts its neuroprotective action through mechanisms which reduce oxidative stress and reduce beta-amyloid secretion. Pre-treatment of the cells with alpha-estradiol did not alleviate the toxic effects of the heavy metals. Our results are significant as they contribute to a better understanding of the mode of action of estrogen with relevance to its use in the treatment of neurodegenerative disorders.

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Environmental medicine, part three: long-term effects of chronic low-dose mercury exposure.

Crinnion WJ. Altern Med Rev. 2000 Jun;5(3):209-23.

Healing Naturally, 11811 NE 128th St., Suite 202, Kirkland, WA 98034, USA.

Mercury is ubiquitous in the environment, and in our mouths in the form of "silver" amalgams. Once introduced to the body through food or vapor, mercury is rapidly absorbed and accumulates in several tissues, leading to increased oxidative damage, mitochondrial dysfunction, and cell death. Mercury primarily affects neurological tissue, resulting in numerous neurological symptoms, and also affects the kidneys and the immune system. It causes increased production of free radicals and decreases the availability of antioxidants. It also has devastating effects on the glutathione content of the body, giving rise to the possibility of increased retention of other environmental toxins. Fortunately, effective tests are available to help distinguish those individuals who are excessively burdened with mercury, and to monitor them during treatment. Therapies for assisting the reduction of a mercury load include the use of 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercato-1-propanesulfonic acid (DMPS). Additional supplementation to assist in the removal of mercury and to reduce its adverse effects is discussed.
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Neuron loss in cerebellar cortex of rats exposed to mercury vapor: a stereological study.

Sorensen FW, Larsen JO, Eide R, Schionning JD. Acta Neuropathol (Berl). 2000 Jul;100(1):95-100

Department of Neurobiology, Institute of Anatomy, University of Aarhus, Denmark. u920932@svfedb.aau.dk

Mercury vapor produces tremor in humans and experimental animals. We have previously reported that mercury vapor intoxication over an 8-week period induces only subtle changes in dorsal root ganglia and nerve roots in rats. In the present study we have carried out stereological analyses of the cerebellum of the same rats, and demonstrated significant losses of Purkinje cells (12.7%, 2P = 0.005) and granule cells (15.6%, 2P = 0.016). All sizes of Purkinje cells were lost with an equal probability, i.e. there were no indication of any preferential loss of any subpopulation of the neurons. The volume of the granular cell layer was significantly reduced (18.9%, 2P = 0.0 15), whereas the volumes of the molecular layer and the white matter were unchanged. Previous stereological studies have demonstrated that methyl mercury intoxication primarily induces degeneration in the peripheral nervous system, while sparing the cerebellum. We therefore suggest that metallic mercury vapor and methyl mercury have different toxicological profiles in rats, where metallic mercury vapor mainly affects the central nervous system and methyl mercury mainly affects the peripheral nervous system.
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Tremor frequency patterns in mercury vapor exposure, compared with early Parkinson's disease and essential tremor.

Biernat H, Ellias SA, Wermuth L, Cleary D, de Oliveira Santos EC, Jorgensen PJ, Feldman RG, Grandjean P.
Neurotoxicology. 1999 Dec;20(6):945-52.

Department of Environmental Medicine, Odense University, Denmark.

A new portable tremometer allows determination of tremor intensities at different tremor frequencies. Based on past studies, two tremor frequency windows of similar size were chosen at 3.0-6.5 Hz and 6.6-10.0 Hz to reflect major tremor intensities in Parkinson's disease and mercury vapor poisoning, respectively. In 81 healthy controls, total tremor intensity was higher for the preferred hand and depended on age. Ten patients treated for Parkinson's disease showed substantially increased tremor intensity, especially within the low-frequency window. This pattern was also apparent in 14 patients with de novo Parkinson's disease whose overall tremor intensity was only mildly elevated. In contrast, ten patients with essential tremor had peak frequencies in both windows, and some patients had increased tremor on one side only. Sixty-three Brazilian gold traders exposed to mercury vapor showed increased tremor predominantly in the high-frequency window. Three of the gold traders had a narrower tremor peak at frequencies of 7-8 Hz. While the urine-mercury concentration was significantly associated with the current number of burning sessions per week, it did not correlate with tremor intensities. However, eight traders had a urinary mercury excretion level above 50 microg and at the same time a greatly increased average tremor intensity within the high-frequency window. These patterns were statistically significant for relative tremor intensities, but were less clear when total intensities were used. These observations suggest that the relative distribution of tremor intensities in specific frequency bands may be a valuable supplement to current diagnostic methods for subjects with mercury vapor exposure.
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[A case of chronic inorganic mercury poisoning with progressive intentional tremor and remarkably prolonged latency of P300] [Article in Japanese]

Shikata E, Mochizuki Y, Oishi M, Takasu T. Rinsho Shinkeigaku. 1998 Dec;38(12):1064-6. Japanese

Department of Neurology, Nihon University School of Medicine.

A 59-year-old man showed slowly progressive intentional tremor for 40 years prior to first visit to us in 1996. He was exposed to mercury vapor for about 3 years (1956-1959) and the diagnosis of chronic inorganic mercury poisoning was made. Hasegawa dementia scale-revised (HDS-R), mini-mental state (MMS) examination and P300 examination were performed. HDS-R and MMS were within normal range but the latency of P300 was remarkably prolonged. His tremor was considered to be due to chronic inorganic poisoning because there were no other causes and the frequency of his tremor was 3-4 Hz. which was lower than that in essential tremor. The prolonged P300 latency was also considered to be due to the same cause because there were no other causes and the head MRI were normal. Chronic inorganic mercury poisoning has been reported to produce organic changes in the brain and P300 is considered to be useful to detect these changes.

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Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: a review.

Buzard GS, Kasprzak KS.
Environ Pathol Toxicol Oncol. 2000;19(3):179-99.

Intramural Research Support Program, SAIC Frederick, MD 21702, USA.

Toxic doses of transition metals are capable of disturbing the natural oxidation/reduction balance in cells through various mechanisms stemming from their own complex redox reactions with endogenous oxidants and effects on cellular antioxidant systems. The resulting oxidative stress may damage redox-sensitive signaling molecules, such as NO, S-nitrosothiols, AP-1, NF-kappaB, IkappaB, p53, p21ras, and others, and thus derange the cell signaling and gene expression systems. This, in turn, may produce a variety of toxic effects, including carcinogenesis. Experimental support for the relevance of oxidative damage to the mechanisms of metal toxicity and carcinogenicity is particularly strong for two essential (but toxic when overdosed) metals--iron and copper-- and three well-established human metal carcinogens--nickel, chromium, and cadmium. However, along with more specific effects of toxic metals associated with their selective binding to particular cell constituents and affecting calcium signaling, oxidative damage seems to become important as well in explaining mechanisms of pathogenicity of other metals, such as lead, mercury, and arsenic.
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Silent latency periods in methylmercury poisoning and in neurodegenerative disease.

Weiss B, Clarkson TW, Simon W. Environ Health Perspect. 2002 Oct;110 Suppl 5:851-4.

Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.

This article discusses three examples of delay (latency) in the appearance of signs and symptoms of poisoning after exposure to methylmercury. First, a case is presented of a 150-day delay period before the clinical manifestations of brain damage after a single brief (<1 day) exposure to dimethylmercury. The second example is taken from the Iraq outbreak of methylmercury poisoning in which the victims consumed contaminated bread for several weeks without any ill effects. Indeed, signs of poisoning did not appear until weeks or months after exposure stopped. The last example is drawn from observations on nonhuman primates and from the sequelae of the Minamata, Japan, outbreak in which low chronic doses of methylmercury may not have produced observable behavioral effects for periods of time measured in years. The mechanisms of these latency periods are discussed for both acute and chronic exposures. Parallels are drawn with other diseases that affect the central nervous system, such as Parkinson disease and post-polio syndrome, that also reflect the delayed appearance of central nervous system damage.
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Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons.

Szucs A, Angiello C, Salanki J, Carpenter DO. Cell Mol Neurobiol. 1997 Jun;17(3):273-88

Wadsworth Center for Laboratories and Research, New York State Department of Health and School of Public Health, Albany 12201-0509, USA.

1. The effects of inorganic Hg2+ and methylmercuric chloride in the ionic currents of cultured hippocampal neurons were studied and compared. We examined the effects of acute exposure to the two forms of mercury on the properties of voltage-activated Ca2+ and Na+ currents and N-methyl-D-aspartate (NMDA)-induced currents. 2. High-voltage activated Ca2+ currents (L type) were inhibited by both compounds at low micromolar concentrations in an irreversible manner. Mercuric chloride was five times as potent as methylmercury in blocking L-channels. 3. Both compounds caused a transient increase in the low-voltage activated (T-type) currents at low concentrations (1 microM) but blocked at higher concentrations and with longer periods of time. 4. Inorganic mercury blockade was partially use dependent, but that by methylmercury was not. There was no effect of exposure of either form of mercury on the I-V characteristics of Ca2+ currents. 5. Na(+)- and NMDA-induced currents were essentially unaffected by either mercury compound, showing only a delayed nonspecific effect at a time of overall damage of the membrane. 6. We conclude that both mercury compounds show a relatively selective blockade of Ca2+ currents, but inorganic mercury is more potent than methylmercury.
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Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in rat brain microsomes.

Freitas AJ, Rocha JB, Wolosker H, Souza DO. Brain Res. 1996 Nov 4;738(2):257-64.

Departamento de Quimica, Universidade Federal de Santa Maria, RS, Brazil.

A permanent increase in cytosolic Ca2+ levels seems to be associated with various pathological situations which may result in cell death. Hg2+ and CH3Hg+ are potent neurotoxic agents, but the precise molecular mechanism(s) underlying their effects are not sufficiently understood. In the present study we investigated the potential role of Ca(2+)-ATPase located in the endoplasmic reticulum as a molecular target for mercury. Hg2+ and CH3Hg+ inhibited Ca(2+)-ATPase and Ca2+ uptake by brain microsomes with similar potencies. However, the inhibitory potency of Hg2+ was higher than that of CH3Hg+, probably reflecting differences in the affinity for the sulfhydryl groups of these compounds. Passive or unidirectional Ca2+ efflux (measured in the absences of Ca(2+)-ATPase ligands) was increased significantly by CH3Hg+ and Hg2+. Again, the potency of Hg2+ was higher than that of CH3Hg+. Blockers of Ca2+ channels (ruthenium red, procaine, heparin) did not affect the increase in passive Ca2+ efflux induced by mercury compounds, possibly indicating that Ca2+ release occurs through Ca(2+)-ATPase. Addition of physiological concentrations of glutathione (GSH) simultaneously with mercury abolished the inhibitory effects of both forms of Hg on ca(2+)-transport. However, if the enzyme was first inhibited with Hg2+ or CH3Hg+ and subsequently treated with GSH, the reversal of inhibition was about 50%, suggesting that part of the cysteinyl residues involved in the inhibitory actions of mercury in Ca(2+)-transport bind to mercury with an extremely high affinity.
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"Evidence of delayed neurotoxicity produced by methyl mercury developmental exposure", D.C. Rice, Neurotoxicology, Fall 1996, 17(3-4), p583-96

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Mercuric chloride induces apoptosis in human T lymphocytes: evidence of mitochondrial dysfunction.

Guo TL, Miller MA, Shapiro IM, Shenker BJ.
Toxicol Appl Pharmacol. 1998 Dec;153(2):250-7.

Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, 19104, USA.

The major objective of our study was to define the mechanism by which mercuric chloride (HgCl2) induces human T-cell death. Human peripheral blood T-cells were exposed to 0-40 microm HgCl2 and then analyzed for biochemical and molecular features of T-cell apoptosis. HgCl2-treated cells exhibited increased Hoechst 33258 fluorescence while maintaining their ability to exclude the vital stain 7-aminoactinomycin D. To further evaluate cell death and distinguish between apoptosis and necrosis, translocation of phosphatidylserine to the outer layer of the plasma membrane (annexin V binding), DNA fragmentation (TUNEL assay), and cleavage of poly (ADP-ribose) polymerase (PARP) were assessed. In the presence of 20-40 microm HgCl2, T-cells exhibited increased annexin V binding (28%) and DNA fragmentation (31%). HgCl2-dependent PARP cleavage was also observed by Western blot analysis. Because degradative changes associated with apoptosis are often preceded by disruption of mitochondrial function, HgCl2-treated cells were assessed for disruption of the mitochondrial transmembrane potential (DeltaPsim) and development of the mitochondrial permeability transition state. Using DiOC6(3), we demonstrated that HgCl2 exposure resulted in a decrease in the DeltaPsim. Because a decline in DeltaPsim can disturb the intracellular pH (pHi), we used the fluorescent probe, SNARF-1, to assess intracellular acidification. Treatment of T-cells with HgCl2 resulted in reduced pHi from 7.0 to 6.7. Concomitant with these observations, the fluorescent probe, hydroethidine, was utilized to demonstrate that uncoupled mitochondrial electron transport resulted in increased reactive oxygen species (ROS) generation. Interestingly, in spite of these alterations to mitochondrial function, translocation of cytochrome c to the cytosol was not detected; this correlated with enhanced bcl-2 levels in HgCl2-treated cells. In conclusion, HgCl2 exposure results in oxidative stress and activation of death signaling pathways leading to apoptosis. Collectively, our studies indicate that individual mercurial species are capable of inducing T-cell death by activating specific apoptotic cascades.

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Mercuric chloride-induced apoptosis is dependent on protein synthesis.

Goering PL, Thomas D, Rojko JL, Lucas AD.
Toxicol Lett. 1999 Apr 12;105(3):183-95.

Division of Life Sciences, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, MD 20852, USA.

Apoptosis is a mode of cell death with morphologic and biochemical features that distinguish it from necrosis. Recent studies demonstrating that mercury compounds initiate apoptosis in cultured cells did not elucidate if the biochemical mechanism of apoptosis involved a dependence on macromolecular synthesis post-insult, i.e. programmed cell death. The objectives of this in vitro study were (1) to determine if HgCl2 cytotoxicity includes an apoptotic component, and (2) to determine if apoptosis is dependent on protein synthesis, i.e. proceeds by an inducible mechanism. Suspensions of mouse lymphoma (L5178Y-R) cells were exposed to 0, 1, 5, or 10 microM HgCl2 and apoptosis was evaluated utilizing qualitative and quantitative methods. At 24 h after exposure, transmission electron microscopy revealed a concentration-related increase in morphologic changes typical of apoptosis: margination of condensed chromatin to the nuclear membrane, dilation of the rough endoplasmic reticulum, cytoplasmic condensation and vacuolation, nuclear dissolution, and plasma membrane blebbing. An increase in Hg-induced DNA fragmentation (DNA 'ladder') was observed using agarose gel electrophoresis. Time- and concentration-dependent increases in the percent of apoptotic cells were observed at 1, 6, 12, and 24 h after HgCl2 exposure using a flow cytometric method that discriminates between cells according to size and granularity. Pretreatment of cells with cycloheximide (CHX), an inhibitor of translation, prior to HgCl2 exposure resulted in a 25-50% reduction in apoptotic cells 24 h after exposure to 10 and 20 microM HgCl2, and concomitantly reduced the overall cytotoxicity compared to HgCl2 alone. These results, although limited to a single cell line, support the hypothesis that HgCl2 induces apoptosis that is dependent, at least in part, upon protein synthesis.
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Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.`

Bagenstose LM, Salgame P, Monestier M. Immunol Res. 1999;20(1):67-78.

Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) class II genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.
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Fibrillarin and other snoRNP proteins are targets of autoantibodies in xenobiotic-induced autoimmunity.

Yang JM, Baserga SJ, Turley SJ, Pollard KM.
Clin Immunol. 2001 Oct;101(1):38-50.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

Exposure of SJL/J mice to mercury induces an anti-nucleolar autoantibody response. The predominant target is fibrillarin, a 34-kDa component of the small nucleolar ribonucleoprotein particles (snoRNP), but other proteins are also recognized. To characterize these proteins, monoclonal IgG anti-nucleolar antibodies were produced from HgC12-treated SJL/J mice. One monoclonal, 17C12, recognized fibrillarin, while two others, 7G3 and 6G10, were found to immunoprecipitate snoRNP particles but not fibrillarin. Antibody 6G10 gave a nucleolar immunofluorescence pattern in human, murine, and amphibian cells, but was negative in immunoblot. The 7G3 monoclone reacted with a 60-kDa protein conserved in human and murine, but not amphibian, cell lines. The 7G3 and 6G10 antigens and fibrillarin colocalized to the nucleolus and Cajal bodies in interphase cells and decorated metaphase chromosomes. These studies suggest that the mercury-induced anti-nucleolar antibody response targets other protein components of the snoRNP particles in addition to fibrillarin. Copyright 2001 Academic Press.

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Murine mast cells exposed to mercuric chloride release granule-associated N-acetyl-beta-D-hexosaminidase and secrete IL-4 and TNF-alpha.

Dastych J, Walczak-Drzewiecka A, Wyczolkowska J, Metcalfe DD.
J Allergy Clin Immunol. 1999 Jun;103(6):1108-14.

Department of Biogenic Amines, Polish Academy of Sciences, Lodz, Poland.

BACKGROUND: Mast cells, by virtue of their location within the skin, respiratory tract, and gastrointestinal system, are considered as potential targets for environmental agents with immunotoxic effects. Mercuric chloride (HgCl2), is a xenobiotic, which induces autoimmune glomerulonephritis and stimulates polyclonal IgE production. OBJECTIVE: We sought to determine the ability of HgCl2 to degranulate murine mast cells and promote cytokine secretion and whether this was an active biologic process. METHODS: Bone marrow-derived murine mast cells were exposed to HgCl2, and the release of N-acetyl-beta-D-hexosaminidase and secretion of IL-4 and TNF-alpha were measured. RESULTS: HgCl2 was found to directly activate murine mast cells to release the granule-associated enzyme N-acetyl-beta-D-hexosaminidase and to secrete the proinflammatory cytokines IL-4 and TNF-alpha. Cytokine secretion occurred hours after exposure to HgCl2 and required transcription and protein synthesis. The secretion of cytokines mediated by HgCl2 was additive to that which followed FcepsilonRI-induced mast cell activation. The IL-4 secretion by mast cells occurred at concentrations of HgCl2 (10(-6) mol/L to 10(-5) mol/L) comparable with those required to induce upregulation of IgE production in experimental animals. CONCLUSION: These findings demonstrate that HgCl2 will directly activate mast cells, which is followed by degranulation and IL-4 and TNF-alpha synthesis and secretion. These findings are consistent with recognition of HgCl2 as a biologically important environmentally derived immunotoxic agent for mast cells.
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Level of HgCl2-mediated phosphorylation of intracellular proteins determines death of thymic T-lymphocytes with or without DNA fragmentation.

Akhand AA, Kato M, Suzuki H, Miyata T, Nakashima I.

J Cell Biochem. 1998 Nov 1;71(2):243-53.

Department of Immunology, Nagoya University School of Medicine, Japan.

Exposure to Hg2+ at a wide range of concentrations (approximately 1-100 microM) more or less caused the death of murine thymic T-lymphocytes, and exposure to 1 microM but not 10 microM (or more) of Hg2- induced DNA fragmentation. Exposure of cells to Hg2+ caused phosphorylation of multiple cellular proteins at the tyrosine residue in a concentration-dependent manner. We found that not only the DNA fragmentation induced by 1 microM Hg2+ but also the cell death bypassing DNA fragmentation caused by 10 microM or more Hg2+ was partly inhibited by protein kinase inhibitors such as staurosporine and herbimycin A. This result suggested the involvement of a protein phosphorylation-linked signal in the mechanism of the Hg2+-mediated cell death with or without DNA fragmentation. Analysis of proteins by both one- and two-dimensional electrophoresis and immunoblot showed that a 52-kDa Shc protein was heavily phosphorylated by an early signal delivered by a high concentration of Hg2+, which also phosphorylated extracellular signal-regulated kinase 1 (ERK1; p44) and ERK2 (p42) of the mitogen-activated protein kinase (MAPK) family in a concentration- and time-dependent manner. The c-Jun amino terminal kinase (p54), which is a distant relative of the MAPK family, was also phosphorylated by the treatment with Hg2+. This eventually formed the signaling cascade that ended with a nuclear target by phosphorylating c-jun at the serine 73. This phosphorylation of c-jun was inhibited by staurosporine. These results suggest that a high level of Hg2+-mediated protein phosphorylation-linked signal induces rapid cell death bypassing DNA fragmentation, whereas a lower level induces cell death accompanying DNA fragmentation. This conclusion in turn implies that DNA fragmentation is not always a prerequisite for the signal transduction-dependent cell death of T-lymphocytes.
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Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms.

El-Fawal HA, Waterman SJ, De Feo A, Shamy MY.
Environ Health Perspect. 1999 Oct;107 Suppl 5:767-75

Pharmacology and Toxicology Laboratory, Mercy College, Dobbs Ferry, NY 10522, USA. neurotox@mercynet.edu

The interactions between the nervous and immune systems have been recognized in the development of neurodegenerative disease. This can be exploited through detection of the immune response to autoantigens in assessing the neurotoxicity of environmental chemicals. To test this hypothesis, the following questions were addressed. a) Are autoantibodies to nervous system (NS) antigens detected in populations exposed to environmental or occupational chemicals? In sera of male workers exposed to lead or mercury, autoantibodies, primarily IgG, to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in mice and rats exposed to either metal. b) Do autoantibodies to NS antigens relate to indices of exposure? In humans exposed to either metal, and similarly in exposed rats, titers of IgG against NFs and MBP significantly correlated with blood lead or urinary mercury, the typical indices of exposure. c) Do autoantibodies correlate with sensorimotor deficits? In workers exposed to lead or mercury, a significant correlation was observed between IgG titers and subclinical deficits. Doses of metals used in rat exposures were subclinical, suggesting that autoantibodies may be predictive of neurotoxicity. d) Is the detection indicative of nervous system pathology? In rats exposed to metals, histopathology indicated central nervous system (CNS) and peripheral nervous system (PNS) damage. In addition there was evidence of astrogliosis, which is indicative of neuronal damage in the CNS, and the presence of IgG concentrated along the blood-brain barrier, as indicated by immunostaining for antibodies. e) Are immune responses to NS antigens pathogenic? Immunoglobulin fractions from rat and human sera interfered with neuromuscular function. These studies suggest that the detection of autoantibodies to NS-specific antigens may be used to monitor the development of neurotoxicity to environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.
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Dental amalgam as one of the risk factors in autoimmune diseases.

Bartova J, Prochazkova J, Kratka Z, Benetkova K, Venclikova Z, Sterzl I.
Neuroendocrinol Lett. 2003 Feb-Apr;24(1-2):65-7.

Institute of Dental Research, lst Medical Faculty, Charles University and General Faculty Hospital Prague, Vinohradska 48, 120 60 Prague 2, Czech Republic. jirina.bartova@post.cz

BACKGROUND: Experimental and clinical data published recently show that dental amalgam can give rise to undesirable immunological responses in susceptible individuals. In genetically susceptible strains of experimental animals, mercury and silver can induce autoimmune responses. Sera of patients sensitive to mercury were found to have a higher incidence of autoantibodies relative to controls. OBJECTIVE: The aim of this study was to determine possible presence of antinuclear SSB/La autoantibodies after the in vitro stimulation of peripheral blood lymphocytes with HgCl2. METHODS: Lymphocytes were obtained from patients with autoimmune thyroiditis and increased response to mercury in vitro. Mononuclear cells were cultivated for 6 days with 100 microl HgCl2 solution or with pure medium and the levels of antinuclear autoantibodies SSB/La were assayed by a commercial SSB/La ELISA kit. RESULTS: Increased production of SSB/La autoantibodies in the media following stimulation of peripheral blood lymphocytes with HgCl2 was found in all cases. Using the Student's paired test, the results were significant on the p=0.05 significance level. CONCLUSION: Results imply that, in some patients with thyroiditis, mercury from dental amalgam can stimulate the production of antinuclear antibodies. Dental amalgam may be a risk factor in some patients with autoimmune disease.
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[Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy] [Article in Czech]

Sterzl I, Hrda P, Prochazkova J, Bartova J, Matucha P.
Vnitr Lek. 1999 Sep;45(9):527-31.

Endokrinologicky ustav, Praha.

Our study was designed to assess the effect of heavy metals on the severity of fatigue in autoimmune thyroid disease associated with autoantibodies against other endocrine organs. We compared our data with those obtained from other groups of patients. A total of five groups of patients were examined by their medical history, dental examination, and using a modified test of blast transformation of metals (Melisa): a) 10 fatigues female patients with autoimmune thyroidism and polyglandular activation of autoimmunity, b) 12 fatigued patients with autoimmune thyroidism, c) 28 fatigued patients free of endocrinopathy, d) 22 professionals without evidence of autoimmunity, e) 13 controls, a population sample, the individuals did not complain of marked fatigue and their laboratory tests did not show signs of autoimmunity and endocrinopathy. Fatigue regardless of the underlying disease is primarily associated with hypersensitivity to inorganic and organic mercury, nickel, and gold. The groups differed in their hypersensitivity to other metals. In the control group, hypersensitivity--mostly to cadmium and lead--was found in four of the examined individuals only. Statistical analysis of data obtained from professionals and controls revealed a higher incidence of positivity to organic and inorganic mercury and nickel in professionals.

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Mercury and nickel allergy: risk factors in fatigue and autoimmunity.

Sterzl I, Prochazkova J, Hrda P, Bartova J, Matucha P, Stejskal VD.
Neuroendocrinol Lett. 1999;20(3-4):221-228

Institute of Endocrinology, Prague, Czech Republic.

This study examined the presence of hypersensitivity to dental and environmental metals in patients with clinical disorders complicated with chronic fatigue syndrome. Three groups of patients were examined through medical history, dental examination, and by using a modified test of blast transformation for metals-MELISA(R). The three groups consisted of the following: 22 patients with autoimmune thyroiditis with or without polyglandular autoimmune activation; 28 fatigued patients free from endocrinopathy; and 22 fatigued professionals without evidence of autoimmunity. As controls, a population sample or 13 healthy subjects without any evidence of metal sensitivity was included. Healthy controls did not complain of marked fatigue and their laboratory tests did not show signs of autoimmunity and endocrinopathy. We have found that fatigue, regardless of the underlying disease, is primarily associated with hypersensitivity to inorganic mercury and nickel. The lymphocyte stimulation by other metals was similar in fatigued and control groups. To evaluate clinical relevance of positive in vitro findings, the replacement of amalgam with metal-free restorations was performed in some of the patients. At a six-month follow-up, patients reported considerably alleviated fatigue and disappearance of many symptoms previously encountered; in parallel, lymphocyte responses to metals decreased as well. We suggest that metal-driven inflammation may affect the hypothalamic-pituitary-adrenal axis (HPA axis) and indirectly trigger psychosomatic multisymptoms characterizing chronic fatigue syndrome, fibromyalgia, and other diseases of unknown etiology.

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Mutagenicity of mercury chloride and mechanisms of cellular defence: the role of metal-binding proteins.

Schurz F, Sabater-Vilar M, Fink-Gremmels J.

Department of Analytical and Molecular Pharmacology, TNO Pharma Zeist, Utrecht, The Netherlands.

The mechanisms of toxicity and, particularly, the potential carcinogenicity of inorganic mercury are still under debate. Results of mutagenicity and genotoxicity testing with mercury have been inconsistent: mercury induces DNA single-strand breaks at low concentrations in mammalian cells but has not proved mutagenic in several bacterial mutagenicity assays. We investigated the mutagenicity of subtoxic concentrations of inorganic mercury and the role of metal-binding proteins and free radicals in this process. A mutagenicity assay using NIH 3T3 cells, transfected with a vector containing lacZ' as a reporter for mutational events, was applied. In this model, inorganic mercury significantly increased the mutation frequency in the lacZ gene, even at the lowest concentration tested. The mutation frequency was greatest at an Hg(2+) concentration of 0.5 microM. To identify the mechanisms involved, different cellular responses to non-cytotoxic concentrations of HgCl(2) were measured. Hg(2+) increased the intracellular amount of reactive oxygen species. This induction of oxidative stress was observed, although the intracellular glutathione (GSH) and metallothionein (MT) concentrations were increased significantly. Mercury-induced MT expression was even more pronounced after GSH depletion. Correspondingly, radical formation was more evident in the presence of the GSH-depleting agent L-buthioneine-[S:,R:]-sulfoximine. These findings suggest that the observed mutations might be a consequence of oxidative processes, rather than due to a direct interaction of mercury with nuclear DNA. The results also indicate that the auto-induction of MT by Hg(2+) fails to prevent these mutational events.
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Urinary mercury levels in patients with autoantibodies to U3-RNP (fibrillarin).

Arnett FC, Fritzler MJ, Ahn C, Holian A.
J Rheumatol. 2000 Feb;27(2):405-10.

Department of Internal Medicine, University of Texas, Houston Medical School, USA. arnett@heart.med.uth.tmc.edu

OBJECTIVE: Autoantibodies to the U3 nucleolar ribonucleoprotein (RNP) fibrillarin occur in some patients with systemic sclerosis (SSc) or other connective tissue diseases and can be induced in certain mouse strains by injections of mercuric chloride, perhaps due to antigenic alteration of fibrillarin by mercury (Hg). Thus, potential occult exposure to Hg was explored in patients with SSc. METHODS: Urinary Hg levels were measured by cold vapor atomic absorption in 13 patients with antifibrillarin antibodies (11 with SSc), 39 SSc patients without antifibrillarin antibodies, and 32 healthy controls. RESULTS: Mean urinary Hg levels were significantly elevated in the antifibrillarin antibody positive patients compared to those in other patients with SSc and controls. After correction for urinary creatinine levels, mean urinary Hg levels remained significantly different than in the other 2 groups, although Hg levels in all were still within the normal or "unexposed" range.
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IV. 8. Parkinson's: see www.myflcv.com/parknew.html

Toxic Exposures and Parkinsons: the Mercury Connection

Bernard Windham(Ed.)- Chemical Engineer

I. Introduction.

Amalgam fillings are the largest source of mercury in most people with daily exposures documented to commonly be above government health guidelines (49,79,183,199,506,600,217). This is due to continuous vaporization of mercury from amalgam in the mouth, along with galvanic currents from mixed metals in the mouth that deposit the mercury in the gums and oral cavity(605). Due to the high daily mercury exposure and excretion into home and business sewers of those with amalgam, dental amalgam is also the largest source of the high levels of mercury found in all sewers and sewer sludge, and thus according to government studies a significant source of mercury in rivers, lakes, bays, fish, and crops(603). People also get significant exposure from vaccinations, fish, and dental office vapor(600,601,603).

When amalgam was placed into teeth of monkeys and rats, within one year mercury was found to have accumulated in the brain, trigeminal ganglia, spinal ganglia, kidneys, liver, lungs, hormone glands, and lymph glands(20). People also commonly get exposures to mercury and other toxic metals such as lead, arsenic, nickel, and aluminum from food, water, and other sources(601). All of these are highly neurotoxic and are documented to cause neurological damage which can result in chronic neurological conditions over time, as well as ADHD, mood, and behavioral disorders(601,605).

II. Mechanisms by which mercury causes neurological conditions found in Parkinson's and neurodegenerative diseases.

Programmed cell death(apoptosis) is documented to be a major factor in degenerative

TNFa(tumor necrosis factor-alpha) is a cytokine that controls a wide range of immune

cell response in mammals, including cell death(apoptosis) in neuronal and immune cells. This process is involved in inflamatory and degenerative neurological conditions like ALS, MS, Parkinson's, rheumatoid arthritis, etc. Cell signaling mechanisms like sphingolipids are part of the control mechansim for the TNFa apoptosis mechanism(126a). Gluthathione is an amino acid that is a normal cellular mechanism for controlling apoptosis. When glutathione is depleted in the brain, reactive oxidative species increased, and CNS and cell signaling mechinsisms are disrupted by toxic exposures such as mercury, neuronal cell apoptosis results and neurological damage. Mercury has been shown to induce TNFa and deplete glutathione, causing inflamatory effects and cellular apoptosis in neuronal and immune cells(126b,126c).

Mercury's biochemical damage at the cellular level include DNA damage, inhibition of DNA and RNA synthesis (42,114,142,296); alteration of protein structure (33,111,114,194,252,442); alteration of the transport of calcium(333,43b,254,263,416,462,507); inhibitation of glucose transport(338,254), and of enzyme function,protein transport, and other essential nutrient transport (96,254,263,264,33,330,331,338,339,347,441,442); induction of free radical formation(13a,43b,405,424), depletion of cellular gluthathione(necessary for detoxification processes) (111,126,424), inhibition of glutathione peroxidase enzyme(13a,442), inhibits glutamate uptake(119,416), induces peroxynitrite and lipid peroxidation damage(521b), causes abnormal migration of neurons in the cerebral cortex(149), immune system damage (34,111,194, 226,252,272,316,325,355); and inducement of inflamatory cytokines(126,181).

Oxidative stress and reactive oxygen species(ROS) have been implicated as major factors in neurological disorders including stroke, Parkinson's Disease(PD), Alzheimer's, ALS, etc.(13,424,442). Mercury induced lipid peroxidation has been found to be a major factor in mercury's neurotoxicity, along with leading to decreased levels of glutathione peroxidation and superoxide dismustase (SOD) (13,441,443). Only a few micrograms of mercury severely disturb cellular function and inhibit nerve growth (149,226,255, 305,442). Exposure to mercury results in metalloprotein compounds that have genetic effects, having both structural and catalytic effects on gene expression (114,241,296,442). Mercury inhibits sulfur ligands in MT and in the case of intestinal cell membranes inactivates MT that normally bind cuprous ions(477,114), thus allowing buildup of copper to toxic levels in many and malfunction of the Zn/Cu SOD function (495,13a, 443). Mercury also causes displacement of zinc in MT and SOD, which has been shown to be a factor in neurotoxicity and neuronal diseases(405,495,517). Some of the processes affected by such metalloprotein control of genes include cellular respiration, metabolism, enzymatic processes, metal-specific homeostasis, and adrenal stress response systems. Significant psysiological changes occur when metal ion concentrations exceed threshold levels. Such metalloprotein formation also appears to have a relation to autoimmune reactions in significant numbers of people (114,313,368,369,405, 442). Increased formation of reactive oxygen species(ROS) has also been found to increase formation of advanced glycation end products(AGEs) that have been found to cause activation of glial cells to produce superoxide and nitric oxide, they can be considered part of a vicious cycle, which finally leads to neuronal cell death in the substantia nigra in PD(424).

Mercury exposure causes high levels of oxidative stress/reactive oxygen species(ROS)(13), which has been found to be a major factor in apoptosis and neurological disease (56,250,441,442,443,13) including dopamine or glutamate related apoptosis(288c). Mercury and quinones form conjugates with thiol compounds such as glutathione and cysteine and cause depletion of glutathione, which is necessary to mitigate reactive damage. Such congugates are found to be highest in the brain substantia nigra with similar congugates formed with L-Dopa and dopamine in Parkinson's disease(56). Mercury depletion of GSH and damage to cellular mitochrondria and the increased lipid perxodation in protein and DNA oxidation in the brain appear to be a major factor in Parkinson's disease(33,56,442). Exposure to mercury vapor and methyl mercury is well documented to commonly cause conditions involving tremor, with populations exposed to mercury experiencing tremor on average proportional to exposure level (250,565). One study found higher than average levels of mercury in the blood, urine, and hair of Parkinson's disease patients(363). Another study(169) found blood and urine mercury levels to be very strongly related to Parkinson's with odds ratios of approx. 20 at high levels of Hg exposure. Another study (145) that reviewed occupational exposure data found that occupational exposure to manganese and copper have high odds rations for relation to PD, as well as multiple exposures to these and lead, but noted that this effect was only seen for exposure of over 20 years.

Glutamate is the most abundant amino acid in the body and in the CNS acts as excitory neurotransmitter(346,386), which also causes inflow of calcium. Astrocytes, a type of cell in the brain and CNS with the task of keeping clean the area around nerve cells, have a function of neutralizing excess glutamate by transforming it to glutamic acid. If astrocytes are not able to rapidly neutralize excess glutamate, then a buildup of glutamate and calcium occurs, causing swelling and neurotoxic effects(119,333). Mercury and other toxic metals inhibit astrocyte function in the brain and CNS(119), causing increased glutamate and calcium related neurotoxicity(119,333,226) which are responsible for much of the fibromylgia symptoms. This is also a factor in conditions such as CFS, Parkinson's, and ALS(346,416).

Parkinson's disease involves the aggregation of alpha-synuclein to form fibrils, which are the major constituent of intracellular protein inclusions (Lewy bodies and Lewy neurites) in dopaminergic neurons of the substantia nigra(564). Occupational exposure to specific metals, especially manganese, copper, lead, iron, mercury, zinc, aluminum, appears to be a risk factor for Parkinson's disease based on epidemiological studies(98,145,564). Elevated levels of several of these metals have also been reported in the substantia nigra of Parkinson's disease subjects (564).

Na(+),K(+)-ATPase is a transmembrane protein that transports sodium and potassium ions across cell membranes during an activity cycle that uses the energy released by ATP hydrolysis. Mercury is documented to inhibit Na(+),K(+)-ATPase function at very low levels of exposure(288ab). Studies have found that in Parkinson's cases there was an elevation in plasma serum digoxin and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity (263). The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. . The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction. It is documented in this paper that mercury is a cause of most of these conditions seen in Parkinson's (13a,111,288,442,521b,43,56,etc.)

Many studies of patients with major neurological or degenerative diseases have found evidence amalgam fillings may play a major role in development of conditions such as such as Alzheimers (66,158, 207,295,300), ALS(92,325,442), MS(102,212,285,291,324), Parkinson's(98,145,169,248,250,258, 363,405,56,84), etc. Mercury exposure causes high levels of oxidative stress/reactive oxygen species(ROS)(13), which has been found to be a major factor in neurological disease(56). Mercury and quinones form conjugates with thiol compounds such as glutathione and cysteine and cause depletion of glutathione, which is necessary to mitigate reactive damage. Such congugates are found to be highest in the brain substantia nigra with similar congugates formed with L-Dopa and dopamine in Parkinson's disease(56,442). Mercury depletion of GSH and damage to cellular mitochrondria and the increased lipid perxodation in protein and DNA oxidation in the brain appear to be a major factor in Parkinson's disease(33,56,442).

An EKM system for evaluating nerve and muscle function ability using a set of 5 measures (precision, imprecision, tremor, Fitts' constant, and irregularity) and tested on a group of Cree Indians with mercury exposure from fish eating(565). Ninety-six participants, including 30 controls subjects, 36 Cree subjects exposed to mercury, 21 subjects with Parkinson disease, 6 with presumed cerebellar deficit, and 3 with essential tremor, participated in the study. An ANOVA on the three largest groups generated significant results for tremor, Fitts' constant, and irregularity between the Cree and the control subjects and on Fitts' constant and irregularity between the subjects with Parkinson's disease and the control subjects. Three subgroups of the same mean age composed of six subjects each were selected. One was composed of Cree subjects with the highest level of mercury exposure, another with Cree subjects having a low level of mercury exposure, and a third with control subjects. An ANOVA on these three groups revealed a significant difference between both groups of Cree subjects and the control group for Fitts' constant and irregularity. These preliminary results suggest that the EKM system is able to discriminate the performance of different groups of subjects and found significant evidence that mercury exposure is related to nerve and muscle function conditions such as tremor and Parkinson's(565).

Though mercury vapor and organic mercury readily cross the blood-brain barrier, mercury has been found to be taken up into neurons of the brain and CNS without having to cross the blood-brain barrier, since mercury has been found to be taken up and transported along nerve axons as well through calcium and sodium channels and along the olfactory path(329, 288,333,34). Exposure to inorganic mercury has significant effects on blood parameters and liver function. Studies have found that in a dose dependent manner, mercury exposure causes reductions in oxygen consumption and availability, perfusion flow, biliary secretion, hepatic ATP concentration, and cytochrome P450 liver content(260), while increasing blood hemolysis products and tissue calcium content and inducing heme oxygenase, porphyria, and platelet aggregation through interfering with the sodium pump.

Mercury has been found to accumulate preferentially in the primary motor function related areas such as the brain stem, cerebellum, rhombencephalon, dorsal root ganglia, and anterior horn motor neurons, which enervate the skeletal muscles(20,291,327,329,442). There is considerable indication this may be a factor in development of ALS and other neurodegenerative conditions(325,405,442). Mercury penetrates and damages the blood brain barrier allowing penetration of the barrier by other substances that are neurotoxic (20,38,85,105,301,311/262). Such damage to the blood brain barrier's function has been found to be a major factor in chronic neurological diseases such as MS(286,289,291, 324). MS patients have been found to have much higher levels of mercury in cerebrospinal fluid compared to controls (35,139). Large German studies including studies at German universities have found that MS patients usually have high levels of mercury body burden, with one study finding 300% higher than controls(271). Most recovered after mercury detox, with some requiring additional treatment for viruses and intestinal dysbiosis. Studies have found mercury related mental effects to be indistinguishable from those of MS (207,212,222,244,271,289,291,183,324). Treatment using IV glutathione, vitaminC, and minerals has been found to be very effective in the stabilizing and amelioration of some of these chronic neurological conditions by neurologists such as Perlmutter in Florida(469).

Low levels of toxic metals have been found to inhibit dihydroteridine reductase, which affects the neural system function by inhibiting brain transmitters through its effect on phenylalanine, tyrosine and tryptophan transport into neurons(258,289,372). This was found to cause severe impaired amine synthesis and hypokinesis. Tetrahydro-biopterin, which is essential in production of nerurotransmitters, is significantly decreased in patients with Alzheimer's, Parkinson's, and MS. Such patients have abnormal inhibition of neurotransmitter production(432).(supplements which inhibit breach of the blood brain barrier such as bioflavonoids have been found to slow such neurological damage).

Clinical tests of patients with MND,ALS, Parkinson's, Alzheimer's, Lupus(SLE), and rheumatoid arthritis have found that the patients generally have elevated plasma cysteine to sulphate ratios, with the average being 500% higher than controls(330,331,56), and in general being poor sulphur oxidizers. Mercury has been shown to diminish and block sulphur oxidation and thus reducing glutathione levels which is the part of this process involved in detoxifying and excretion of toxics like mercury(33,442). Glutathione is produced through the sulphur oxidation side of this process. Low levels of available glutathione have been shown to increase mercury retention and increase toxic effects(111), while high levels of free cysteine have been demonstrated to make toxicity due to inorganic mercury more severe(333,194,56). Mercury has also been found to play a part in neuronal problems through blockage of the P-450 enzymatic process(84). Other toxic metals and toxics such as pesticides have also been found to cause the types of damage seen in Parkinson's and to exposure to have positive correlation to Parkinson's (400,98,145). There are synergistic effects of various toxics that result in conditions like Parkinson's(524b,13c). Determination of one's factors by history assessment and tests is a first step in improving the condition.

One genetic difference found in animals and humans is cellular retention differences for metals related to the ability to excrete mercury(426). For example it has been found that individuals with genetic blood factor type APOE-4 do not excrete mercury readily and bioaccumulate mercury, resulting in susceptibility to chronic autoimmune conditions such as Alzheimer's, Parkinsons, etc. as early as age 40, whereas those with type APOE-2 readily excrete mercury and are less susceptible. Those with type APOE-3 are intermediate to the other 2 types(437,35).

The Huggins Clinic(35) using total dental revision(TDR) has successfully treated over a thousand patients with chronic autoimmune conditions like MS, Parkinson's,Lupus, ALS, AD, diabetes, etc.(35), including himself with the population of over 600(approx. 85%) who experienced significant improvement in MS.

Huggins Total Dental Revision Protocol(35):

(a) history questionnaire and panel of tests.

(b) replace amalgam fillings starting with filling with highest negative current or highest negative quadrant, with supportive vitamin/mineral supplements.

(d) test and treat cavitations and amalgam tattoos where relevant

(e) supportive supplementation, periodic monitoring tests, evaluate need for further treatment(not usually needed).

(f) avoid acute exposures/challenges to the immune system on a weekly 7/14/21 day pattern.

Tests suggested by Huggins/Levy(35) for evaluation and treatment of mercury toxicity:

(a) hair element test(386) (low hair mercury level does not indicate low body level)(more than 3 essential minerals out of normal range indicates likely metals toxicity)

(b) CBC blood test with differential and platelet count

(d) urinary mercury (for person with average exposure with amalgam fillings, average mercury level is 3 to 4 ppm; lower test level than this likely means person is poor excretor and accumulating mercury, often mercury toxic(35)

(e) fractionated porphyrin urine test(note test results sensitive to light, temperature, shaking)

(f) individual tooth electric currents(replace high negative current teeth first)

(g) patient questionnaire on exposure and symptom history

(h) specific gravity of urine(test for pituitary function, s.g>1.022 normal; s.g.< 1.008 consistent with depression and suicidal tendencies(35)}

Note: during initial exposure to mercury the body marshalls immune system and other measures to try to deal with the challenge, so many test indicators will be high; after prolonged exposure the body and immune system inevitably lose the battle and measures to combat the challenge decrease- so some test indicator scores decline. Chronic conditions are common during this phase. Also high mercury exposures with low hair mercury or urine mercury level usually indicates body is retaining mercury and likely toxicity problem(35). In such cases where (calcium> 1100 or < 300 ppm) and low test mercury,manganese,zinc,potassium; mercury toxicity likely and hard to treat since retaining mercury.

Test results indicating mercury/metals toxicity(35):

(a) white blood cell count >7500 or < 4500

(b) hemocrit > 50% or < 40%

(d) blood protein level > 7.5 gm/100 ml

(e) triglycerides > 150 mg %ml

(f) BUN > 18 or < 12

(g) hair mercury > 1.5 ppm or < .4 ppm

(h) oxyhemoglobin level < 55% saturated

(I) carboxyhemoglubin > 2.5% saturated

(j) T lymphocyte count < 2000

(k) DNA damage/cancer

(l) TSH > 1 ug

(m) hair aluminum > 10 ppm

(n) hair nickel > 1.5 ppm

(o) hair manganese > 0.3 ppm

(p) immune reactive to mercury, nickel, aluminum, etc.

(q) high hemoglobin and hemocrit and high alkaline phosphatase(alk phos) and lactic dehydrogenese(LDA) during initial phases of exposure; with low/marginal hemoglobin and hemocrit plus low oxyhemoglobin during long term chronic fatigue phase.

note: after treatment of many cases of chronic autoimmune conditions such as MS, ALS, Parkinson's, Alzheimer's, CFS, Lupus, Rheumatoid Arthritis, etc., it has been observed that often mercury along with root canal toxicity or cavitation toxicity are major factors in these conditions, and most with these conditions improve after TDR if protocol is followed carefully(35).

There are extensive documented cases (many thousands) where removal of amalgam fillings led to cure or significant improvement of serious health problems such as MS(95,102,212,222,271,291,35,229,405), ALS(229,325,405,35), Parkinson's/ muscle tremor(248,229,271,212,222,98,35), muscular/joint pain/fibromyalgia (222,293,317,322,369), anxiety & mental confusion (212,222,229,233,271,317,320,322,57), Chronic Fatigue Syndrome (212,293,229,222, 232,233,271,313,317,320, 368,369,376,405), memory disorders (35,94,212,222,322)

Medical studies and doctors treating fibromylagia have found that supplements which cause a decrease in glutamate or protect against its effects have a positive effect on fibromyalgia. Some that have been found to be effective in treating metals related autoimmune conditions including include Vit B6, CoenzymeQ10, methyl cobalamine(B12), L-carnitine, choline, ginseng, Ginkgo biloba, vitamins C and E, nicotine, and omega 3 fatty acids(fish and flaxseed oil)(417,444). Reduced glutathione(GSH) and N-acetyl cysteine(NAC) have been found to be protective against cellular apoptosis seen in Parkinson's and other neurodegenerative conditions( 56ab,462c, 149b). Vitamins C and E along with zinc(517) have also been found protective against oxidative stresss and some effects of mercury toxicity(462c,56a). IGF-1 treatments have also been found to alleviate some of the symptoms of ALS(424).

Some clinics have found root canals, cavitations, and amalgam tattoos to also be a factor in such autoimmune conditions and that treatment of them improves prognosis in recovery from these conditions(35,437).

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(602) The mechanisms by which mercury causes chronic immune and inflamatory condtions, B.Windham(Ed.),

2002, www.myflcv.com/immunere.html

(603) B. Windham(Ed.), The environmental effects of dental amalgam affect everyone, 2002,

www.myflcv.com/damspr2f.html

(604) Mechanisms of mercury release from amalgam dental fillings: vaporization, oral galvanism, and effects of Electromagnetic fields,

www.myflcv.com/galv.html

(605) Developmental and neurological effects of mercury vapor, B.Windham(Ed)

www.myflcv.com/damspr13.html

Note: etc. when it is used in a list of references means that Author knows of several more references supporting the statement, in #600 for example, but doesn't think them necessary here.

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IV. 9. Lupus (done) see allergy

IV. 10. Chronic degenerative eye conditions

Eye Conditions & mercury exposure: references with snips from abstracts (sent)

Toimela and Tähti studied the effect of HgCl₂on cultured retinal pigment epithelial cells from pig and from a human cell line. They observed that 0.1 mM mercury reduced glutamate uptake by some 25 per cent. They interpreted this effect as due to inhibition of protein kinase C (PKC).

Toimela TA, Tahti H (2001) Effects of mercuric chloride exposure on the glutamate uptake by cultured retinal pigment epithelial cells. Toxicology In Vitro : an International Journal Published in Association with BIBRA 15: 7-12

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The retina of the eye accumulates mercury when there is exposure to mercury vapour. Mercury remains in the retina for a very long time -- often for years. Accumulation of mercury is seen, in monkeys, in the inner portion of the retina, in pigment epithelial cells and capillary walls (Warfvinge and Bruun 2000).

Warfvinge K (2000) Mercury distribution in the neonatal and adult cerebellum after vapor exposure of pregnant squirrel monkeys. Environ Res 83: 93-101

& Warfvinge K, Bruun A (2000) Mercury distribution in the squirrel monkey retina after in Utero exposure to vapor. Environ Res 83: 102-109

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Squirrel monkeys were exposed to mercury vapour at different concentrations and for different numbers of days. The calculated total mercury absorption ranged between 1.4-2.9 mg (range of daily absorption 0.02-0.04 mg). The monkeys were killed at different intervals after the end of exposure (range 1 month - 3 years) and the eyes were enucleated. Mapping of the mercury distribution in the eye revealed that the non-myelin-containing portion of the optic disc was densely loaded with mercury deposits, which are mostly confined to the capillary walls and the glial columns. The pigmented epithelium of the pars plicata of the ciliary body and of the retina contained a considerable amount of mercury. In addition, the retinal capillary walls were densely loaded with mercury deposits, even 3 years after exposure. It was also found that the inner layers of the retina accumulated mercury during a 3-year period. It is known that the biological half-time of mercury in the brain may exceed years. This seems also to be the case for the ocular tissue.

Warfvinge K, Bruun A. Mercury accumulation in the squirrel monkey eye after mercury vapour exposure. Toxicology. 1996 Mar 18;107(3):189-200.

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These data indicate that metallic Hg can induce a reversible impairment in color perception. This suggests that color vision testing should be included in studies on the early effects of Hg.

Cavalleri A, Gobba F. Reversible color vision loss in occupational exposure to metallic mercury. Environ Res 1998 May;77(2):173-7

& Cavalleri A, Belotti L, Gobba FM, Luzzana G, Rosa P & Seghizzi P. Colour vision loss in workers exposed to elemental mercury vapour. Toxicology Letters 77(1-3):351-356 (1995)

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Rudolph CJ, Samuels RT, McDanagh EW. Cheraskin E. Visual Field Evidence of Macular Degeneration Reversal Using a Combination of EDTA Chelation and Multiple Vitamin and Trace Mineral Therapy.In: Cranton EM, ed. A Textbook on EDTA Chelation Therapy, Second Edition. Charlottesville, Virginia: Hampton Roads Publishing Company; 2001

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Mercury can induce retinitis pigmentosa and cataracts

Uchino M, Tanaka Y, Ando Y, Yonehara T, Hara A, Mishima I, Okajima T, Ando M: Neurologic features of chronic minamata disease (organic mercury poisoning) and incidence of complications with aging. J Environ Sci Health B 1995 Sep;30(5):699-715

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Subclinical colour vision loss, mainly in the blue-yellow range, was observed in the workers. This effect was related to exposure, as indicated by the correlation between HgU and CCI (r=0.488, P<0.001).

Cavalleri A, Belotti L, Gobba FM, Luzzana G, Rosa P & Seghizzi P. Colour vision loss in workers exposed to elemental mercury vapour. Toxicology Letters 77(1-3):351-356 (1995)

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The effect of inorganic mercury on the integrity of the endothelium of isolated bullfrog (Rana catesbeiana) corneas was examined by spectrophotometric analysis of corneal uptake of the vital stain Janus green, and by both transmission (TEM) and scanning (SEM) electron microscopy.

TEM and SEM demonstrate significant ultrastructural damage to the endothelium exposed to inorganic mercury, including cellular swelling, increased vacuolization, focal denuding of Descemet's membrane, and diminished integrity at the intercellular junctions.

Sillman AJ, Weidner WJ. Low levels of inorganic mercury damage the corneal endothelium.
Exp Eye Res. 1993 Nov;57(5):549-55.

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Ubels JL, Osgood TB. Inhibition of corneal epithelial cell migration by cadmium and mercury.

Bull Environ Contam Toxicol. 1991 Feb;46(2):230-6.

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Khayat A, Dencker L. Whole body and liver distribution of inhaled mercury vapor in the mouse: influence of ethanol and aminotriazole pretreatment. J Appl Toxicol. 1983 Apr;3(2):66-74.

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Khayat A, Dencker L. Whole body and liver distribution of inhaled mercury vapor in the mouse: influence of ethanol and aminotriazole pretreatment. J Appl Toxicol. 1983 Apr;3(2):66-74

Mercury accumulates in the uvea and retina of the eye.

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see: www.myflcv.com/eyeshg.html

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IV. 11. Allergic inflamatory conditions

Mechanisms by which mercury causes immune reactive and allergic conditions like oral lichen planus, eczema, psoriasis, allergies, asthma, lupus, Scleroderma, rheumatoid arthritis, etc.

Mercury causes immune reactivity in susceptible animals(58-60,etc.) and

individuals (3-15,55-57,63,65). These include a significant portion of the population(11,12,etc.). Mercury immune reactivity is one of the most common causes of allergic inflammatory diseases such as contact dermatitis(6-10,91), eczema(3-9,18-20,34) and psoriasis(33-36), oral lichen planus (11,39-42), systemic eczematous contact-type dermatitis(baboon syndrome)(7), stomatitis(54),leukoplakia and burning mouth syndrome(11b), Scleroderma(47,87), allergies(11-15,43-49), asthma (47-51,16), lupus(27,29,30,88) and rheumatoid arthritis (47,49,88-90,etc.,29,30), celiac disease and chron's disease(47,88-90,etc.) through its toxic effects, inhibition of enzymatic processes(29,30,etc.), and induction of inflammatory cytokines such as TNFa(47) (more details in other submitals).

Mercury causes release of inflamatory cytokines such as Tumor Necrosis Factor-alpha(TNFa) and increased levels of the Na+K+ATPase inhibitor digoxin, which are documented to be factors in the chronic inflamatory conditions discussed here, including asthma, lupus, rheumatoid arthritis, etc. and also is involved in chronic heart problems(47,49,87-92). The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction, 5) immune dysfunction and oncogenesis(88).

Allergic contact eczema is the most frequent occupational disease(1,91b), occurring in over 10% of children in some areas and majority in some occupational settings; and the most common cause of contact eczema is exposure to toxic metals(1, 5-9). The metals most commonly causing allergic immune reactivity are nickel, mercury, chromium, cobalt, and palladium(5-16,91) and in recent years the largest increase in infant reactivity appears to be related to mercury exposure(6,7, 32,86).

Antigen specific LST-test was performed on a large number of patients with atopic eczema(33), using T-cells of peripheral blood. 87% showed LST positive reactions to Hg, 87% to Ni, 38% to Au and 40% to Pd They removed LST positive dental metals from the oral cavities of patients. Improvement of symptoms was obtained in 82% (160/196) of the patients within 1-10 months. Similar results have been obtained at other clinics(11,12,34-38).

Dental staff have been found to have significantly higher prevalence of eye problems, conjunctivitis, atopic dermatitis, and contact urticaria(91c). Finnish dental staff have the highest occupational risk of contact dermatitis with 71% affected over time(91b) with plastics, rubber, and mercury the most common causes of sensitization. Korean dental technicians have a high incidence of contact dermatitis, with dental metals the most common sensitizers. Over 25% had contact dermatitis with over 10% sensitive to 5 metals, chromium, mercury, nickel, cobalt, and palladium(91a). 16.3% were immune reactive to mercury.

One mechanism of mercury's affect on contact sensitivities is the inhibition of glutathione S- transferase(92), which is a modulator of inflamation. Mercury also causes intestinal damage and leaky gut, causing metabolic damage and increasing food sensitivities(93). Inorganic mercury was found to be a cause of systemic eczema and digestive problems by a Japanese study(19).

Many studies including patch tests and immune reactivity tests have been carried out to assess the level of mercury sensitivity in different populations. They have found that there is a significant portion of the population that are reactive and sensitive to mercury and such have significant effects. In a group of medical students tested by patch test, 12.8 % were sensitive to mercury(17). The mercury sensitized students were found to have more than average number of amalgam fillings, higher urine mercury than non-sensitized students, and more allergic reactions to other things such as cosmetics, soaps, shampoos, etc. Many other studies have found similar levels of sensitization in recent years, with those populations with higher exposures such as those with many fillings or dental staff tending to have higher levels of sensitization(11,12,16) and more adverse health effects. In a group of 8 with contact eczema patch tested for mercury in Spain, all were positive for mercurochrome, six to inorganic mercury, and some to thimerosal(18). This study like several others noted the danger in patch tests for mercury as 2 of the patients suffered anaphylactic shock after the patch test due to the extreme immune reactivity of some to mercury. There is consensus among researchers and dental authorities that amalgam fillings are the main cause of oral lichen planus and the condition is usually cured by amalgam removal(11,39-42).

Many clinics and studies involving thousands of patients have found that patients with allergic reactive conditions such as oral lichen planus, eczema, chronic allergies etc. usually recover or have significant improvements after amalgam replacement. Of a group of 86 patients with CFS symptoms, 78% reported significant health improvements after replacement of amalgam fillings within a relatively short period, and MELISA test found significant reduction in lymphocyte reactivity compared to pre removal tests(12). The improvement in symptoms and lymphocyte reactivity imply that most of the Hg-induced lymphocyte reactivity is allergenic in nature. Patients with other systemic neurological or immune symptoms such as arthritis, myalgia, CFS, MCS, MS, etc. also often recover after amalgam replacement(11,12,16). Cases of documented clinical cases with recovery after amalgam replacement include:

eczema and contact dermatitis(22,33,34,52-54,11,12), psoriasis(33-36), asthma(49-52,72),

lupus(12,27,33,70,71,31), allergies(31,32,43,48,51,49,52,53,66-74),

chronic multiple chemical sensitivities (32,52,70,71,73,75-77,12,31),

Oral lichen planus(11,39-42), CFS (12,31,33,52-54,66,70,71,75,84,85)

and muscular/joint pain/fibromyalgia (12,31,53,72,84).

As an example of experience of those with allergic conditions after amalgam replacement, a

German study(52) followed a large group of patients. Over 50% followed indicated they experienced significant improvement after amalgam replacement for 5 chronic conditions followed: asthma, chronic bronchitis, polymyosis, eczema, contact allergy and food allergy. The study showed that skin allergy(patch) test apparently is not a reliable indicator of those with mercury related health problems. Patch test was positive in only 13.1 % of patients, whereas more than 50% of patients had significant health improvement for most conditions followed.

(note abstracts on clinic amalgam replacement results at end)

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1) American Academy of Dermatology, Press Release, February, 2000

(3) Silhan P, Arenberger P. Standard epicutaneous tests in ambulatory care of patients.

Cas Lek Cesk 1999, 138(15):469-73.

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(6) Brasch J, Geier J, Schnuch A. Differentiated contact allergy lists serve in quality improvement. Hautarzt 1998; 49(3): 184-91; & Ockenfels HM, Seemann U, Goos M., Contact allergy in patients with periorbital eczema: an analysis of allergens. Data recorded by the Information Network of the Departments of Dermatology. Dermatology. 1997;195(2):119-24; & Audicana MT, Munoz D, del Pozo MD, Fernandez E, Gastaminza G, Fernandez de Corres L. Allergic contact dermatitis from mercury antiseptics and derivatives: study protocol of tolerance to intramuscular injections of thimerosal. Am J Contact Dermat. 2002 Mar;13(1):3-9.; & Patrizi A, Rizzoli L, Vincenzi C, Trevisi P, Tosti A. Sensitization to thimerosal in atopic children. Contact Dermatitis, 1999, 40(2): 94-7.

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(9) Xue C, He Z, Zhang H, Li S. Study on the contact allergen in patients with dermatitis and eczema. Wei Sheng Yen Chiu 1997, 26(5): 296-8;

& Meding B, Jarvholm B. Hand eczema in Swedish adults and children - J Invest Dermatol 2002 Apr;118(4):719-23.

(11)V.D.M.Stejskal, Dept. Of Clinical Chemistry, Karolinska Institute, Stockholm, Sweden, LYMPHOCYTE IMMUNO-STIMULATION ASSAY -MELISA" V.D.M.Stejskal et al, "Mercury-specific Lymphocytes: an indication of mercury allergy in man", J. Of Clinical Immunology, 1996, Vol 16(1);31-40. www.melisa.org

(12) Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999;

& Jenny Stejskal, Vera Stejskal. The role of metals in autoimmune diseases and the link to neuroendocrinology Neuroendocrinology Letters, 20:345-358, 1999;

& Sterzl I, Prochazkova J, Stejskal VDM et al, Mercury and nickel allergy: risk factors in fatigue and autoimmunity. Neuroendocrinology Letters 1999; 20:221-228;

& Sterzl I, Hrda P, Prochazkova J, Bartova J, Reactions to metals in patients with chronic fatigue and autoimmune endocrinopathy. Vnitr Lek 1999 Sep;45(9):527-31 www.melisa.org

& Stejskal VDM, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A et al. Metal- specific memory lymphocytes: biomarkers of sensitivity in man. Neuroendocrinology Letters, 1999; 20: 289-98.

& Valentine-Thon E, Schiwara HW, Validity of MELISA for metal sensitivity testing; Neuroendocrinol Lett, 2003, Feb-Apr, 24(1-2): 57-64.

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&Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice.
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Mercury inhibits suflur metabolism which causes enzymatic blockages, increases in inflamatory cytokines such as TNFa, and inflamatory conditions.

(29) C.Gordon et al, "Abnormal sulphur oxidation in systemic lupus erythrmatosus(SLE)", Lancet, 1992,339:8784,25-6; & P.Emory et al, "Poor sulphoxidation in patients with rheumatoid arthitis", Ann Rheum Dis, 1992, 51:3,318-20; & C.M. Tanner et al,"Abnormal Liver Enzyme Metablolism in Parkinson's",Neurology, 1991, 41(5): Suppl 2, 89-92;

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(32)Barnett JH, Discoid lupus erythematosus exacerbated by contact dermatitis. Cutis 1990 Nov;46(5):430-2 (nickel & lupus)

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(33) P.Dallmann,"kon nen durch Quecksilber entstehen? PeDa_Eigenverisg, 1995;

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(59) Johansson U, Hansson-Georgiadis H, Hultman P. The genotype determines the B cell response in mercury-treated mice. Int Arch Allergy Immunol. 1998 Aug;116(4):295-305.

(60) D.W.Eggleston, "Effect of dental amalgam and nickel alloys on T-lympocytes",J Prosthet Dent. 51(5):617-623, 1984;

(62)

(63) BJ Shenker, "Low-level MeHg exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial disfunction", Environ Res, 1998, 77(2):149-159;

& O.Insug et al, "Mercuric compounds inhibit hunan moncyte function by inducing apoptosis: evidence for formation of reactive oxygen species(ROS), development of mitochondrial membrane permeability, and loss of reductive reserve", Toxicology, 1997, 124(3):211-24;

(64) W.Kostler, "Beeinflubung der zellularen Immunabwehr drch Quecksilberfreisetzung", Forum Prakt. Allgem. Arzt, 1991, 30(2):62-3; & P.Schleicher, "Schwermetalle schadigen das Immunsystem", Mineraloscope, 1996, (1): 37;

(65) Badou A, Savignac M, Moreau M, Leclerc C, Pasquier R, Druet P, Pelletier L. "HgCl2-induced IL-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels", J Biol Chem. 1997 Dec 19;272(51):32411-8; & A. Szucs et al, Cell Mol Neurobiol, 1997,17(3): 273-8;

(66)Melchart D, Wuhr E, Weidenhammer W, Kremers L. A multicenter survey of amalgam fillings and subjective complaints in non-selected patients in the dental practice. Eur J Oral Sci 1998; 106:770-77 (6,744 patients in 34 clinics)

(71) Sven Langworth et al,"Amalgamnews and Amalgamkadefonden, 1997 and Svenska Dogbladet,1997 (286 cases); & F.Berglund,Bjerner/Helm,Klock,Ripa,Lindforss,Mornstad,Ostlin), "Improved Health after Removal of dental amalgam fillings", Swedish Assoc. Of Dental Mercury Patients, 1998. (www.tf.nu) (over 1000 cases) (Sweden Gov't maintains health records on all citizens) ; & Heavy Metal Bulletin, No.3,1996 and No.1, 1999, p7,8;

& Klock B, Blomgren J, Ripa U, Andrup B, "Effekt av amalgamavlägsnande på patienter som misstänker att de lider eller har lidit av amalgamförgiftning", Tandläkartidn 81(23):1297-1302 (1989) .

(72) P.Engel, "Beobachtungen uber die gesundheit vor und nach amalgamentfernug",Separatdruck aus Schweiz. Monatsschr Zahnm. 1998, vol 108(8).(75 cases amalgam removal) http://soho.globalpoint.ch/paul-engel (89% sigificant improvement)

(73) Lichtenberg H, "Symptoms before and after proper amalgam removal in relation to serum-globulin reaction to metals", Journal of Orthomolecular Medicine,1996, 11(4): 195-203.

(119 cases)

(74)K.H.Friese, "Homoopathische Behandlung der Amalgamvergiftung", Allg. Homoopathische Z, 241(5); 184-187, &Erfahrungsheikunde, 1996, (4): 251-253;

(75)Adolph Coors Foundation, "Coors Amalgam Study: Effects of placement and removal of amalgam fillings", 1995. (www) & Internations DAMS Newsletter, p17, Vol VII, Issue 2, Spring 1997. (31 cases)

(77) U.F.Malt et al, "Physical and mental problems attributed to dental amalgam fillings", Psychosomatic medicine, 1997, 59:32-41. (99 cured)

78)A.P.Tanchyk, "Amalgam Removal for Treatment of Arthritis", Gen Dent,v42,n4, July 1994, p354-

;&P.E. Emory et al, "Increased Prevalence of poor sulphuoxidation in patients with Rheumatoid Arthritis", Ann Rheum Dis, 1992, 51(3): 318-20

(82) H.A.Huggins & TE Levy, "Cerebrospinal fluid protein changes in MS after Dental amalgam removal", Alternative Med Rev, Aug 1998, 3(4):295-300.

(84) Kidd RF. Results of dental amalgam removal and mercury detoxification. Altern Ther Health Med 2000 Jul;6(4):49-55.

(86)Geier M.R., Geier DA; Timerosal in Childhood Vaccines, Neurodevelopmental Disorders, and Heart Disease in the U.S. ; J of Amer Physicians and Surgeons, Vol 8(1), Spring 2003;

& & Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999 Oct;107 Suppl 5:743-8.

(87) Overzet K, Gensler TJ, Kim SJ, Geiger ME, van Venrooij WJ, Pollard KM, Anderson P, Utz PJ. Small nucleolar RNP Scleroderma autoantigens associate with phosphorylated serine/arginine splicing factors during apoptosis. Arthritis Rheum 2000 Jun;43(6):1327-36;

& Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999 Oct;107 Suppl 5:743-8; &. Bigazzi PE. Metals and kidney autoimmunity. Environ Health Perspect. 1999 Oct;107 Suppl 5:753-65

(88) (Kumar AR, Kurup PA. Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders. J Assoc Physicians India. 2002 Mar;50:400-6; & Anner BM, Moosmayer M, Imesch E. Mercury blocks Na-K-ATPase by a ligand-dependent and reversible mechanism.. Am J Physiol. 1992 May;262(5 Pt 2):F830-6. );

& Feighery L, Collins C, Feighery C, Mahmud N, Coughlan G, Willoughby R, Jackson J. Anti-transglutaminase antibodies and the serological diagnosis of coeliac disease. Br J Biomed Sci. 2003;60(1):14-8.

(89)Straub RH, Pongratz G, Scholmerich J, Kees F, Schaible TF, Antoni C, Kalden JR, Lorenz HM.
Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion. Arthritis Rheum. 2003 Jun;48(6):1504-12;

(90) Hide I. [Mechanism of production and release of tumor necrosis factor implicated in inflammatory diseases] Nippon Yakurigaku Zasshi. 2003 Mar;121(3):163-73; & Straub RH, Pongratz G, Scholmerich J, Kees F, Schaible TF, Antoni C, Kalden JR, Lorenz HM., Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion.. Arthritis Rheum. 2003 Jun;48(6):1504-12.; & Kim SH, Johnson VJ, Sharma RP. Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: differential modulation of NF-kappaB and p38 MAPK signaling pathways. Nitric Oxide. 2002 Aug;7(1):67-74.

(91) Lee JY, Yoo JM, Cho BK, Kim HO. Contact dermatitis in Korean dental technicians. Contact Dermatitis. 2001 Jul;45(1):13-6; & (b)Kanerva L, Lahtinen A, Toikkanen J, Forss H, Estlander T, Susitaival P, Jolanki R., Increase in occupational skin diseases of dental personnel. Contact Dermatitis. 1999 Feb;40(2):104-8; &(c) E.C.Lonnroth et al, "Adverse health reactions in skin, eyes, and respiratory tract among dental personnel in Sweden", Swed Dent J, 1998, 22(1-2): 33-45

(92) Muller M, Westphal G, Vesper A, Bunger J, Hallier E., Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal., Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81; & Lutz W, Tarkowski M, Nowakowska E., [Genetic polymorphism of glutathione s-transferase as a factor predisposing to allergic dermatitis] [ Polish], Med Pr. 2001;52(1):45-51.

(93) Watzl B, Abrahamse SL, Treptow-van Lishaut S, Neudecker C, Hansch GM, Rechkemmer G, Pool-Zobel BL., Enhancement of ovalbumin-induced antibody production and mucosal mast cell response by mercury. Food Chem Toxicol. 1999 Jun;37(6):627-37.

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Recovery from Chronic Health Conditions after Amalgam replacement

Lindh U, Hudecek R, Danersund A, Eriksson S, Lindvall A. Removal of dental amalgam and other metal alloys supported by antioxidant therapy alleviates symptoms and improves quality of life in patients with amalgam-associated ill health. Neuroendocrinol Lett. 2002 Oct-Dec;23(5-6):459-82.

Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory,

SE-751 85 Uppsala, Sweden. Ulf.Lindh@bms.uu.se

OBJECTIVES: The purpose of this study was to evaluate treatment of patients suffering from chronic ill health with a multitude of symptoms associated with metal exposure from dental amalgam and other metal alloys. SETTING AND DESIGN: We included 796 patients in a retrospective study using a questionnaire about symptom changes, changes in quality of life as a consequence of treatment and assessment of care taking. METHODS: Treatment of the patients by removal of offending dental metals and concomitant antioxidant therapy was implemented according to the Uppsala model based on a close co-operation between physicians and dentists. RESULTS: More than 70% of the responders, remaining after exclusion of those who had not begun or completed removal, reported substantial recovery and increased quality of life. Comparison with similar studies showed accordance of the main results. Plasma concentrations of mercury before and after treatment supported the metal exposure to be causative for the ill health. MAIN FINDINGS: Treatment according to the Uppsala model proved to be adequate for more than 70% of the patients. Patients with a high probability to respond successfully to current therapy might be detected by symptom profiles before treatment. CONCLUSIONS: The hypothesis that metal exposure from dental amalgam can cause ill health in a susceptible part of the exposed population was supported. Further research is warranted to develop laboratory tests to support identification of the group of patients responding to current therapy as well as to find out causes of problems in the group with no or negative results.

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"The Marburg Amalgam Study", Arzt und Umwelt, Apr, 1995

From: "Dr.B. Weber, Amalgaminformation Marburg, <b.weber@FIREMAIL.DE> http://home,t-online.de/home/Institut_f._Naturheilverfahren/patinf.htm"

Subject: Information about treatment of 3000 patients with amalgam-problems in german and englisch

�Amalgam and allergy":

we have compared the number and quality of allergies with the number of amalgam fillings in 322 patients. We were able to show that only 12 % of the people without or with only one or two fillings had allergies, compared to 76 % in those patients with 8 or more fillings (see graphic). The main health problems and allergies were asthma, chronic bronchitis, polymyosis, eczema, contact allergy and food allergy. skin allergy(patch) test was positive in 13.1 % of patients.

allergies number with condition percent with significant improvement

contact eczema 26 (10.5 %) 61.5 %

food allergy 32 (16.5 %) 62.5 %

hay fever 34 (18.4 %) 50.0 %

eczema (neurodermatitis) 27 (13.5 %) 51.8 %

asthma/chronic bronchitis (n 45) 9 (20.0 %) 55.5 %

itching/pruritus 27 (19.5 %) 75.0 %

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Kidd RF. Results of dental amalgam removal and mercury detoxification using DMPS and neural therapy. Altern Ther Health Med. 2000 Jul;6(4):49-55.

Sixty consecutive patients who had undergone replacement of dental amalgam fillings and a protocol of nutritional support and heavy metal detoxification using dimercapto-propanyl-sulfate and neural therapy were surveyed. The most common complaints were problems with memory and/or concentration; muscle and/or joint pain; anxiety and insomnia; stomach, bowel, and bladder complaints; depression; food or chemical sensitivities; numbness or tingling; and eye symptoms, in descending order of frequency.

Headache and backache responded best to treatment, but all symptoms showed considerable improvement on average. Of the respondents, 78% reported that they were either satisfied or very satisfied with the results of treatment, and 9.5% reported that they were disappointed.
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Hilu RE, Zmener O. Mental nerve paresthesia associated with an amalgam filling: a case report. Endod Dent Traumatol. 1999 Dec;15(6):291-3.

Department of Clinical Endodontics, Maimonides University, Buenos Aires, Argentine Republic.

We present a case report in which a mental nerve paresthesia occurred in connection with an amalgam filling placed in direct contact with the pulp of a mandibular first molar. The main evidence for amalgam being the dominant etiological factor was the positive epicutaneous patch testing response to the components of the amalgam alloy, and the total remission of symptoms without further clinical complications after removal of the amalgam filling and subsequent endodontic therapy.

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[Observations on health before and after amalgam removal] [Article in German]

Engel P. Schweiz Monatsschr Zahnmed. 1998;108(8):811-3. www.melisa.org/articles/engel-e.pdf

75 patients treated at a dental clinic by P. Engel complained of multiple chronic health conditions including headaches, migraines, parasthesia, dizzyness, gastro-intestinal disturbances, allergies, vision disturbances, mental conditions including depression, back and shoulder pain,

joint pain, MS, etc. All were treated by amalgam replacement. The majority with most of these conditions reported them significantly better or cured after amalgam replacement and some for all conditions noted. 68 % of those treated reported their health had become "much better", 12% "better", 9% "somewhat better", 7% "no improvement", and 1% worsening (MS).

Case history information was provided for each patient.

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A multicenter survey of amalgam fillings and subjective complaints in non-selected patients in the dental practice.

Melchart D, Wuhr E, Weidenhammer W, Kremers L.
Eur J Oral Sci. 1998 Jun;106(3):770-7.

Munchener Modell, Centre for Complementary Medicine Research, II. Medical Clinic, Technische Universitat Munchen, Munich, Germany.

The aims of this study were to examine whether there is a difference in symptoms between patients with amalgam fillings and patients without such restorations, to investigate the relationship between particular symptoms and the number of amalgam filled surfaces, and the differences in symptoms between patients with and without removal of amalgam fillings. Data from 6744 consecutive patients in 34 dental offices located throughout Germany were documented. Patients completed a questionnaire answering 48 items, and the current oral findings in the patients were registered. The analysis was restricted to 4,787 patients aged 21 to 60 yr because of special dental conditions in children and elderly persons. A higher number of symptoms as well as a higher intensity of symptoms were found in patients before amalgam removal compared to the remaining patients. The question remains open whether or not there may be a certain kind of relationship between the complaints and amalgam fillings in individual patients.

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Amalgam allergy associated with exacerbation of aspirin-intolerant asthma.
Yoshida S, Mikami H, Nakagawa H, Hasegawa H, Onuma K, Ishizaki Y, Shoji T, Amayasu H. Clin Exp Allergy. 1999 Oct;29(10):1412-4.

Dental Allergy Research Group, Clinical Research Division, AOKI International Medical Center, Yokohama, Japan.

BACKGROUND: Aspirin-intolerant asthma can be induced not only by acidic analgesics (including acetylsalicylic acid), which effectively inhibit cyclo-oxygenase, but also by cross-reactivity with paraben, and other chemical additives. OBJECTIVE: We examined whether amalgam allergy is involved in the pathogenesis of a aspirin-intolerant asthma. METHODS: We present the first case of aspirin-intolerant asthma that improved after the removal of dental amalgam. In addition, we performed both the methacholine provocation testing and sulpyrine provocation testing before and after the removal of dental amalgam. RESULTS: In addition, the methacholine concentration causing a 20% fall in FEV1 in provocation tests rose significantly, though hypersensitivity to analgesics evaluated with sulpyrine provocation testing did not decrease. These results suggest that amalgam sensitization is involved in bronchial hyperresponsiveness in aspirin-intolerant asthma. CONCLUSION: Sensitivity to amalgam may cause exacerbation of aspirin-intolerant asthma in some patients. To the best of our knowledge, this is the first case report of amalgam allergy associated with aspirin-intolerant asthma.
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Cerebrospinal fluid protein changes in multiple sclerosis after dental amalgam removal. Huggins HA, Levy TE. Altern Med Rev. 1998 Aug;3(4):295-300.

Center for Progressive Medicine, Puerto Vallarta, Mexico.

A relationship between multiple sclerosis (MS) and dental silver-mercury fillings has been suggested by some investigators, but never proven. This study documents objective biochemical changes following the removal of these fillings along with other dental materials, utilizing a new health care model of multidisciplinary planning and treatment. The dramatic changes in photolabeling of cerebrospinal fluid (CSF) proteins following these dental interventions suggest CSF photolabeling may serve as an objective biomarker for monitoring MS. The clear-cut character of these changes should also encourage more research to better define this possible association between dental mercury and MS.

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A case of high mercury exposure from dental amalgam.

Langworth S, Stromberg R. Eur J Oral Sci. 1996 Jun;104(3):320-1.

Dept. Occupational Medicine, Huddinge University Hospital, Sweden.

This report describes a patient who suffered from several complaints, which by herself were attributed to her amalgam fillings. Analysis of mercury in plasma and urine showed unexpectedly high concentrations, 63 and 223 nmol/l, respectively. Following removal of the amalgam fillings, the urinary excretion of mercury became gradually normalized, and her symptoms declined.
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Potential efficacy of low metal diets and dental metal elimination in the management of atopic dermatitis: an open clinical study.
Adachi A; Horikawa T; Takashima T; Komura T; Komura A; Tani M; Ichihashi M
J Dermatol, 1997 Jan, 24:1, 12-9
Abstract
We performed an open clinical study on the effects of low metal diets and/or dental metal elimination on 27 patients with moderate to severe atopic dermatitis (AD), who showed positive patch tests for metal allergens and/or clinical exacerbation by oral provocation tests with metal salts. All the patients were recommended to ingest low metal diets for 3 months and/or undergo dental metal elimination. Marked or moderate improvement was noted in 18 patients (67%); 7 patients (26%) showed marked improvement and 11 patients (41%), moderate improvement. Nine patients (33%) showed minimal improvement or no change. In the patients who showed marked or moderate improvement, we observed statistically significant decreases (p < 0.05) in both peripheral blood eosinophil counts and serum LDH levels after 3 months of treatment. The present study suggests that restriction of ingested metal allergens to which patients have positive patch tests and/or oral challenge tests may be useful in the management of some patients with AD who have metal sensitivity.

(note: requiring both treatments would likely yield higher results)

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Jones, L(1999). Dental Amalgam and Health Experience: Exploring Health Outcomes and Issues for People Medically Diagnosed with Mercury Poisoning. The Bulletin of the New Zealand Psychological Society 97, 29-33.

A group of 32 patients who had been tested and diagnosed with mercury toxicity, from a medical practice that treats people for metals toxicity and who had begun amalgam replacement, were interviewed. The most common health problems were chronic fatigue, candida, allergies, migraines, muscular pain, chronic flu symptoms, memory loss, and depression. The group had either undergone or were in the process of amalgm replacement and detoxification using DMSA or DMPS. Of the 32 interviewed, 29 reported lasting health gains. www.melisa.org

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Lichtenberg H.J., Symptoms before and after proper amalgamremoval in relation to serum globulin reaction to metals, J of Orthomol Med., 1996, 11(4):195-9. (119 cases)

The results of this study indicate that proper amalgam removal - and in some cases removal of all the other metals too - and replacement with biocompatible composites - can eliminate or reduce 80% of the classic symptoms of chronic mercury poisoning. These results also show that the strength of an individual's serum-globulin reactions, to many metals used in dentistry, especially the five metals present in amalgam, has important implications for recovery.

The survey covered 38 symptoms and complaints common to chronic mercury poisoning, as found in related literature. Participating in the survey were 118 patients who have been with my clinic since 1984.

The following symptoms and complains were common - before amalgam removal - to more than 50% of the participants.

Fatigue 83% ,Headache 58%, Poor concentration, 76% Bloating ,58% Poor memory 65% , Throat pain 57% , Irritability 64% , Joint pain 57% Muscle fatigue 62 Allergies 55%, Metallic taste 61% Poor appetite 51% , etc.

82% of patients were immune reactive to mercury, and many to other metals as well.

All amalgam fillings were replaced in all participants. 2,600 amalgam areas were removed, averaging 22 areas per patient. 29 patients had all other metals replaced, especially gold/porcelain. This group had 128 gold surfaces, average 4.4 per patient.

In total within 1 to 4 years after filling out the symptom survey again, 79% of the symptoms and complaints were reduced or eliminated after amalgam removal.

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Amalgam fillings may damage kidneys.
Amalgam fillings and skin-lightening creams both contain significant amounts of mercury. Researchers at the King Faisal Hospital in Riyadh, Saudi Arabia have just completed a study aimed at determining whether the mercury actually gets into the blood stream. The study involved 225 women (aged 17 to 58 years) who had their urine measured for mercury, creatinine, urea, uric acid, phosphorus, magnesium, calcium, and glucose. The urinary mercury level varied between 0 and 204.8 micrograms per liter and was directly related to the number of dental amalgam fillings present in the women's mouths. The researchers conclude that chronic exposure to mercury may be associated with deterioration of renal (kidney) function.
al-Saleh I, Shinwari N. Urinary mercury levels in females: influence of dental amalgam fillings. Biometals, Vol. 10, October 1997, pp. 315-23

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Effects of removing amalgam fillings from patients with diseases affecting the immune system.

Lindqvist B & Mornstad H. Med Sci Res 24:355-356 (1996)

ABSTRACT: "53 patients with complaints which they attributed to their amalgam fillings, and with pathological tests indicating abnormality of the immune system, were followed for 1-3 years after the removal of all, part of, or none of their amalgam fillings. Within the group of 34 individuals who had all their amalgam fillings replaced, there was a significant number of decreased antibody titres, but only two had normalised their laboratory tests after 1-3 years. A significant improvement in subjective symptoms occurred in 20 (59%) of cases. In the group of patients who still had amalgam fillings, there were no statistically significant changes in the antibody titres. It thus seems that mercury released from amalgam fillings may initiate or support an ongoing immune disease.

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see: www.home.earthlink.net/~berniew1/immunere.html

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V. Recovery after Amalgam Replacement

1. Oral Conditons

Documentation on Oral conditions caused by amalgam

First is a list of references on oral effects of amalgam, and recovery from oral effects after amalgam replacement. Then abstract for each article is included(some abstracts snipped).

larger review with much more documentation at:

www.myflcv.com/periodon.html

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1. Certosimo AJ, O'Connor RP. Oral electricity. Gen Dent. 1996 Jul-Aug;44(4):324-6.

3. Rose MD, Costello JP. The tarnished history of a posterior restoration. Br Dent J. 1998 Nov 14;185(9):436.

5. Kissel SO, Hanratty JJ. Periodontal treatment of an amalgam tattoo. Compend Contin Educ Dent. 2002 Oct;23(10):930-2, 934, 936.

6. Nadarajah V, Neiders ME, Aguirre A, Cohen RE. J Toxicol Environ Health. Localized cellular inflammatory responses to subcutaneously implanted dental mercury. 1996 Oct 11;49(2):113-25.

7. Tosti A, Piraccini BM, Peluso AM. Contact and irritant stomatitis. Semin Cutan Med Surg. 1997 Dec;16(4):314-9.

8. Rusch-Behrend GD, Gutmann JL. Management of diffuse tissue argyria subsequent to endodontic therapy: report of a case. Quintessence Int. 1995 Aug;26(8):553-7.

9. Weaver T, Auclair PL, Taybos GM. An amalgam tattoo causing local and systemic disease?

Oral Surg Oral Med Oral Pathol. 1987 Jan;63(1):137-40.

(note: the last 2 represent extremely widespread and common effects that are well known and commonly treated, but I'm not familiar with recent journal articles regarding amalgam tattoos.)

Recovery from oral conditions caused by mercury after amalgam replacement

1. Certosimo AJ, O'Connor RP. Oral electricity. Gen Dent. 1996 Jul-Aug;44(4):324-6.

2. Adachi A, Horikawa T, Takashima T, Ichihashi M.. Mercury-induced nummular dermatitis.

J Am Acad Dermatol. 2000 Aug;43(2 Pt 2):383-5.

3. Britschgi M, Pichler WJ. Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inflammatory processes orchestrated by T cells. Curr Opin Allergy Clin Immunol. 2002 Aug;2(4):325-31.

4. Guttman-Yassky E, Weltfriend S, Bergman R. Resolution of orofacial granulomatosis with amalgam removal. J Eur Acad Dermatol Venereol. 2003 May;17(3):344-7.

5. Ostman PO, Anneroth G, Skoglund A. Amalgam-associated oral lichenoid reactions. Clinical and histologic changes after removal of amalgam fillings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Apr;81(4):459-65.

6. Ibbotson SH, Speight EL, Macleod RI, Smart ER, Lawrence CM. The relevance and effect of amalgam replacement in subjects with oral lichenoid reactions. Br J Dermatol. 1996 Mar;134(3):420-3.

7. Wong L, Freeman S. Oral lichenoid lesions (OLL) and mercury in amalgam fillings. Contact Dermatitis. 2003 Feb;48(2):74-9.

8. Koch P, Bahmer FA. Oral lesions and symptoms related to metals used in dental restorations: a clinical, allergological, and histologic study. J Am Acad Dermatol. 1999 Sep;41(3 Pt 1):422-30.

9. Thornhill MH, Pemberton MN, Simmons RK, Theaker ED. Amalgam-contact hypersensitivity lesions and oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003 Mar;95(3):291-9.

10. Dunsche A, Kastel I, Terheyden H, Springer IN, Christophers E, Brasch J. Oral lichenoid reactions associated with amalgam: improvement after amalgam removal. Br J Dermatol. 2003 Jan;148(1):70-6.

11. Camisa C, Taylor JS, Bernat JR Jr, Helm TN. Contact hypersensitivity to mercury in amalgam restorations may mimic oral lichen planus. Cutis. 1999 Mar;63(3):189-92.

12. Bratel J, Hakeberg M, Jontell M. Effect of replacement of dental amalgam on oral lichenoid reactions. J Dent. 1996 Jan-Mar;24(1-2):41-5.

13. Laine J, Kalimo K, Happonen RP. Contact allergy to dental restorative materials in patients with oral lichenoid lesions. Contact Dermatitis. 1997 Mar;36(3):141-6.

14. van Joost T, Laeijendecker R. [Amalgam. VI. Allergy to mercury in dental materials; oral and systemic reactions] [Article in Dutch] Ned Tijdschr Tandheelkd. 1993 Jul;100(7):303-7.

15.Lame J, Konttinen YT, Beliaev N, Happonen RP.. Immunocompetent cells in amalgam-associated oral lichenoid contact lesions. J Oral Pathol Med 1999 Mar;28(3):117-21

16. Larsson A, Warfvinge G. Immunohistochemistry of 'tertiary lymphoid follicles' in oral amalgam-associated lichenoid lesions. Oral Dis. 1998 Sep;4(3):187-93.

17. Dunsche A, Harle F. Precancer stages of the oral mucosa: a review] [Article in German]
Laryngorhinootologie. 2000 Jul;79(7):423-7.

18. Bergdahl BJ, Anneroth G, Anneroth I. Clinical study of patients with burning mouth.Scand J Dent Res. 1994 Oct;102(5):299-305.

19. Larsson A, Warfvinge G. Immunohistochemistry of 'tertiary lymphoid follicles' in oral amalgam-associated lichenoid lesions. Oral Dis. 1998 Sep;4(3):187-93.

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Abstracts:

Oral electricity.
Certosimo AJ, O'Connor RP. Gen Dent. 1996 Jul-Aug;44(4):324-6.
National Naval Dental Center, Naval Dental School, Bethesda, Maryland, USA.

"Oral electricity," "electrogalvanism," or "galvanic currents" has long been recognized as a potential source of oral pain and discomfort. This phenomenon of oral galvanism results from the difference in electrical potential between dissimilar restorative metals located in the mouth. In this case report, the literature is reviewed, and an interesting case study'is presented. The patient's clinical presentation, and the duration and constancy of the oral symptoms