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;

& 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.

(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.home.earthlink.net/~berniew1/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.home.earthlink.net/~berniew1/als.html

(14)previous submission, and also: Alzheimer's Disease: the Mercury Connection, www.home.earthlink.net/~berniew1/alzhg.html

(15) previous submission, and also: Depression: the Mercury Connection: www.home.earthlink.net/~berniew1/depress.html

(16) Mercury exposure and related health effects from amalgam fillings, (B.Windham(Ed.), www.home.earthlink.net/~berniew1/amalg6.html

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

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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.

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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;

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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).

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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.home.earthlink.net

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II. 1. 2. 3. Environmental Effects

www.home.earthlink.net/~berniew1/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