Mercury release from dental amalgams

The basic premise for regarding the amalgam filling as safe was the assumption that the amalgamation process resulted in a stabilization of the normally volatile mercury. This premise has now been shown to be entirely false. Since the 1980s, it has been well established that mercury vapor is continuously released from amalgam fillings. The release of this vapor into the mouth increases immediately after chewing(6) or tooth brushing(7) and can result in a daily absorbed dose of mercury which exceeds the excretory capacity via the urine and stool. It has now been well established and published by several authorities, including the World Health Organization, that amalgam tooth fillings are, by far, the major source of mercury exposure for the general population.(8) This was recently reiterated by Health Canada in its 1995 position paper on dental amalgam.(9) According to the World Health Organization's expert committee, the daily human exposure to mercury vapor from amalgam fillings ranges from 3micrograms to 17micrograms as compared to a maximum of 2.6micrograms from all other sources. It is disturbing to note that mercury was recently removed from latex paint in North America due to the health risks associated with inhalation of mercury vapor from the paint. Exposure to mercury from paint was estimated to be 4.6micrograms per day for approximately two weeks following application of the paint.(10) If mercury in latex paint was clearly considered such a health risk, why are amalgam fillings such a source of scornful dialog amongst the dental and medical community when amalgams are a much greater source and a far more persistent source of inhaled mercury?

 

Pharmacokinetics of inhaled mercury

Mercury vapor released from dental amalgams is efficiently absorbed through the alveoli. Following absorption through the lungs, elemental mercury vapor (Hg0) is only found very transiently in the blood. Due to its high lipid solubility elemental mercury is rapidly transported through cell membranes (including cell membranes of the cells comprising the blood-brain barrier). Once inside metabolically active cells, elemental mercury (Hg0) is then oxidized by catalase to form ionic mercury (Hg2+). Ionic mercury (Hg2+) is not lipid soluble and it therefore results in a high degree of retention of absorbed mercury and a tissue half life ranging from days to decades depending on the particular organ.(11,8,12,13,14,15) This phenomenon clarifies why, studies have repeatedly demonstrated that after placement of amalgam fillings, blood and urinary mercury levels remain relatively low even though many organs develop concentrations of mercury many times greater than that of the blood.(16,17,18) Thus, blood or non-challenged urinary mercury levels bear little relationship to the total body burden of mercury gradually acquired from amalgam fillings.(19)

 

Biochemical effects of inhaled mercury

 

Once mercury enters the cell, it ultimately becomes bound covalently to the sulfhydryl groups found in glutathione, and to a lesser degree to cysteine, biotin, lipoic acid, coenzyme A as well as to other protein sulfhydryl groups. The major intracellular sulfhydryl compound in mammals is the tripeptide glutathione. Glutathione and the glutathione rich enzyme, glutathione peroxidase are probably the most important antioxidant defenses in most species including the human.(20) Mercury has been shown to cause a marked reduction in glutathione production and glutathione peroxidase activity and thus it may result in a marked rise in oxidative stress within the brain and other organs.(21,22,23) Apart from the loss of antioxidant protection from mercury induced inhibition of glutathione and glutathione peroxidase, mercury results in a marked increase in free radical generation through Fenton reactions and other mechanisms.(22)

In addition to its key role in antioxidant defenses, glutathione is also a critical component in the liver's detoxification mechanisms. Enzymes within the liver must form conjugates between glutathione and certain toxic metabolites, organic xenobiotics, and heavy metals to enable these toxins to be eliminated from the body. This process of glutathione conjugation makes toxic molecules more water soluble and enables their excretion via the bile or through the kidney. If liver glutathione production is markedly inhibited, as occurs when mercury accumulates within hepatocytes, mercury and numerous other toxic substances may more readily accumulate throughout the body because the excretion of such substances are significantly impaired.(24,25,26,22) Furthermore, because the majority of mercury is excreted through the stool and urine as a glutathione conjugate, individuals with long standing body burdens of mercury (and thus depleted glutathione production) may not demonstrate elevated levels of mercury in the urine, blood or stool when specimens are gathered in the absence of a challenge with an appropriate metal chelating agent. Thus, tissue biopsy of target organs or a provocation test measuring urinary mercury after the administration of a chelating agent, may be the only valid means to assess chronic mercury body burden.(27,28,29,30)

Uptake and distribution of inhaled mercury

Numerous studies have been performed demonstrating the body tissue uptake and distribution of mercury from dental amalgams. Studies using whole body imaging in primates with dental amalgams have clearly demonstrated that the amalgams result in high levels of mercury in the kidney, intestinal tract, brain, liver, and other organs. (31,16) Of great concern are human fetal and neonatal studies which demonstrate that mercury concentrations in kidney, liver, and brain correlate significantly with maternal amalgam surfaces.(32) Furthermore, a recently published study has firmly established the presence of mercury from dental amalgam in the milk of nursing mothers.(33)

 

Clinical effects of inhaled mercury

The impact of chronic, low level mercury exposure is now known to adversely impact numerous other cellular and organ system processes.(19) Ionic mercury is antigenic and may contribute significantly to autoimmune processes.(34,35) Mercury is also immunotoxic and it may result in immune suppression and allergy.(36,37,38,39) Recent research has also demonstrated that multiple strains of antibiotic resistant bacteria develop rapidly in the gut and oral cavity of both humans as well as non-human primates following the placement of amalgam fillings.(40)

Amalgam fillings have been shown to contribute to mercury accumulation in human and animal kidneys and this has been associated with a significant decrease in renal function.(41,42) Human fertility has also been shown to be significantly impacted by low level exposure to mercury vapor. A recent study examining 7000 dental assistants demonstrated that this group experiences a fertility rate approximately 40% less than that of women who have no occupational exposure to mercury.(43)

Of perhaps greatest concern is the potential role of low level, chronic mercury exposure upon central nervous system function. It is now well established, that amalgam derived mercury accumulates in monkey and human brain tissues.(41,31,13) Mercury has been shown to concentrate selectively in human brain regions involved with memory function and it may play a significant role in the etiology of Alzheimer's disease.(44,45) Other reports have shown subclinical motor and neuropsychological deficits amongst dentists and dental workers as compared to control subjects.(46,47) Mounting evidence has lead some to suggest that, in fact, mercury from amalgams may play a highly significant role in the etiology of numerous mental illnesses and neuropsychological disorders.(48, 49,50,51,52,53)

Pharmacology of DMPS (Dimaval; 2,3-dimercapto-1-propane sulfonate, Na+)

DMPS (sodium salt of 2,3-dimercapto-1-propane sulfonic acid) is not a new drug. It was developed in the former Soviet Union in 1958. In 1978, DMPS became available to the western world following its synthesis and production by the German pharmaceutical company, Heyl.54 DMPS is a chelating agent in the group of dithiols, along with dimercaprol (BAL, British anti-Lewisite) and succimer (DMSA, 2,3-dimercaptosuccinic acid).

DMPS has been used extensively in Europe and on a limited basis in North America as a treatment for mercury (55), arsenic (56) or lead intoxication (57). It is a registered drug in Germany and, in fact, due to its long record of safety, is now available without prescription.(28) When compared with D-penicillamine and N-acetyl-DL-penicillamine, DMPS was the most effective agent to clear mercury from the blood of victims of the Iraqi mercury disaster in the 1960's. (58)

In addition to its safety and utility as an agent for detoxification, DMPS has been used frequently as an agent to approximate mercury body burden.(56,59) As described above, resting urine or blood levels of mercury bear little relationship to body burden of mercury in cases of long standing, low level intoxication, such as that which may occur from dental amalgams.(27),

There is a great wealth of scientific literature on the use of DMPS as both a diagnostic tool and a treatment agent in cases of acute and chronic heavy metal intoxication. Much of the European literature surrounding DMPS has been summarized in the English language in a thorough scientific monograph which is in its sixth edition.60 This monograph forms the basis for the rational use of DMPS by clinicians throughout the world. This monograph also formed the basis for the FDA sanctioned, multicentered trial on the use of DMPS in the evaluation of mercury body burden and response to mercury detoxification therapy in polysymptomatic patients with dental amalgams. (As an aside, Dr. Cline was a participant in the official training program for researchers participating in this multicentered trial and he achieved a mark in the 90th percentile range on the examination required for participation).

In the DMPS monograph, there is extensive reference to the work being done by European clinicians in the treatment of the polysymptomatic patient suffering from demonstrable mercury body burden. DMPS is initially used to assess the body burden of mercury and other heavy metals through provocation testing. Several methodological variations of this test are described. Because of the high degree of patient compliance, and because this methodology is in keeping with the pharmacokinetics of DMPS, I have elected to use the provocation testing methodology advocated by the German toxicologist, M. Daunderer, M.D.(61, 60) In this methodology, DMPS is given as a slow IV push. The patient then provides the first voided specimen after one to one and one half hours. The urine is then sent overnight to a toxicology laboratory. Mercury and other heavy metals are reported as micrograms metal per gram of urinary creatinine. The creatinine compensates for variations in urinary dilution. This has proven to be a simple test to perform, with a high degree of patient compliance. The quantity of heavy metal returned has generally correlated well to the symptom severity of the patients I have seen. Furthermore, the changes in metal excretion with this provocation test have corresponded well to the changes in symptom severity of the patients which I have seen. The provocation test forms a rational approach to the use of DMPS. When high quantities of toxic metals are no longer found with provocation urine testing, the DMPS is of no further value and its use may discontinued.

As mentioned previously, the pharmacology of DMPS has been extensively described.(54,28) Both oral and parenteral preparations of this agent are available. Pharmacokinetic data on both preparations are available.(62,63) The parentaral from of this agent allows for better control over the dosage in highly sensitive patients (the treatment can be interrupted if the patient experiences adverse effects). The parenteral route also avoids transport of metals from the gut to the liver through the portal circulation and may be better tolerated by the highly sensitive patient.

The metabolism of DMPS has also been studied thoroughly. DMPS is excreted largely through the urine. Before its excretion, DMPS is biotransformed largely to acyclic and cyclic disulfides. This mode of biotransformation may suggest one advantage of DMPS over the other dithiol chelator, DMSA (succimer). As opposed to DMPS, DMSA is biotransformed almost completely to a cysteine conjugate. Because of this, DMSA may lead to further depletion of cysteine and glutathione stores, which are often already low in metal toxic patients.(64,62,65,23) DMPS undergoes both renal and biliary excretion.(66) DMPS is distributed in both an intracellular and extracellular manner.(66,67,68) However, Unlike most other chelating agents, such as BAL and EDTA, DMPS does not cross the blood brain barrier and does not redistriute mercury to the brain(28).

The toxicity of DMPS is well known and, in this regard, it provides very distinct advantages to the officially approved dithiol chelator, Dimercaprol (BAL). Although BAL continues to be stockpiled by the military in preparation for chemical warfare attack with the arsenical nerve gas, lewisite, it is 300 times more toxic than DMPS, has no corresponding challenge test and it clearly causes redistribution of metals to the brain.(69) Animal studies on the acute and chronic toxicity of DMPS have been carried out and the results illustrate the safety of this agent and its wide therapeutic window.(60) Numerous human studies have failed to uncover any significant adverse impacts of DMPS upon human renal function, liver function, cardiovascular system, blood, immune system, G.I. tract or any other organs or systems. Minor or avoidable side effects such as local irritation at the site of parenteral infusion or hypotension with overly rapid infusion of the agent have been reported.(60)  

Rationale For Using DMPS: 

The scientific rationale for using DMPS in determining the body burden of and the removal of mercury and other heavy metals has been outlined above. The clinical rationale for using DMPS in people suffering from idiopathic polysymptomatic disorders such as fibromyalgia and chronic fatigue syndrome is as follows. Current scientific understanding of these disorders suggests that the etiologies are multifactorial and may have significant environmental components including accumulation of heavy metals in key target organs. Most patients coming to my clinic with these chronic disorders have already attended several practitioners and have tried all sorts of therapies, usually to no avail. These patients are well educated regarding the various possible underlying etiologies and want to explore the possibility that heavy metals may be an underlying factor. I have observed that in most individuals in which mercury and other heavy metals are present, that a major improvement in their health usually occurs when they undergo detoxification using DMPS. This is in keeping with the observations made by numerous clinicians in Europe and in the USA by the principle investigators in the multicenter phase III, FDA approved clinical trial mentioned earlier. Finally, I want to emphasize that DMPS is not being utilized as the sole treatment in individuals suffering from these disorders, but rather it is being utilized as a method to relieve the patient of significant physiological stresses by decreasing the body burden of heavy metals. Although further research is clearly required in this area, my clinical experience over the last year in using DMPS has convinced me that this valuable agent has a key role to play in the management of highly disabling and previously intractable cases of chronic fatigue syndrome and fibromyalgia. There are many patients in my practice who are now healthy productive citizens instead of hopeless invalids, thanks to the use of DMPS administered in a safe manner.

1. Bremner MDK. The Story of Dentistry, 3rd Ed. . Brooklyn: Dental Items of Interest Publ. Co.; 1954.

2. Ring ME. Dentistry: An Ilustrated History. . New York: H.N. Abrams Inc.; 1985.

3. Dexter JE. A History of Dental and Oral Science in America. In: Science AAoD, ed. Philadelphia: S.S. White; 1876.

4. Reinhardt JW. Risk assessment of mercury exposure from dental amalgams. J. Pub. Hlth. Dent. 1988;48:172-7.

5. Berry TG, Nicholson J, Troendle K. Almost two centuries with amalgam: Where are we today? J. Am. Dent. Assn. 1994;125:392-9.

6. Vimy MJ, Lorscheider FL. Intr-oral air mercury released from dental amlgam. J. Dent. Res. 1985;64:1069-71.

7. Patterson JE, Weissgerg B, Dennison PJ. Mercury in human breath from dental amalgam. Bull. Environ. Contam. Toxicol. 1985;34:459-68.

8. Friberg L. Inorganic Mercury. In: Organization WH, ed. Environmental Health Criteria 118. Geneva: WHO; 1991.

9. Richardson MG. Assessment of mercury exposure and risks from dental amalgam. . Ottawa: Medical Devices Bureau, Environmental Health Directorate, Health Canada; 1995.

10. Lorscheider FL. Mercury exposure from indoor latex paint. N Engl J Med. 1991;324:851-852.

11. Skare I, Engqvist A. Human exposure to mercury and silver released from dental amalgam restorations. Arch. Environ. Hlth. 1994;49:384-394.

12. Clarkson TW, Friberg L, Hursh JB, Nylander M. The prediction of intake of mercury vapor from amalgams. In: Clarkson TW, ed. Biological Monitoring of Toxic Metals. New York: Plenum Press; 1988:247-260.

13. Goering PL, Galloway DW, Clarkson TW, Lorscheider FL, Berlin M, Rowland AS. Toxicity assessment of mercury vapor from dental amalgams. Fundam. Appl. Toxicol. 1992;19:319-329.

14. Klassen CD. Heavy metals and heavy metal antagonists. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The Pharmacological Basis of Therapeutics. New York: Pergamon Press; 1990:1598-1602.

15. Hargreaves RJ, Evans JG, Janota I. Persisent mercury in nerve cells 16 years after metallic mercury poisoning. Neuropath Applied Neurobiol. 1988;14:443-452.

16. Hahn LJ, Kloiber R, Vimy MJ, Takahashi Y, Lorscheider FL. Dental 'silver' tooth fillings: a source of Hg exposure revealed by whole-body image scan and tissue analysis. FASEB J. 1989;3:2641-46.

17. Vimy MJ, Takahashi Y, Lorscheider FL. Maternal-fetal distribution of mercury (203-Hg) released from dental amalgam fillings. Am. J. Physiol. 1990;258:R939-R945.

18. Friberg L, Kullman I, Lind B. Mercury in the central nervous system and its relationship with amalgam fillings. Lakartidningen. 1986;83:519-522.

19. Lorscheider FL, Vimy MJ, Summers AO. Mercury exposure from "silver" tooth fillings: emerging evidence questions a traditional dental paradigm. FASB J. 1995;9:504-508.

20. Meister A, Anderson ME. Glutathione. Ann. Rev. Biochem. 1983;52:711-60.

21. Hussain S, Rodgers D, Duhart H, Ali S. Mercuric chloride-induced reactive oxygen species and its effect on antioxidant enzymes in different regions of rat brain. J Environ Sci Health B. 1997;32:395-409.

22. Stohs S, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med. 1995;18:321-36.

23. Zalups R, Lash L. Depletion of glutathione in the kidney and the renal disposition of administered inorganic mercury. Drug Metab Dispos. 1997;25:516-23.

24. Bose S, Mukhopadhyay B, Chaudhury S, Bhattacharya S. Correlation of metal distribution, reduced glutathione and metallothionein levels in liver and kidney of rat. Indian J Exp Biol. 1994;32:679-81.

25. Gregus Z, Varga F. Role of glutathione and hepatic glutathione S-transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors. Acta Pharmacol Toxicol (Copenh). 1985;56:398-403.

26. Hinchman C, Ballatori N. Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process. J Toxicol Environ Health. 1994;41:387-409.

27. Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3 dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992;6:2472-76.

28. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology. 1995;97:23-38.

29. Nylander M, Friberg L, Weiner J. Muscle biopsy as an indicator for predicting mercury concentrations in the brain. Br J Ind Med. 1990;47:575-6.

30. Godfrey MG, Campbell N. Confirmation of mercury retention and toxicity using 2,3-dimercapto-1-propane-sulfonic acid sodium salt (DMPS). J. Adv. Med. 1994;7:19-30.

31. Hahn LJ, Kloiber R, Leininger RW, Vimy MJ, Lorscheider FL. Whole-body imaging of the distribution of mercury released from dental fillings into monkey tissues. FASEB J. 1990;4:3256-60.

32. Drasch G, Schupp I, Hofl H, Reinke R, Roider G. Mercury burden of human fetal and infant tissues. Eur. J. Pediat. 1994;153:607-10.

33. Vimy MJ, Hooper DE, King WW, Lorscheider FL. Mercury from maternal "silver" tooth fillings in sheep and human breast milk: a source of neonatal exposure. Biological Trace Element Res. 1997;56:143-52.

34. Druet P, Bernard A, Hirsch F, et al. Immunologically medicated glomerulonephritis induced by heavy metals. Arch. Toxicol. 1982;50:187-194.

35. Hirsch F, Kuhn J, Ventura M, Vial M, Fournie G, Druet P. Autoimmunity indiced by HgCl2 in Brown-Norway rats. J. Immunol. 1986;136:3272-3276.

36. Koller LD. Immunotoxicology of heavy metals. Int. J. of Immunopharm. 1980;2:269-70.

37. Perlingeiro R, Queiroz M. Polymorphonuclear phagocytosis and killing in workers exposed to inorganic mercury. Int J Immunopharmacol. 1994;16:1011-7.

38. Queiroz M, Perlingeiro R, Dantas D, Bizzacchi J, De CE. Immunoglobulin levels in workers exposed to inorganic mercury. Pharmacol Toxicol. 1994;74:72-5.

39. Wild L, Ortega H, Lopez M, Salvaggio J. Immune system alteration in the rat after indirect exposure to methyl mercury chloride or methyl mercury sulfide. Environ Res. 1997;74:34-42.

40. Summers AO, Wireman J, Vimy MJ, et al. Mercury released from dental "silver" fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrob. Agents & Chemother. 1993;37:825-34.

41. Nylander M, Friberg L, Lind B. Mercury concentrations in the human brain and kidneys in relation to exposure from dental amalgam fillings. Swed Dent J. 1987;11:179-87.

42. Boyd N, Benediktsson H, Vimy M, Hooper D, Lorscheider F. Mercury from dental "silver" tooth fillings impairs sheep kidney function [see comments]. Am J Physiol. 1991;261:R1010-4.

43. Rowland AS, Baird DD, Weinberg CR, Shore DL, C.M. S, Wilcox AJ. The effect of occupational exposure to mercury vapour on the fertility of female dental assistants. Occup. Environ. Med. 1994;51:28-34.

44. Thompson C, Markesbery W, Ehmann W, Mao Y, Vance D. Regional brain trace-element studies in Alzheimer's disease. Neurotoxicology. 1988;9:1-7.

45. Wenstrup D, Ehmann W, Markesbery W. Trace element imbalances in isolated subcellular fractions of Alzheimer's disease brains. Brain Res. 1990;533:125-31.

46. Echeverria D, Heyer N, Martin M, Naleway C, Woods J, Bittner AJ. Behavioral effects of low-level exposure to elemental Hg among dentists. Neurotoxicol Teratol. 1995;17:161-8.

47. Gonzalez-Ramirez D, Maiorino RM, Zuniga-Charles M, et al. Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury in humans. II. Urinary mercury, porphyrins and neurobehavioral changes of dental workers in Monterrey, Mexico. J. Pharmacol. Exp. Ther. 1995;272:264-74.

48. Siblerud R. The relationship between mercury from dental amalgam and mental health. Am J Psychother. 1989;43:575-87.

49. O'Carroll R, Masterton G, Dougall N, Ebmeier K, Goodwin G. The neuropsychiatric sequelae of mercury poisoning. The Mad Hatter's disease revisited. Br J Psychiatry. 1995;167:95-8.

50. Siblerud R, Motl J, Kienholz E. Psychometric evidence that mercury from silver dental fillings may be an etiological factor in depression, excessive anger, and anxiety. Psychol Rep. 1994;74:67-80.

51. Siblerud R. A comparison of mental health of multiple sclerosis patients with silver/mercury dental fillings and those with fillings removed. Psychol Rep. 1992;70:1139-51.

52. Hua M, Huang C, Yang Y. Chronic elemental mercury intoxication: neuropsychological follow-up case study. Brain Inj. 1996;10:377-84.

53. Soleo L, Urbano M, Petrera V, Ambrosi L. Effects of low exposure to inorganic mercury on psychological performance. Br J Ind Med. 1990;47:105-9.

54. Aposhian HV. DMSA and DMPS - water soluble antidotes for heavy metal poisoning. Annu. Rev. Pharmacol. Toxicol. 1983;23:193-215.

55. Campbell JR, Clarkson TW, Omar MD. The therapeutic use of 2,3-dimercaptopropane-1-sulfonate in two cases of inorganic mercury poisoning. J. Am. Med. Assoc. 1986;256:3127-30.

56. Gerhard I, Waldbrenner P, Thruo H, Runnebaum B. Diagnosis of heavy metal loading by the oral DMPS and chewing-gum tests. Klin. Lab. 1992;38:404-11.

57. Chisolm JJ, Jr., Thomas DJ. Use of 2,3-dimercaptopropane-1-sulfonate in treatment of lead poisoning in children. J. Pharmacol. Exp. Ther. 1985;235:665-69.

58. Clarkson TW, Magos L, Cox C, et al. Tests of efficacy of antidotes for removal of methyl mercury in human poisoning during the Iraq outbreak. J. Pharmacol. Exp. Ther. 1981;218:74-83.

59. Schiele R, Schaller KH, Weltle D. Mobilization of mercury reserves in the organism by means of DMPS (Dimaval). Med. Soc. Med. Prevent. Med. 1989;24:249-51.

60. Ruprecht J. Scientific Monograph, DimavalR (DMPS). . Houston, Texas: Heyltex Corporation; 1997.

61. Daunderer M. Mobilization test for environmental metal poisonings. Forum des praktischen und allgemdn-artztes. 1989;28:88.

62. Maiorino RM, Dart RC, Carter DE, Aposhian HV. Determination and metabolism of dithiol chelating agents. XII. Metabolism and pharmacokinetics of sodium 2,3-dimercaptopropane-1-sulfonate in humans. J. Pharmacol. Exp. Ther. 1991;259:808-14.

63. Hurlbut TD, Maiorino RM, Mayersohn M, Dart RC, Bruce DC, Aposhian HV. Determination and metabolism of dithiol chelating agents. XVI. Pharmacokinetics of 2,3-dimercapto-1-propanesulfonate after intravenous administration to human volunteers. J. Pharmacol. Exp. Ther. 1994;268:662-68.

64. Maiorino RM, Bruce DC, Aposhian HV. Determination and metabolism of dithiol chelating agents: VI. Isolation and identification of the mixed sidulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine. Toxicol. Appl. Pharmacol. 1989;97:338-49.

65. Maiorino RM, Xu Z, Aposhian HB. Determination and metabolism of dithiol chelating agents. XVII. In humans, sodium 2,3-dimercapto-1-propanesulfonate is bound to plasma albumin via mixed disulfide formation and is found in the urine as cyclic polymeric disulfides. J. Pharmacol. Exp. Ther. 1995;In Press.

66. Zheng W, Maiorino RM, Brendel K, Aposhian HV. Determination and metabolism of dithiol chelating agents. VII. Biliary excretion of dithiols and their interactions with cadmium and metallothionein. Fund. Appl. Toxicol. 1990;14:598-607.

67. Wildenauer DB, Reuther H, Weger N. Interactions of the chelating agent 2,3-dimercaptopropane-1-sulfonate with red blood cells in vitro. I. Evidence for carrier mediated transport. Chem. Biol. Interact. 1982;42:165-77.

68. Reuther H, Wildenauer DB, Weger N. Interactions of the chelating agent 2,3-dimercaptopropane-1-sulfonate with red blood cells in-vitro. II. Effects on metalloproteins. Chemico-Biol. Interact. 1982;42:179-94.