Use of Chelating Agents in Environmental Medicine?

Position Statement from the "Human Biomonitoring"
Commission of the federal environmental agency

Up to the early 1990s Dimercaprol and calcium disodium ethylene diaminetetraamino acid (CaNa2EDTA) were the accepted chelating agents in the treatment of metal poisonings. A great disadvantage of these two substances is their relatively high toxicity, as well as the need for their parenteral administration. Therefore, recent research has been focused on the development of new chelating agents with similar or better efficacy, lower toxicity, and that can be used orally. We now have available two antidotes, DMPS and DMSA, which much better satisfy the required conditions. They are two closely related vicinal dithiol substances that have a very similar profile of effectiveness. They show good activity, are tolerable, are relatively specific, and are easy to administer, and compared to the earlier established chelating agents, therefore, constitute a definite improvement.

DMPS is a sodium salt racemate of 2,3-dimercaptopropan-1-sulfonic acid. It is commercially available in Germany under the trademark Dimaval and also the trademarks DMPS-Heyl or Dimercuval. DMPS is used especially with mercury, lead, and arsenic poisonings. With acute intoxications a daily intravenous DMPS dose of 10-30 mk/kg is administered. With chronic metal poisonings DPMS is given orally: adults 3 x 100 mg DPSM per day; children receive a daily dose of 5 mg/kg, divided into 3 single portions.

DMSA is meso-2,3-dimercaptosuccinic acid, currently imported as the trademarked Chemet preparation. According to its usage recommendations, a treatment cycle lasts 19 days, with single doses of 10 mg/kg given every 8 hours for the first 5 days, then every 12 hours for the next 14 days [1-3]. Between two treatment cycles there should be an interval of 2 weeks. For the treatment of acute poisonings these new chelating agents have by now become indispensable. Because of their good tolerance and oral use, it has become inevitable that these new preparations are now also used in environmental medicine with cases of suspected chronic metal poisonings. However, as of today there are still too many unanswered questions to broaden the spectrum of recommendations for their general use.

  1. Of the results available to us on chelating therapy with clinical improvements, almost all deal with acute metal poisoning treatments. These results, however, are not readily applicable to chronic metal poisonings since the mobilization behaviors of chelate formers can be different in acute and chronic metal poisonings.
  2. As of today, even with acute metal poisonings we have no blood or urine data that would be indicative at what concentrations chelation therapy would be necessary. The only reference level we now have in chelation therapy is for children with lead poisoning and a lead concentration of 450 microgram/liter of blood [2].
  3. Chelation therapy for chronic metal poisonings has not yet been satisfactorily studied with regard to dose, mode of application, and duration, as well as efficacy and safety.
  4. The safety of long-term therapy with chelating agents is largely unknown [4].
  5. The redistribution of metals in an organism, as induced by chelating agents, could possibly lead to further poisoning symptoms; this phenomenon has not been well observed in the past. With several chelating agents it has been shown that chelation therapy not only increased renal metal elimination, but also caused a redistribution of the metal in the organism with enrichment of the toxic metal by critical organs, for example, the brain [5-11].
  6. As of today, no reliable studies exist on the clinical progression during chelation therapy for chronic metal poisoning and whether its progress can be positively affected [12-16].
  7. The mobilization test with DMPS to assess an amalgam-related lead burden does not provide significant insight into the determination of spontaneously urine-excreted mercury within 24 hours. No validity can be assigned to such a mobilization test, as demonstrated by Drasch and others [17] and Kleber and others [18]. Furthermore, there do not exist any reference values for the stimulated mercury excretion in urine, and also no scientifically validated data beyond which health concerns exist; therefore, therapeutic consequences can not be deduced from the data of DMPS mobilization tests [19].

In summary, we now have two antidotes, DMPS and DMSA, which have become indispensable in the treatment of acute metal poisonings. However, based on existing data, their use in suspected chronic metal poisonings, as now is occasionally done in the practice of environmental medicine, is not recommended. According to the "Human Biomonitoring" Commission, even exceeding HBM-II values is not an indication for chelation therapy. The only exception is lead poisoning in children. Then chelation therapy is justified when the lead concentration is above 450 microgram per liter whole blood.

References

  1. Angle CR (1993) Childhood lead poisoning and its treatment. Annu Rev Pharmacol Toxicol 32:409- 434.
  2. Committee on Drugs of the American Academy of Pediatrics (1995) Treatment guidelines for lead exposure in children. Pediatr 96: 155-160.
  3. Mann KV, Travers JD (1991) Succimer, an oral lead chelator. Clin Pharm 10:914-922.
  4. Graziano JH (1993) Conceptual and practical advances in the measurement and clinical management of lead toxicity. Neurotoxicology 14(2-3): 219-224.
  5. Aposhian HV, Carter DE, Hoover TD, Chin-An Hsu, Maiorino RM, Stine E (1984) DMSA, DMPS, and DMPA - as arsenic antidotes. Fundamental and Applied Toxicology 4: S58-S70.
  6. Berlin M, Jerksell L-G, Nordberg G (1965) Accelerated uptake of mercury by brain caused by 2,3- dimercaptopropanol (BAL) after injection into the mouse of a methylmercuric compound. Acta Pharmacol Toxicol 23: 312-320.
  7. Cory-Slechta DA, Weiss B, Cox C (1987) Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther 243(3): 804-813.
  8. Graziano JH (1986) Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisoning. Med Toxicol 1: 155-162
  9. Hoover TD, Aposhian HV (1983) BAL increases the arsenic-74 content of rabbit brain. Toxicol Appl Pharmacol 70: 160-162
  10. Kreppel H, Paepcke U, Thiermann H, Szinicz L, Reichl FX, Singh PK, Jones MM (1993) Therapeutic efficacy of new dimercaptosuccinic acid (DMSA) analogues in acute arsenic poisoning in mice. Arch Toxicol 67: 580-585.
  11. Schäfer SG, Storp M, Richter E (1982) Subchronic treatment with sodium 2,3-dimercaptopropane-1- sulfonate in methylmercury poisoning. Bull Environm Contam Toxicol 29: 416-421.
  12. Glotzer DE, (1993) The current role of 2,3-dimercaptosuccinic acid (DMSA) in the management of childhood lead poisoning. Drug Safety 9(2): 85-92.
  13. Hofmann U, Segewitz G (1975) Influence of chelation therapy on acute lead intoxication in rats. Arch. Toxikol. 34 (3): 213-225
  14. Kosnett MJ (1992) Unanswered questions in metal chelation. J Toxicol Clin Toxicol 30(4): 529-547
  15. Mortensen ME, Walson PD (1993) Chelation therapy for childhood lead poisoning. Clin Pediatr 32: 284-291.
  16. Mortensen ME (1994) Succimer chelation: What is known? J Pediatr 125.
  17. Drasch G, Scharl K, Roider G, Schiwara HW, Zilker T, Steiner M, Schümann M (1997) Aussagekraft des DMPS-Test auf Quecksilber. Umweltmed Forsch Prax 2 (1): 2-10.
  18. Kleber JJ, Ganzert M, Zilker T (1995) Quecksilberkonzentration im Urin nach DMPS-Gabe: Korrelation zur Anzahl der Amalgamfüllungen. In: Friberg LT, Schrauzer GN (Hrsg) Status Quo and Perspectives of Amalgam and other Dental Materials. Georg Thieme Verlag, Stuttgart-New York, pp 61-69.
  19. Eis D, Ewers U, Schweinsberg F, Wilhelm M (1997) Pro und Contra DMPS-Mobilisations test. Umweltmed Forsch Prax 2(3): 161-164.

The above statement, announced in 1999 by the German federal environmental agency, was translated by Manfred Kroger, Ph.D., Professor of Food Science Emeritus, The Pennsylvania State University.

This article was posted on March 30, 2011

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