Katherine M. Hurlbut

Mobilization of heavy metals by newer, therapeutically useful chelating agents

Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.

Human Studies with the Chelating Agents, DMPS and DMSA

Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin in humans and appears to be excreted in the urine as the DMSA-cysteine mixed disulfide. The pharmacokinetics of DMSA have been determined after its administration to humans po. For the blood, the tmax and t1/2 were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax was 26.2 microM + 4.7 SE. To determine whether dental amalgams influence the human body burden of mercury, we gave volunteers the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of subjects over a 9 h period. There was a positive correlation between the amount of mercury excreted and the amalgam score. DMPS might be useful for increasing the urinary excretion of mercury and thus increasing the significance and reliability of this measure of mercury exposure. DMSA analogs have been designed and synthesized in attempts to increase the uptake by cell membranes of the DMSA prototype chelating agents. The i.v. administration of the monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc chelate of dimethyl DMSA increases the biliary excretion of platinum and cadmium in rats.

Intravenous administration of oral N-acetylcysteine.

OBJECTIVE To report the indications and adverse events associated with administration of the oral N-acetylcysteine preparation by the intravenous route. DESIGN Retrospective consecutive case series analysis of 226,720 Toxic Exposure Surveillance System data sheets from a certified regional poison center during the period January 1, 1992 through December 31, 1993. SETTING A regional poison center certified by the American Association of Poison Control Centers. PATIENTS Seventy-six patients treated with the oral N-acetylcysteine solution by the intravenous route. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We report the indications and adverse events associated with the intravenous administration of the oral N-acetylcysteine preparation. Four (4/76, 5.3%) patients developed adverse events attributable to N-acetylcysteine. None of these events involved hemodynamic, cardiovascular, or pulmonary effects. All reactions occurred during infusion of the initial N-acetylcysteine dose. There were three (3/76, 3.9%) deaths overall; however, they were not attributable to the intravenous administration of the oral N-acetylcysteine preparation. CONCLUSIONS Intravenous administration of the oral N-acetylcysteine preparation appears to have limited adverse effects and offers another mechanism of delivery of the potentially lifesaving N-acetylcysteine when oral administration is not possible.

Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score.

There is considerable controversy as to whether dental amalgams may cause systemic health effects in humans because they liberate elemental mercury. Most such amalgams contain as much as 50% metallic mercury. To determine the influence of dental amalgams on the mercury body burden of humans, we have given volunteers, with and without amalgams in their mouth, the sodium salt of 2,3‐dimercaptopropane‐1‐sulfonic acid (DMPS), a chelating agent safely used in the Soviet Union and West Germany for a number of years. The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of the amalgam group from 0.70 to 17.2 μg and that of the nonamalgam group from 0.27 to 5.1 μg over a 9‐h period. Two‐thirds of the mercury excreted in the urine of those with dental amalgams appears to be derived originally from the mercury vapor released from their amalgams. Linear regression analysis indicated a highly significant positive correlation between the mercury excreted in the urine 2 h after DMPS administration and the dental amalgam scores. DMPS can be used to increase the urinary excretion of mercury and thus increase the significance and reliability of this measure of mercury exposure or burden, especially in cases of micromercurialism.—Aposhian, H. V.; Bruce, D. C.; Alter, W.; Dart, R. C.; Hurlbut, K. M.; Aposhian, M. M. Urinary mercury after administration of 2,3‐dimercaptopropane‐1‐sulfonic acid: correlation with dental amalgam score. FASEB J. 6: 2472‐2476; 1992.

Aldicarb Poisoning: A Case Report With Prolonged Cholinesterase Inhibition and Improvement After Pralidoxime Therapy

Aldicarb is the most potent of the commercially available carbamate pesticides and is an unusual source of acute human poisonings. We present the case of a 43-year-old man exposed to aldicarb who developed severe cholinergic symptoms and progressive weakness requiring intubation for 5 days. Both his red blood cell cholinesterase and plasma pseudocholinesterase levels were depressed for a minimum of 44 hours. He demonstrated neuromuscular improvement concurrent with pralidoxime administration. The pertinent medical literature on aldicarb poisoning is reviewed.

Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults.

We compared the pharmacokinetics of meso-2,3-dimercaptosuccinic acid (DMSA) in three children with lead poisoning, three adults with lead poisoning, and five healthy adult volunteers. All subjects received DMSA orally. Maximum blood concentration and time to maximum blood concentration of total DMSA concentration were not statistically different among the groups. Unaltered DMSA was detected in the blood of all poisoned patients but in only one of five healthy volunteers. Elimination half-life of total DMSA (parent drug plus oxidized metabolites) was longer in children with lead poisoning (3.0 +/- 0.2 hours) than in adults with lead poisoning (1.9 +/- 0.4 hours) and healthy adults (2.0 +/- 0.2 hours). Renal clearance of total DMSA was greater in healthy adults (77.0 +/- 13.2 ml/min per square meter) than in either adults (24.7 +/- 3.3 ml/min per square meter) or children with lead poisoning (16.6 ml/min per square meter); renal clearance of the metabolites of DMSA was also greater in healthy adults (64.6 +/- 10.1 ml/min per square meter) than in either adults (35.4 +/- 8.4 ml/min per square meter) or children with lead poisoning (19.5 ml/min per square meter). The DMSA appeared to enter the erythrocytes of patients with lead poisoning to a greater extent than in healthy adults. We conclude that renal clearance of DMSA and its metabolites may be impaired and that the distribution of DMSA in children with lead poisoning may be different from that in adults.