Human acute intoxication from monochloroacetic acid: proposals for therapy

Monochloroacetic acid is an industrial chemical, used mainly for carboxylation reactions. It is handled either in molten form at 600 C, as crystalline flakes or in highly concentrated aqueous solutions. Monochloroacetic acid is readily absorbed after oral or dermal exposure. As it is a strong acid, it is corrosive. It can also induce severe systemic intoxication. Following accidental dermal exposure, 27 fatal (7 described in detail) and 15 non-fatal cases of severe acute systemic intoxication have been reported. The body surface involved was usually 10/ or higher in the fatal cases and 5-10/ in two of the non-fatal accidents. In one fatal and 13 non-fatal accidents, only the two hands (3-5/ of body surface) were involved, but contact was unusually long. In a few other incidents, workers had up to 10 / of their body surface burned without any signs of systemic intoxication. At least another 20 cases have been mentioned in the literature. Following accidental ingestion, one fatality has been described in detail. Symptoms are delayed for about one to three and a half hours following exposure. Vomiting occurs initially, followed by central nervous system disturbances (hyperexcitability, disorientation, convulsions), central nervous system depression and coma. There is cardiovascular involvement in all cases, with arrhythmia, tachycardia and cardiovascular shock. Blood creatinine levels are increased. In several cases, a severe metabolic acidosis has been observed; this is difficult to overcome and death generally occurs within four hours to seven days due to cardiovascular shock, renal failure and cerebral oedema. Data from animal and in vitro experience indicate that, due to inhibition of pyruvate-dehydrogenase and a-ketoglutarate hydrogenase enzyme complexes, clinical signs of toxicity and mortality develop directly in relation to an increase of cerebrospinal fluid lactate levels. Limited clinical data in humans and reproducible experimental data in rodents indicate that lactic acidosis is the main mechanism leading to toxic effects. It has been suggested that sodium bicarbonate solution is more effective than water for decontamination of the skin following exposure to monochloroacetic acid. There is, however, no clear experimental evidence to support this assumption. For practical purposes it is more important that decontamination begins as soon as possible, whether water or sodium bicarbonate solution is used. In the 1970s, various compounds from different therapeutic classes were investigated in experimental animals towards finding an effective antidote for monochloroacetic acid poisoning. These included antidotes for monofluoroacetic intoxication, sulphydryl donors, cytochrome P450 modulators, cholinergic, serotoninergic, GABAergic, and dopaminergic agonists and antagonists. None proved effective. The identification at the end of the 1980s of the role of lactic acidosis in monochloroacetic acid toxicity, opened the door for research into effective antidotes. Dichloroacetate, and to a lesser degree phenobarbitone, were identified as effective in reducing mortality and in decreasing lactate accumulation in the blood and cerebral spinal fluid of rats and mice following sub-lethal intoxication with monochloroacetic acid. Dichloroacetate acts directly on the involved enzyme systems while phenobarbitone probably acts through a non-specific "hibernation" effect. Based on the above data, a clinical workshop established a protocol for the treatment of monochloroacetic acid intoxication. The protocol, which has been incorporated by IPCS-INTOX into their Poison Information Monograph on MCAA, proposed the early administration of dichloroacetate (50 mg/kg, iv) as specific antidotal therapy to prevent the development of monochloroacetic acid-induced lactic acidosis. The Task Force supports this proposal and recommends improving the availability of dichloroacetate. Additionally the Task Force considers that if dichloroacetate is not available, treatment with phenobarbitone might be considered, provided that intensive care facilities are available