A methylmercury toxicity model to test for possible adverse effects resulting from chelating agent therapy

Abstract

A daily dosing model for methylmercury (MM) intoxication was developed for the purpose of testing for possible adverse effects resulting from the administration of complexing agents used in the treatment of MM poisoning. The dithiol complexing agents 2,3‐dimercaptopropanol (BAL) and meso‐2,3‐dimercaptosuccinic acid (DMSA) were chosen to test the discriminative ability of this model, since the former is contraindicated for MM poisoning and causes an increase in target organ MM burden, while the latter compound is known to be efficacious in reducing both toxicity and brain MM content. The basic design of the model called for daily observation of treated animals with identification of the following signs of MM intoxication: loss of body weight, onset of signs of toxicity, and mortality. The degree of toxicity was evaluated, and a toxicity score (0–5) was provided for each animal. A dose‐dependent decrease in body weight was found in MM‐treated mice. The latent period for development of signs of intoxication varied inversely with the dose rate. The rate of progression of severity of signs of intoxication was also dependent upon the dose. A dose rate of 14 mg Hg per kg per day was utilized to test the effects of BAL and DMSA on the onset and progression of signs of MM intoxication. Onset and progression of signs of methylmercury intoxication were similar for animals receiving methylmercury either alone or with administration of BAL at 2 mg per kg per day. Animals which received BAL at a dose rate of 20 mg per kg per day developed signs of intoxication significantly earlier. DMSA (500 mg kg⁻¹) either alone or in combination with BAL (20 mg kg⁻¹) protected animals against all signs of methylmercury poisoning. There was an insignificantly higher brain mercury concentration in animals receiving the 20 mg kg⁻¹ BAL dose when compared to controls, whereas animals receiving the 500 mg kg⁻¹ DMSA dose had brain concentrations one‐tenth that of matched control animals. The ability of DMSA to protect animals from the toxic effects of MM was confirmed, while BAL was shown to lack protective effects when given at the lower dose rate and to enhance MM toxicity when administered at the higher dose rate. This animal model of MM intoxication is useful in assessing both adverse and beneficial effects of new chelating agents on methylmercury intoxication.