Toxicogenetics of niridazole in inbred mice

The lethal potency of the antischistosomal agent niridazole (NDZ) was compared in C57BL/6J (B6) and DBA/2J (D2) mice and in their F1 hybrid, backcross and F2 progeny. A daily i.p. dosage range was chosen so that the lethal effect, ascribed to central nervous system toxicity, did not occur before 4 to 5 days. Death was always preceded by a generalized tonic-clonic seizure which terminated in respiratory arrest. In B6 mice the LD50 was 202 mg kg-1 day-1 while in D2 mice the LD50 was 146 mg kg-1 day-1; the LD50 for NDZ in similarly treated F1 hybrid mice was found to be the arithmetic mean of the LD50 values for the parental strains (172 mg kg-1 day-1). Determination of the level of NDZ in the plasma and brains of B6 and D2 mice treated subacutely with the same daily dose of NDZ failed to reveal any strain differences. Moreover, there was no evidence of in vivo accumulation of NDZ with subacute treatment which suggests that a NDZ metabolite is responsible for the observed toxicity. An association between susceptibility to the lethal effects of NDZ and the Ah locus is suggested by experiments in backcross and F2 mice. The incidence of death observed after subacute treatment with 162 mg/kg-1 day-1 of NDZ matched that predicted on the basis of genotype, i.e., it was lethal to 72% of nonresponsive and 38% of aromatic hydrocarbon responsive mice.