The genetic toxicology of ethylenethiourea: a case study concerning the evaluation of a chemical's genotoxic potential

Ethylenethiourea (ETU) is a metabolite, environmental degradation product and minor technical impurity of the ethylenebisdithiocarbamate (EBDC) class of fungicides. The genetic toxicology of ETU is important given that ETU causes thyroid tumors in rodents and liver tumors in mice. Although it is clear that ETU induces thyroid tumors via a non-genotoxic, threshold mechanism, the role ETU plays in inducing mouse liver tumors remains to be fully elucidated. Recently, Dearfield (Mutation Res., 317, 111–132, 1994) reviewed the genetic toxicology of ETU, and concluded that, although ETU is not a potent genotoxic agent, it is weakly genotoxic. This view stands in contrast to reports from several independent authorities that have generally concurred that ETU is not a mammalian genotoxin (IARC, 1987; MAFF, 1990; NTP, 1992; FAO/WHO, 1994). These conflicting reports highlight a generic problem in genotoxicity safety assessment: although individual test results typically yield either a positive or negative response, the overall evaluation of an extensive battery of tests for a particular chemical rarely yields an unambiguous conclusion. Recently, Mendelsohn et al. (Mutation Res., 266, 43–60, 1992) showed that the response of a chemical to a battery of genotoxicity tests is not a dichotomous (i.e., either positive or negative) property, but rather, appears to be a continuous property that ranges from strongly negative to strongly positive. We have used these data, together with a four-step weight of the evidence procedure, to evaluate ETU. Our analysis indicates that ETU is not genotoxic in mammalian systems and suggests that ETU likely induces mouse liver tumors by a non-genotoxic mechanism.