THE GENETIC TOXICOLOGY OF ETHYLENETHIOUREA - A CASE-STUDY CONCERNING THE EVALUATION OF A CHEMICALS GENOTOXIC POTENTIAL

Ethylenethiourea (ETU) is a metabolite, environmental degradation prod uct and minor technical impurity of the ethylenebisdithiocarbamate (EB DC) class of fungicides. The genetic toxicology of ETU is important gi ven that ETU causes thyroid tumors in rodents and liver tumors in mice . Although it is clear that ETU induces thyroid tumors via a non-genot oxic, threshold mechanism, the role ETU plays in inducing mouse liver tumors remains to be fully elucidated. Recently, Dearfield (Mutations Res, 317, 111-132, 1994) reviewed the genetic toxicology of ETU, and c oncluded that, although ETU is not a potent genotoxic agent, it is wea kly genotoxic. This view stands in contrast to reports from several in dependent authorities that have generally concurred that ETU is not a mammalian genotoxin (IARC, 1987; MAFF, 1990; NTP, 1992; FAO/WHO, 1994) . These conflicting reports highlighted a generic problem in genotoxic ity safety assessment: although individual test results typically yiel d 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, 26 6, 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 neg ative) 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 indicated that ETU is not genotoxic in mamm alian systems and suggests that ETU likely induces mouse liver tumors by a non-genotoxic mechanism.