ETHYLENE THIOUREA (ETU) - A REVIEW OF THE GENETIC TOXICITY STUDIES

Ethylene thiourea (ETU) is a common contaminant, metabolite and degrad ation product of the fungicide class of ethylene bisdithiocarbamates ( EBDCs); as such, they present possible exposure and toxicological conc erns to exposed individuals. ETU has been assayed in many different te sts to assess genotoxicity activity. While a great number of negative results are found in the data base, there is evidence that demonstrate s ETU is capable of inducing genotoxic endpoints. These include respon ses for gene mutations (e.g. Salmonella), structural chromosomal alter ations (e.g. aberrations in cultured mammalian cells as well as a domi nant lethal assay) and other genotoxic effects (e.g. bacterial rec ass ay and several yeast assays). It is important to consider the magnitud e of the positive responses as well as the concentrations/doses used w hen assessing the genotoxicity of ETU. While ETU induces a variety of genotoxic endpoints, it does not appear to be a potent genotoxic agent . For example, it is a weak bacterial mutagen in the Salmonella assay without activation in strain TA1535 at concentrations generally above 1000 mug/plate. Weak genotoxic activity of this sort is usually observ ed in most of the assays with positive results. Since ETU does not app ear very potent and is not extremely toxic to test cells and organisms , it is not surprising to find that ETU does not produce consistent ef fects in many of the assays reviewed. Consequently, in many instances, mixed results for the same assay type are reported by different inves tigators, but as reviewed herein, these results may be dependent upon the test conditions in each individual laboratory. A primary shortcomi ng with many of the reported negative results is that the concentratio ns or doses used are not high enough for an adequate test for ETU acti vity. There are also problems with many of the negative assays general ly in protocol or reporting, particularly with the in vivo studies (e. g. inappropriate sample number and/or sampling times; inadequate top d ose employed). Overall, while ETU does not appear to be a potent genot oxic agent, it is capable of producing genotoxic effects (e.g. gene mu tations, structural chromosomal aberrations). This provides a basis fo r weak genotoxic activity by ETU. Furthermore, based on a suggestive d ominant lethal positive result, there may be a concern for heritable e ffects. Due to the many problems with the conduct and assessment of th e in vivo assays, it is worth repeating in vivo cytogenetic assays and a dominant lethal assay (with acceptable test procedures and data gen eration) to determine if these results would continue to support a her itable mutagenicity concern.