Nongenotoxic (epigenetic) carcinogens: pesticides as an example. A critical review.

The following groups of pesticides are considered in this review by supposed mechanisms of their carcinogenicity: hepatocarcinogenic pesticides, pesticides - peroxisome proliferators, pesticides as endocrine disruptors, goitrogenic pesticides, pesticides producing sustained cell proliferation and some others. With very rare exceptions, pesticides do not react with DNA directly and the mechanisms of their carcinogenicity are, in general, similar to those of other nongenotoxic (epigenetic) carcinogens, namely: promotion of spontaneous initiation, cytotoxicity with sustained cell proliferation, oxidative stress, formation of activated receptors and some others. Genotoxicity of pesticides varies from its complete absence (propiconazol as an example) to a very pronounced one (captafol) with remaining compounds in between. These two compounds demonstrate full correlation between genotoxicity and carcinogenicity (or their absence). Many pesticides give positive results in some tests for genotoxicity but these results are frequently controversial, not readily reproducible, or obtained only at toxic dose levels. The weak genotoxicity of the majority of pesticides is easily explainable by their rather severe testing before their introduction into practical use. The above mechanisms are threshold-based and therefore pesticides are regulated through NOEL/safety factor. There exist examples of lack of correlation between genotoxicity and carcinogenicity: some pesticides are genotoxic (although not strongly) but noncarcinogenic, others are considered as nongenotoxic but are strongly carcinogenic (chlorothalonil, acetochlor). The general scheme of the promoters' effect is presented in which an important role is attributed to the cytochrome P-450 induction (some pesticides are the cytochrome P-450 inducers), formation of reactive oxygen species and peroxitome proliferation. Teratogenesis Carcinog. Mutagen. 20:229-240, 2000. Copyright 2000 Wiley-Liss, Inc.