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

The following groups of pesticides are considered in this review by suppose d mechanisms of their carcinogenicity: hepatocarcinogenic pesticides, pesti cides - peroxisome proliferators, pesticides as endocrine disrupters, goitr ogenic pesticides, pesticides producing sustained cell proliferation and so me others. With very rare exceptions, pesticides do not react with DNA dire ctly and the mechanisms of their carcinogenicity are, in general, similar t o those of other nongenotoxic (epigenetic) carcinogens, namely: promotion o f spontaneous initiation, cytotoxicity with sustained cell proliferation, o xidative stress, formation of activated receptors and some others. Genotoxi city of pesticides varies from its complete absence (propiconazol as an exa mple) to a very pronounced one (captafol) with reminaing compounds in betwe en. These two compounds demonstrate full correlation between genotoxicity a nd carcinogenicity (or their absence). Many pesticides give positive result s in some tests for genotoxicity but these results are frequently controver sial, not readily reproducible, or obtained only at toxic dose levels. The weak genotoxicity of the majority of pesticides is easily explainable by th eir rather severe testing before their introduction into practical use. The above mechanisms are threshold-based and therefore pesticides are regulate d through NOEL/safety factor. There exist examples of lack of correlation b etween genotoxicity and carcinogenicity: some pesticides are genotoxic (alt hough not strongly) but noncarcinogenic, others are considered as nongenoto xic 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 cyto chrome P-450 inducers), formation of reactive oxygen species and peroxitome proliferation. Teratogenesis Carcinog. Mutagen. 20:229-240, 2000. (C) 2000 Wiley-Liss, Inc.