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

Abstract

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.

International regulatory needs for development ofan IATA for non-genotoxic carcinogenic chemical substances

“…The MoA for mammary gland tumors in the rat is species and strain specific (Simpkins et al, 2011) due to differences in the modulation of gonadotrophin releasing hormone (GnRH) pulse and impact upon the release of luteinizing hormone with alteration of ovulatory cycles -which are markedly different and not of human relevance, as recently concluded by the Risk Assessment Committee at ECHA (ECHA, 2015). The third example, captafol, a pesticide, is not considered genotoxic, but displays both hepatic and renal carcinogenicity (Rakitsky et al, 2000;IARC, 1991). However, most NGTxC that are renal carcinogens are negative in a standard cancer bioassay, and thus captafol is an example of a NGTx carcinogen related to the peroxisome proliferation in the liver of treated animals (Melnick, 2001), and this is not considered relevant to humans.…”

“…Induction of CYP 2B10 associated with CAR activation (Ren et al, 2010) In vitro liver microsomal CYP 1A2 induction (Lang et al, 1996(Lang et al, , 1997 Assessment of effects on CYP 1A1 and CYP 2B (Rahden-Staron et al, 2001) Level 0 (Q)SAR and structure activity information (Benigni, 2012;Serafimova et al, 2007; SAR and grouping based upon mammary gland tumor induction by various striazine compounds in rats (US EPA, 2002) Existing literature data (Rakitsky et al, 2000;NTP, 2008NTP, , 2011IARC, 1991 is important, also low probability of false negatives is critical.…”

Micronucleus assay in human lymphocytes after exposure to alloxydim sodium herbicide in vitro

“…Genotoxicity and cytotoxicity studies are frequently used to test numerous agrochemical compounds with different test systems (Ergene et al 2007;Lin and Garry 2000;Rakitsky et al 2000;Soloneski et al 2007Soloneski et al , 2008Soloneski and Larramendy 2010;Zeljezic et al 2006). These test systems are valuable and very well-known tools for the early and sensitive detection or estimation of genotoxic potential of chemicals.…”

Genotoxicity of the pestiside in Ames test and the possibility to formate the complexeses with DNA

“…Имеется до-статочное количество фактов, подтверждающих реальность генетической опасности накопления пестицидов в почве, воде и атмосфере [23,26,28]. В ряде работ показана генотоксичность пестицидов в отношении челове-ка [5,8,22,31]. Так у растений, обработанных базаграном обнаружи-вается большое количество хромосомных нарушений, проявляющихся на разных стадиях мейотического деления [32].…”