A 90-day study in rats with the monoglutathione conjugate of chlorothalonil

Wilson, Nelson H.; Killeen, James C.; Ford, William H.; Siou, G.; Busey, William M.; Eilrich, Gary L.

doi:10.1016/0378-4274(90)90113-z

Cited by 7 publications

(2 citation statements)

References 2 publications

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“…Other examples acting through this pathway include the fungicide chlorothalonil (Wilkinson and Killeen 1996), the widespread solvent, trichloroethylene (Lock and Reed 2006), and certain quinones (Monks and Lau 1992). For chlorothalonil, thiol metabolites have been detected in the urine of rats exposed to chlorothalonil (Wilson et al 1990) supporting the notion that a thiol metabolite is the likely proximate carcinogen for haloalkenes acting through GSH conjugation.…”

Section: Multiphase Bioactivation Involving Glutathione (Gsh) Conjugamentioning

confidence: 98%

Mechanisms of Rodent Renal Carcinogenesis Revisited

Hard¹

2018

Toxicol Pathol

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The important renal tumors that can be induced by exposure of rats to chemical carcinogens are renal tubule tumors (RTTs) derived from tubule epithelium; renal pelvic carcinoma derived from the urothelial lining of the pelvis; renal mesenchymal tumors (RMTs) derived from the interstitial connective tissue; and nephroblastoma derived from the metanephric primordia. However, almost all of our knowledge concerning mechanisms of renal carcinogenesis in the rodent pertains to the adenomas and carcinomas originating from renal tubule epithelium. Currently, nine mechanistic pathways can be identified in either the rat or mouse following chemical exposure. These include direct DNA reactivity, indirect DNA reactivity through free radical formation, multiphase bioactivation involving glutathione conjugation, mitotic disruption, sustained cell proliferation from direct cytotoxicity, sustained cell proliferation by disruption of a physiologic process (alpha 2u-globulin nephropathy), exaggerated pharmacologic response, species-dominant metabolic pathway, and chemical exacerbation of chronic progressive nephropathy. Spontaneous occurrence of RTTs in the rat will be included since one example is a confounder for interpreting kidney tumor results in chemical carcinogenicity studies in rats.

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Section: Multiphase Bioactivation Involving Glutathione (Gsh) Conjugamentioning

confidence: 98%

Mechanisms of Rodent Renal Carcinogenesis Revisited

Hard¹

2018

Toxicol Pathol

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“…The NOEL for these lesions in studies with chronic chlorothalonil feeding was about 2 mg/kg/day and chlorothalonil itself was responsible for the effect: its metabolite monoglutathione conjugate was unable to produce hyperplasia. Hyperplasia and hyperkeratosis regress after the cessation of chlorothalonil treatment for a limited period of time [33,34].…”

Section: Chlorothalonilmentioning

confidence: 99%

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

Rakitsky¹,

Koblyakov

Turusov

2000

Teratog. Carcinog. Mutagen.

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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.

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