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Mode of action analysis for pesticide‐induced rodent liver tumours involving activation of the constitutive androstane receptor: relevance to human cancer risk
Author(s) -
Lake Brian G,
Price Roger J,
Osimitz Thomas G
Publication year - 2015
Publication title -
pest management science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 125
eISSN - 1526-4998
pISSN - 1526-498X
DOI - 10.1002/ps.3854
Subject(s) - constitutive androstane receptor , biology , cytochrome p450 , rodent , mode of action , carcinogen , pharmacology , nuclear receptor , liver injury , cyp2e1 , receptor , pregnane x receptor , toxicology , endocrinology , genetics , metabolism , gene , ecology , transcription factor
A number of non‐genotoxic chemicals, including some pesticides, have been shown to increase the incidence of liver tumours in rats and/or mice. Frameworks for analysing the modes of action ( MOAs ) by which chemicals produce liver tumours in rodents and the relevance of such tumour data for human risk assessment have now been established. One common MOA for rodent liver tumour formation by non‐genotoxic chemicals involves activation of the constitutive androstane receptor ( CAR ). Key and associative events for a CAR ‐activation MOA include receptor activation, liver hypertrophy, induction of cytochrome P450 enzyme activities, increased replicative DNA synthesis, altered hepatic foci and liver tumours. While some effects of rodent CAR activators can be observed in human liver, a major species difference is that, unlike rodents, CAR activators do not increase replicative DNA synthesis in human hepatocytes. The CAR ‐activation MOA for rodent liver tumour formation is thus not plausible for humans, and hence such compounds do not pose a hepatocarcinogenic hazard for humans. © 2014 Society of Chemical Industry