title: Mode of action analysis for pesticide-induced rodent liver tumours involving activation of the constitutive androstane receptor: relevance to human cancer risk.
abstract: 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.
authors.affiliation: Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lake
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Price
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Osimitz
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D004261:DNA Replication / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010575:Pesticides / Q000633:toxicity*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012306:Risk
chemical_list: D000090702:Constitutive Androstane Receptor; D010575:Pesticides; D018160:Receptors, Cytoplasmic and Nuclear
keywords: constitutive androstane receptor; cytochrome P450; human risk assessment; mode of action; pesticides; rodent liver tumours