Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans

Samuel M. Cohen, Elliot B. Gordon, Pramila Singh, Gail T. Arce, Abraham Nyska

Research output: Contribution to journalReview article

29 Scopus citations

Abstract

A framework has been evolving for evaluation of mode of action (MOA) of rodent toxicity and carcinogenicity findings and their relevance to humans. Folpet produces duodenal glandular tumors in mice, but is not carcinogenic in rats. A wealth of information is available regarding folpet's mode of action, providing an excellent example of how this tumor can be evaluated using this framework. Folpet reacts with thiol groups, and is rapidly hydrolyzed at pH 7. Both reactions produce thiophosgene that reacts with thiols and other functional groups. Folpet is not genotoxic in vivo. At sufficiently high, prolonged dietary doses, folpet irritates the mouse duodenum, resulting in cytotoxicity with consequent regenerative proliferation and ultimately tumor development. Forestomach lesions secondary to cytotoxicity are also induced. Dogs have stomachs similar to humans and show no evidence of gastrointestinal toxicity or tumor formation at exposure levels at least as high as rodents. The data support a MOA in mice involving cytotoxicity and regenerative proliferation. Based on MOA analysis and assessment of human relevance, folpet, like captan, another trichloromethylthio-related fungicide with similar toxic and carcinogenic effects, is not likely to be a human carcinogen at dose levels that do not cause cytotoxicity and regenerative proliferation.

Original languageEnglish (US)
Pages (from-to)531-545
Number of pages15
JournalCritical reviews in toxicology
Volume40
Issue number6
DOIs
StatePublished - Jul 2010

Keywords

  • Captan
  • cytotoxicity
  • duodenum
  • folpet
  • regeneration
  • thiophosgene

ASJC Scopus subject areas

  • Toxicology

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