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

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.

Genetic toxicology of folpet and captan.

Folpet and captan are fungicides whose genotoxicity depends on their chemical reaction with thiols. Multiple mutagenicity tests have been conducted on these compounds due to their positive activity in vitro and their association with gastrointestinal tumors in mice. A review of the collective data shows that these compounds have in vitro mutagenic activity but are not genotoxic in vivo. This dichotomy is primarily due to the rapid degradation of folpet and captan in the presence of thiol-rich matrices typically found in vivo. Genotoxicity has not been found in the duodenum, the mouse tumor target tissue. It is concluded that folpet like captan presents an unlikely risk of genotoxic effects in humans.