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

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.

Keywords::

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

Acknowledgments

We gratefully acknowledge the assistance of Cheryl Putnam with the preparation of the manuscript.

Declaration of interest

The authors’ employment affiliations are shown on the front page. Dr. Singh is employed by Makhteshim Agan of North America, Inc., a producer of folpet and captan. Drs. Cohen, Gordon, and Arce have served as consultants for Makhteshim Agan of North America, Inc., and Dr. Nyska was the study pathologist on some of the folpet chronic bioassays. The contents of this review reflect solely the view of the authors.