Folpet-induced short term cytotoxic and proliferative changes in the mouse duodenum

Abstract

Folpet, an agricultural fungicide, induces tumors in the mouse gastrointestinal tract, primarily in the duodenum. Bioassays show a threshold for tumors at ~1000 ppm dietary administration. We investigated the early histologic changes to the mouse duodenum in mice fed a diet containing 6000 ppm folpet for 28 days. Reversibility of folpet-induced changes was evaluated after treatment for 28 days and a recovery period of 17 days. Macroscopic changes in the cecum (dilatation) and duodenum (roughening) were evident by day 7, continued through day 28, then returned to normal by recovery day 17. The duodenal mucosa also appeared to be thickened. Macroscopic changes to the forestomach were also evident as a rough surface or depressions; they also decreased in incidence and severity in the recovery animals. Histologic changes of the duodenum (crypt cell hyperplasia, villous hypertrophy, numerous intraepithelial lymphocytes, and elongation of epithelial columnar cells) were evident in all treated mice by day 7 and continued and increased in severity through 28 days of administration. The incidence and severity of these findings was reduced on recovery day 17, indicating reversibility. Histologic changes (epithelial hyperplasia and hyperkeratosis) of the non-glandular squamous epithelium in the forestomach occurred later than the changes to the duodenum. The incidence and severity of these changes also lessened by recovery day 17. These early histologic changes support a non-DNA reactive mode of action for folpet carcinogenicity in mice involving the key events of mucosal cytotoxicity with consequent regenerative proliferation. Exposures that are not sufficient to produce cytotoxicity would also not lead to tumor formation.

Keywords::

• Carcinogenesis
• risk assessment
• duodenum
• pesticide
• fungicide

Acknowledgements

We gratefully acknowledge the assistance of Cheryl Putnam in the preparation of this manuscript, Gail Arce, PhD for her critical review and Dr. B. Gangadharam, BVSc&AH; MCSc(Path); PhD and Mrs. C. J. Chesher, BSc(Hons) at Huntingdon Life Sciences for their work in the conduct of this study.

Declaration of interest

Elliot Gordon and Samuel M. Cohen are consultants that have worked for Makhteshim Agan of North America, Inc. Pramila Singh was formerly employed by Makhteshim Agan of North America, Inc., a producer of folpet.