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

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

Research output: Contribution to journalReview article

27 Citations (Scopus)

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 - Jan 1 2010

Fingerprint

Cytotoxicity
Tumors
Sulfhydryl Compounds
Toxicity
Rodentia
Neoplasms
Captan
Fungicides
Poisons
Duodenum
Carcinogens
Functional groups
folpet
Rats
Stomach
Dogs

Keywords

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

ASJC Scopus subject areas

  • Toxicology

Cite this

Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans. / Cohen, Samuel Monroe; Gordon, Elliot B.; Singh, Pramila; Arce, Gail T.; Nyska, Abraham.

In: Critical reviews in toxicology, Vol. 40, No. 6, 01.01.2010, p. 531-545.

Research output: Contribution to journalReview article

Cohen, Samuel Monroe ; Gordon, Elliot B. ; Singh, Pramila ; Arce, Gail T. ; Nyska, Abraham. / Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans. In: Critical reviews in toxicology. 2010 ; Vol. 40, No. 6. pp. 531-545.
@article{edd2d1e68de74e63a5624b2a16ef5a12,
title = "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",
author = "Cohen, {Samuel Monroe} and Gordon, {Elliot B.} and Pramila Singh and Arce, {Gail T.} and Abraham Nyska",
year = "2010",
month = "1",
day = "1",
doi = "10.3109/10408441003742903",
language = "English (US)",
volume = "40",
pages = "531--545",
journal = "Critical Reviews in Toxicology",
issn = "1040-8444",
publisher = "Informa Healthcare",
number = "6",

}

TY - JOUR

T1 - Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans

AU - Cohen, Samuel Monroe

AU - Gordon, Elliot B.

AU - Singh, Pramila

AU - Arce, Gail T.

AU - Nyska, Abraham

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

KW - Captan

KW - cytotoxicity

KW - duodenum

KW - folpet

KW - regeneration

KW - thiophosgene

UR - http://www.scopus.com/inward/record.url?scp=77953896264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953896264&partnerID=8YFLogxK

U2 - 10.3109/10408441003742903

DO - 10.3109/10408441003742903

M3 - Review article

VL - 40

SP - 531

EP - 545

JO - Critical Reviews in Toxicology

JF - Critical Reviews in Toxicology

SN - 1040-8444

IS - 6

ER -