An evaluation of the human relevance of the lung tumors observed in female mice treated with permethrin based on mode of action

Tomoya Yamada, Miwa Kondo, Kaori Miyata, Keiko Ogata, Masahiko Kushida, Kayo Sumida, Satoshi Kawamura, Thomas G. Osimitz, Brian G. Lake, Samuel Monroe Cohen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Permethrin increased the incidence of bronchiolo-alveolar adenomas in female mice but not male mice or female or male rats. Studies were conducted to determine whether permethrin has mitogenic activity in Club cells in mouse lung as the basis for the mode of action (MOA) for the lung adenoma induction. Several short-term experiments focusing on timecourse, dose-response, reversibility, sex difference, strain difference, and species difference were evaluated for Club cell proliferation and morphology. The findings demonstrated that permethrin slightly and continuously enhanced Club cell proliferation at tumor-associated dose levels in female mice, but did not increase proliferation in male mice or in female rats. Electron microscopic examination demonstrated that permethrin produced morphological alterations in Club cells prior to increasing the Club cell proliferation. There was no evidence of increased cell death. These alterations in Club cells were also observed with a close structural analog cypermethrin. Taken together, the present studies provide evidence that the MOA for induction of mouse lung adenomas by permethrin involves slight morphological effects on Club cells, sustained Club cell proliferation, and eventually hyperplasia and bronchiolo-alveolar adenoma in susceptible mice. The potential human carcinogenic hazard of permethrin based on the tumorigenic MOA for lung tumors in mice was evaluated using the International Programme on Chemical Safety Human Relevance Framework. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and tumor formation in mice, it is not likely permethrin will lead to an increase in susceptibility to lung tumor development in humans. Epidemiological data for permethrin strongly supports this conclusion.

Original languageEnglish (US)
Pages (from-to)465-486
Number of pages22
JournalToxicological Sciences
Volume157
Issue number2
DOIs
StatePublished - Jan 1 2017

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Permethrin
Tumors
Cell proliferation
Lung
Adenoma
Neoplasms
Cell Proliferation
Rats
Chemical Safety
Cell death
Human Development
Sex Characteristics
Hazards
Microscopic examination
Hyperplasia
Cell Death
Electrons

Keywords

  • Cell proliferation
  • Lung tumorigenesis
  • Nongenotoxic
  • Risk assessment
  • Toxicogenomics

ASJC Scopus subject areas

  • Toxicology

Cite this

An evaluation of the human relevance of the lung tumors observed in female mice treated with permethrin based on mode of action. / Yamada, Tomoya; Kondo, Miwa; Miyata, Kaori; Ogata, Keiko; Kushida, Masahiko; Sumida, Kayo; Kawamura, Satoshi; Osimitz, Thomas G.; Lake, Brian G.; Cohen, Samuel Monroe.

In: Toxicological Sciences, Vol. 157, No. 2, 01.01.2017, p. 465-486.

Research output: Contribution to journalArticle

Yamada, T, Kondo, M, Miyata, K, Ogata, K, Kushida, M, Sumida, K, Kawamura, S, Osimitz, TG, Lake, BG & Cohen, SM 2017, 'An evaluation of the human relevance of the lung tumors observed in female mice treated with permethrin based on mode of action', Toxicological Sciences, vol. 157, no. 2, pp. 465-486. https://doi.org/10.1093/toxsci/kfx066
Yamada, Tomoya ; Kondo, Miwa ; Miyata, Kaori ; Ogata, Keiko ; Kushida, Masahiko ; Sumida, Kayo ; Kawamura, Satoshi ; Osimitz, Thomas G. ; Lake, Brian G. ; Cohen, Samuel Monroe. / An evaluation of the human relevance of the lung tumors observed in female mice treated with permethrin based on mode of action. In: Toxicological Sciences. 2017 ; Vol. 157, No. 2. pp. 465-486.
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