Evaluation of the human hazard of the liver and lung tumors in mice treated with permethrin based on mode of action

Abstract

The non-genotoxic synthetic pyrethroid insecticide permethrin produced hepatocellular adenomas and bronchiolo-alveolar adenomas in female CD-1 mice, but not in male CD-1 mice or in female or male Wistar rats. Studies were performed to evaluate possible modes of action (MOAs) for permethrin-induced female CD-1 mouse liver and lung tumor formation. The MOA for liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), increased hepatocellular proliferation, development of altered hepatic foci, and ultimately liver tumors. This MOA is similar to that established for other PPARα activators and is considered to be qualitatively not plausible for humans. The MOA for lung tumor formation by permethrin involves interaction with Club cells, followed by a mitogenic effect resulting in Club cell proliferation, with prolonged administration producing Club cell hyperplasia and subsequently formation of bronchiolo-alveolar adenomas. Although the possibility that permethrin exposure may potentially result in enhancement of Club cell proliferation in humans cannot be completely excluded, there is sufficient information on differences in basic lung anatomy, physiology, metabolism, and biologic behavior of tumors in the general literature to conclude that humans are quantitatively less sensitive to agents that increase Club cell proliferation and lead to tumor formation in mice. The evidence strongly indicates that Club cell mitogens are not likely to lead to increased susceptibility to lung tumor development in humans. Overall, based on MOA evaluation it is concluded that permethrin does not pose a tumorigenic hazard for humans, this conclusion being supported by negative data from permethrin epidemiological studies.

Keywords:

• Carcinogenicity
• cell proliferation
• Club cells
• enzyme induction
• hepatocytes
• liver tumor
• lung tumor
• mitogen
• mode of action
• non-genotoxic
• human relevance
• permethrin
• peroxisome proliferator-activated receptor alpha
• species differences
• risk assessment

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

The authors gratefully acknowledge members of the Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd. for their encouragement to collect data for this manuscript; and also to Dr. Keiko Ogata for the internal review of the manuscript; and to the external reviewers selected by the Editor and anonymous to the authors whose comments were valuable in revising and refining the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declaration of interest

The affiliations of the authors are shown on the cover page. Dr. Tomoya Yamada is employed by Sumitomo Chemical Company, Ltd. Prof. Samuel M. Cohen and Prof. Brian G. Lake consult for Sumitomo Chemical Company, Ltd. regarding research on chemical-induced carcinogenicity as well as other matters. The manuscript was written as part of the authors’ normal employment, but the authors have sole responsibility for the writing and content of this paper. The views presented in this manuscript are those of the authors based on many years of research in the respective areas of the investigation reported in this paper. This work was supported by the Sumitomo Chemical Company, Ltd. (https://www.sumitomo-chem.co.jp/english/company/). This company is interested in the human relevance of the MOA for chemical-induced rodent tumor formation because some company products (e.g. pesticides) have carcinogenicity in rodents. Permethrin is also one of the company products. Some of the research on permethrin produced by Sumitomo Chemical Company, Ltd. has been utilized by the company in regulatory submissions to provide MOA information for interpreting the relevance to humans of the liver and lung tumors in mice. An additional review of the paper for internal approval purposes was conducted by Dr. Kyoko Odawara, a research director of Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd. No external funding was obtained for manuscript preparation. None of the authors has appeared in any legal or regulatory proceedings related to the contents of this paper. No potential conflict of interest was reported by the authors.