An Evaluation of the Human Relevance of the Lung Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action

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 time-course, 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.