Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies

Toxicol Sci. 2016 Dec;154(2):296-308. doi: 10.1093/toxsci/kfw168. Epub 2016 Sep 7.


Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284-294.) reported MOA studies identifying the following key events: increased metabolism of fluensulfone by CYP2f2 in mouse lung Club cells, followed by local proliferation, finally leading to adenoma formation. Human lung microsomes were found not to metabolize fluensulfone. The Joint FAO/WHO Meeting on Pesticide Residues has reviewed the previous data and concluded that the MOA is plausible however some areas of uncertainty were identified. This publication provides additional data to address these. New cell proliferation studies in mice showed that the MOA is functionally independent of sex. A threshold of cell proliferation in Club cells correlating with the dose response for adenoma formation was shown. CYP2f2 knockout mice did not react to fluensulfone exposure with cell proliferation like wild-type mice, confirming the key role of this enzyme. The collective data for fluensulfone were evaluated according to the International Programme on Chemical Safety (IPCS) Mode of Action Framework which leads to the conclusion that the mouse-specific lung tumors after fluensulfone are not relevant to humans.

Keywords: IPCS; cell proliferation; fluensulfone; human relevance; mode of action.; mouse lung tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activation, Metabolic
  • Adenoma / chemically induced*
  • Adenoma / metabolism
  • Adenoma / pathology
  • Animals
  • Cell Proliferation / drug effects*
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cytochrome P-450 Enzyme System / deficiency
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pesticides / metabolism
  • Pesticides / toxicity*
  • Risk Assessment
  • Species Specificity
  • Sulfones / metabolism
  • Sulfones / toxicity*
  • Thiazoles / metabolism
  • Thiazoles / toxicity*
  • Time Factors


  • Pesticides
  • Sulfones
  • Thiazoles
  • Cytochrome P-450 Enzyme System
  • Cyp2f2 protein, mouse
  • fluensulfone