Based on an analysis of mode of action, styrene-induced mouse lung tumors are not a human cancer concern

Regulatory Toxicology and Pharmacology : RTP
George CruzanRobbie Waites

Abstract

Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung. Although styrene-7,8-oxide (SO) is a common genotoxic styrene metabolite in in vitro studies, the data clearly demonstrate that SO is not the proximate toxicant and that styrene does not induce a genotoxic mode of action. Based on complete attenuation of styrene short-term and chronic toxicity in CYP2F2 knockout mice and similar attenuation in CYP2F1 (humanized) transgenic mice, limited metabolism of styrene in human lung by CYP2F1, 2 + orders of magnitude lower SO levels in human lung compared to mouse lung, and lack of styrene-related increase in lung cancer in humans, styrene does not present a risk of cancer to humans.

Citations

Aug 30, 2019·Journal of Occupational and Environmental Medicine·Nalini SathiakumarElizabeth Delzell
May 27, 2020·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Samuel M CohenJames S Bus
Jul 10, 2019·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·M I BantonS S Sarang
Feb 13, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Melvin E Andersen, James S Bus
Mar 8, 2021·Molecular and Cellular Endocrinology·Typhanie Dumontet, Antoine Martinez
Jun 5, 2021·Mutation Research. Reviews in Mutation Research·B Bhaskar GollapudiJames S Bus
Jul 30, 2021·Chemico-biological Interactions·Nalini SathiakumarElizabeth Delzell

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