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ToxSci Advance Access originally published online on January 27, 2009
Toxicological Sciences 2009 108(1):59-68; doi:10.1093/toxsci/kfp007
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Case Study: An Evaluation of the Human Relevance of the Synthetic Pyrethroid Metofluthrin-Induced Liver Tumors in Rats Based on Mode of Action

Tomoya Yamada*,1, Satoshi Uwagawa*, Yasuyoshi Okuno*, Samuel M. Cohen{dagger} and Hideo Kaneko*

* Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka, Japan {dagger} Department of Pathology and Microbiology, Havlik-Wall Professor of Oncology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135

1 To whom correspondence should be addressed at Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd. 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka, Japan. Fax: +81-66466-5354. E-mail: yamadat8{at}sc.sumitomo-chem.co.jp.

Received December 24, 2008; accepted January 6, 2009


  Abstract

In recent years, mode of action (MOA) frameworks have been developed through the International Life Sciences Institute Risk Science Institute and the International Programme on Chemical Safety, including an evaluation of the human relevance of the animal MOA data. In the present paper, the MOA for rat liver tumors induced by Metofluthrin is first analyzed through this framework based on data from studies on Metofluthrin and information on related chemicals from the literature. The human relevance of the rat liver carcinogenic response is then discussed based upon the human relevance framework. Two-year treatment with high dose of Metofluthrin produced hepatocellular tumors in both sexes of the Wistar rats. Metofluthrin induced CYP2B (increased smooth endoplasmic reticulum), resulted in increased liver weights which were associated with centrilobular hepatocyte hypertrophy, and induction of increased hepatocellular DNA replications. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. Furthermore, CYP2B induction by Metofluthrin was shown to involve activation of the constitutive androstane receptor in rat hepatocytes. Based on the evidence, including a comparison with the results with another chemical, phenobarbital, acting by a similar MOA, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans.

Key Words: chemical carcinogenesis; risk assessment; conceptual framework; dose-response relationships; phenobarbital.


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