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

• Published in: Toxicological sciences Vol. 108; no. 1; pp. 59 - 68
• Main Authors: Yamada, Tomoya, Uwagawa, Satoshi, Okuno, Yasuyoshi, Cohen, Samuel M., Kaneko, Hideo
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2009
• Subjects: Animals; Cell Proliferation; chemical carcinogenesis; conceptual framework; Cyclopropanes - toxicity; Cytochrome P-450 Enzyme System - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; dose-response relationships; Female; Fluorobenzenes - toxicity; Liver - enzymology; Liver - metabolism; Liver Neoplasms, Experimental - chemically induced; Male; Organ Size; phenobarbital; Phenobarbital - toxicity; Pyrethrins - toxicity; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - metabolism; Risk Assessment; Species Specificity; Time Factors; risk assessment; phenobarbital; chemical carcinogenesis; dose-response relationships; conceptual framework
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfp007

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.