Mode-of-action analysis for induction of rat liver tumors by pyrethrins: relevance to human cancer risk

Abstract

High doses of pyrethrins have been shown to produce liver tumors in female rats. Pyrethrins are not genotoxic agents. Pyrethrins produce liver tumors in rats by a mode of action (MOA) involving induction of hepatic xenobiotic metabolising enzymes, hypertrophy, increased cell proliferation, and the development of altered hepatic foci. The relevance of pyrethrins-induced rat liver tumors to human health was assessed by using the 2006 International Programme on Chemical Safety Human Relevance Framework. The postulated rodent tumor MOA was tested against the Bradford Hill criteria and was found to satisfy the conditions of dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity that fit with an established mode of action for rodent liver tumor formation by phenobarbital and related compounds, which are activators of the constitutive androstane receptor. Other possible MOAs including mutagenicity, cytotoxicity, hepatic peroxisome proliferation, porphyria, and hormonal pertubation were excluded. The proposed MOA is considered not to be plausible in humans because pyrethrins, like phenobarbital, do not induce cell proliferation in human hepatocytes. Moreover, epidemiological studies with phenobarbital demonstrate that such compounds do not increase the risk of liver tumors in humans. It is concluded that pyrethrins do not pose a hepatocarcinogenic hazard for humans.

Keywords::

• Cell proliferation
• cytochrome P-450 induction
• liver carcinogenesis
• mode of action
• pyrethrins

Acknowledgement

This work was supported by the Pyrethrin Joint Venture part of the Product Ingredient Review Program, Consumer Specialty Products Association, Washington, DC.

Declaration of interest: The authors alone are responsible for the content and writing of the paper.

Notes

¹ These numbers are an average of the values for 7 and 14 days of treatment.

² During calculation of the benchmark dose, the doses from the animal study are converted to the human equivalent dose. The calculated BMD and BMDL values were reduced 3.76-fold using current U.S. EPA default assumptions as described in the text. Thus the 10 × uncertainty factor for interspecies extrapolation is unnecessary and only the 10 × factor for intraspecies variability is needed. Even if the interspecies factor is considered, this is often broken down into times 3 for toxicokinetic and times 3 for toxicodynamic differences. Based on the HED adjustment, a maximum 3 times factor would be supported for species differences. Thus, regardless of whether most appropriate MOE is 10 times or 30 times, it is clear that the calculated HED, BMD, and BMDL values provide a very large MOE.