Relevance of mouse lung tumors to human risk assessment

ABSTRACT

Mouse lung is a common site for chemical tumorigenicity, but the relevance to human risk remains debated. Long-term bioassays need to be assessed for appropriateness of the dose, neither exceeding Maximum Tolerated Dose (MTD) nor Kinetically based Maximum Dose (KMD). An example of the KMD issue is 1,3-dichloropropene (1,3-D), which only produced an increased incidence of lung tumors at a dose exceeding the KMD. In addition, since mouse lung tumors are common (>1% incidence), the appropriate statistical significance is p < .01. Numerous differences exist for mouse lung and tumors compared to humans, including anatomy, respiratory rate, metabolism, tumor histogenesis, and metastatic frequency. The recent demonstration of the critical role of mouse lung specific Cyp2 F2 metabolism in mouse lung carcinogenicity including styrene or fluensulfone indicates that this tumor response is not qualitatively or quantitatively relevant to humans. For non-DNA reactive and non-mutagenic carcinogens, the mode of action involves direct mitogenicity such as for isoniazid, styrene, fluensulfone, permethrin or cytotoxicity with regeneration such as for naphthalene. However, the possibility of mixed mitogenic and cytotoxic modes of action cannot always be excluded. The numerous differences between mouse and human, combined with epidemiologic evidence of no increased cancer risk for several of these chemicals make the relevance of mouse lung tumors for human cancer risk dubious.

KEYWORDS:

• Mouse lung carcinogenesis
• 1,3-dichloropropene (1,3-D)
• isoniazid
• styrene
• club cell proliferation
• human relevance
• mode

Acknowledgments

Support for the preparation of this manuscript was provided by Corteva Agriscience.

Declaration of Interests

Dr. Yan is employed by Corteva Agriscience, the company that supported the preparation of this manuscript. Drs. Cohen and Bus are consultants to Corteva Agriscience. All of the authors have been involved with research on various chemicals that produce lung tumors in mice, including 1,3-D, styrene, isoniazid, fluensulfone, and permethrin.

Additional information

Funding

This work was supported by the Corteva Agriscience.