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A Data-Based Assessment of Alternative Strategies for Identification of Potential Human Cancer Hazards
1 Imperial College London, London, United Kingdom Correspondence: Nancy G. Doerrer, MS, ILSI Health and Environmental Sciences Institute, 1156 Fifteenth Street, NW, Second Floor, Washington, D.C. 20005, USA; e-mail:ndoerrer{at}hesiglobal.org. The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.
Key Words: carcinogenesis • carcinogenicity testing • DNA reactivity • liver carcinogenesis • kidney carcinogenesis • lung carcinogenesis • immunosuppression • nongenotoxic carcinogens • mode of action Abbreviations: AAF, 2-acetylaminofluorene • ALT, alanine transaminase • B[a]P, benzo[a]pyrene • CAR, constitutive androstane receptor • CHIS, Cancer Hazard Identification Strategies (HESI Project Committee) • DNA, deoxyribonucleic acid • EPA, U.S. Environmental Protection Agency • HESI, Health and Environmental Sciences Institute • ICH, International Conference on Harmonisation • ILSI, International Life Sciences Institute • IPCS, International Programme on Chemical Safety • MN-NCE, micronucleated normochromatic erythrocytes • MN-PCE, micronucleated polychromatic erythrocytes • MOA, mode of action • NCI, National Cancer Institute • NOS, not otherwise specified • NTP, National Toxicology Program • OECD, Organisation for Economic Cooperation and Development • SCE, sister chromatid exchange • SDH, sorbitol dehydrogenase
This version was published on October
1, 2009 Toxicologic Pathology, Vol. 37, No. 6,
714-732 (2009) |
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