TY - JOUR
AU - Rice, Jerry, M.
AB - In the Forum article in this issue of Toxicological Sciences, Cohen et al. (2004) discuss a framework for systematic analysis of data on modes of carcinogenic action of chemicals in experimental animals, and its application to cancer risk assessment. This summarizes an exercise recently completed by the ILSI Risk Science Institute (Cohen et al., 2003), which builds on a harmonization initiative of the International Programme on Chemical Safety (Sonich-Mullin et al., 2001). The framework approach is based fundamentally on advances that have been achieved in recent decades in understanding the pathogenesis of neoplasia. It is now recognized that cancers originating from at least some cell types may arise by a variety of independent pathways. It is also established that different carcinogens may have different modes of action (MOAs), and that some carcinogens can act by more than one MOA in different tissues. Some MOAs lead to cancers in both experimental rodents and humans, but others that lead to cancers in rodents do not do so in humans, at least under realistic circumstances of human exposure. To refine and improve the process of carcinogenic hazard identification, and to avoid misidentification of harmless substances as possible human carcinogens, it has therefore become imperative that MOA analysis be undertaken for regulatory purposes, and that data to support such analysis be collected in a thorough and scientifically rigorous manner. Some who claim to represent the public interest do not share this view. They continue to affirm that chemically induced tumors in experimental animals invariably predict human cancer hazard, and to denounce any deviation from this faith as heretical and dangerous apostasy (Huff, 2003; Tomatis, 2002). They deny that toxicological science has until now provided adequate proof that any substance that causes tumors in rodents may do so by an MOA that is not relevant to humans, or that toxicology can achieve this in the foreseeable future. They argue that in the interest of public health, any chemical that is empirically shown to cause tumors in experimental rodents must be considered a cancer hazard to humans, on that basis alone. Never mind that there is real public health benefit in not having to classify orange juice as possibly carcinogenic to humans because it contains the rat renal carcinogen d-limonene, a conclusion that only advances in toxicology made possible. The fact is that incorporation of properly conducted MOA analysis into cancer risk assessments supports, rather than undermines, public health by focusing attention where it belongs, on substances that are most likely to pose a carcinogenic risk to humans. As MOA analysis gains momentum and continues to evolve, it is important that constructive criticism of the process and its underlying principles be encouraged. Thoughtful criticism can improve the process, and must not be confused with the often strident diatribes of those who utterly reject the concept. The framework approach addresses each experimental tumor site individually, and requires specific identification of key events for any proposed MOA, as well as identification and listing of data gaps. The burden of proof is on establishing the MOA. When data are insufficient to characterize a proposed MOA for carcinogenicity in experimental animals, the bioassay data are appropriately assumed to be relevant to humans by default. Cohen et al. (2004) describe the application of this approach to evaluation of six chemicals, considering seven putative MOAs. The examples described include one compound (acrylonitrile) for which neither of two proposed MOAs could be confidently established, and another (phenobarbital) for which an MOA could be confidently established for one tumor type (thyroid follicular cell tumors), but MOA analysis was not attempted for tumors of another kind (liver cell tumors). These conclusions highlight two major challenges for MOA analysis as a practical tool for carcinogen risk assessment: the limits of available data and the need for consensus on the acceptability of negative findings, especially for genotoxicity. Most chemicals that are known to cause human cancer are DNA-reactive, by themselves or via their metabolites, and evidence of genotoxicity cannot easily be dismissed by regulators. It is not uncommon, however, for one or more tests for genotoxicity to be weakly positive while others are negative. Under these circumstances not everyone may reach the same conclusion regarding weight of evidence for or against genotoxicity as an MOA. More effort needs to be focused on how to minimize discordance in interpreting inconsistent data sets for genotoxicity. MOA analysis depends on a robust scientific foundation for its validity, and building that foundation is still “work in progress.” To strengthen the credibility of MOA analysis, consensus is needed, preferably international consensus: to formulate and validate adequate and precise definitions of proposed modes of carcinogenic action; to establish that an MOA as defined actually does lead to tumor development; to develop criteria to establish that a substance causes tumors via a particular MOA; to conclude that any given MOA that operates in experimental animals does or does not also operate in humans under realistic conditions of human exposure. Consensus building is crucial for validation of novel MOAs that are not yet well established and that lack accepted precedents. The process of consensus building is best undertaken by focused, international, multidisciplinary scientific meetings with published proceedings that are convened by credible sponsors specifically for this purpose. Such meetings have been sponsored by national regulatory agencies, including the U.S. EPA; by ILSI, on behalf of national government agencies; and by international organizations, including agencies of the World Health Organization. For example, the IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans has undertaken to establish internationally accepted criteria for some MOAs and their application to human hazard identification, including peroxisome proliferation (IARC, 1995); α2-urinary globulin nephropathy, thyroid hormone dysregulation, and urinary bladder stones and precipitates (Capen et al., 1999); and on the predictive value of gastric neuroendocrine and forestomach tumors in rodents (IARC, 2003). More such efforts are needed to clarify the status of additional MOAs, such as particle overload in the respiratory tract and oxidative stress. Risk assessors cannot be expected to apply MOA analysis confidently and effectively without the support of solid reference documents on the MOAs in question. REFERENCES Capen, C. C., Dybing, E., Rice, J. M., and Wilbourn, J. D. 1999 . Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis. IARC Scientific Publication No. 147, International Agency for Research on Cancer, Lyon. Cohen, S. M., Fenner-Crisp, P. A., and Patton, D., Eds. 2003 . Special issue: Cancer modes of action and human relevance. Crit. Rev. Toxicol. 66, 581 –780. Cohen, S. M., Klaunig, J., Meek, M. E., Hill, R. N., Pastoor, T., Lehman-McKeeman, L., Bucher, J., Longfellow, D. G., Seed, J., Dellarco, V., Fenner-Crisp, P., and Patton, D. 2004 . Evaluating the human relevance of chemically induced animal tumors. Toxicol. Sci. xx, xxx –xxx. Huff, J. 2003 . IARC and the DEHP quagmire. Int. J. Occup. Environ. Health 9, 402 –404. IARC 1995 . Peroxisome Proliferation and Its Role in Carcinogenesis. Views and Expert Opinions of an IARC Working Group. IARC Technical Report No. 24, International Agency for Research on Cancer, Lyon. IARC 2003 . Predictive Value of Rodent Forestomach and Gastric Neuroendocrine Tumours in Evaluating Carcinogenic Risks to Humans. Views and Expert Opinions of an IARC Working Group. IARC Technical Publication No. 39, International Agency for Research on Cancer, Lyon. Sonich-Mullin, C., Fielder, R., Wiltse, J., Baetcke, K., Dempsey, J., Fenner-Crisp, P., Grant, D., Hartley, M., Knaap, A., Kroese, D., Mangelsdorf, I., Meek, E., Rice, J. M., and Younes, M. 2001 . IPCS Conceptual framework for evaluating a mode of action for chemical carcinogenesis. Reg. Toxicol. Pharmacol. 34, 146 –152. Tomatis, L. 2002 . The IARC monographs program: Changing attitudes towards public health. Int. J. Occup. Environ. Health 8, 144 –152. Toxicological Sciences vol. 78 no. 2 © Society of Toxicology; all rights reserved.
TI - On the Application of Data on Mode of Action to Carcinogenic Risk Assessment 2Formerly Chief, IARC Monographs Programme (1996–2002).
JO - Toxicological Sciences
DO - 10.1093/toxsci/kfh102
DA - 2004-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/on-the-application-of-data-on-mode-of-action-to-carcinogenic-risk-ID6B12Jr6F
SP - 175
EP - 177
VL - 78
IS - 2
DP - DeepDyve
ER -