T OXICOLOGIC PATHOLOGY, vol 29(Suppl.), pp 5– 12, 2001 Copyright C 2001 by the Society of Toxicologic Pathology Setting the Stage Assessment of Human Cancer Risk: Challenges for Alternative Approaches GILBERT S. OMENN The University of Michigan, Ann Arbor, Michigan ABSTRACT The ILSI/HESI Workshopon Alternatives to Carcinogenicity Testing aims to develop and apply new methods for assessment of potential carcinogenic risk to humans from various chemicals. The Workshop represents a major cooperative scientic effort. The long-term goals should be to greatly enhance the efciency and reliability of such testing and to supplant, not just supplement, lifetime rodent bioassays. There are now well-established frameworks for risk assessment and risk management, putting risks into public health context and engaging stakeholders. The Lave-Omenn value-of-information model provides a useful way to assess the social costs and benets of different strategies for testing large numbers of chemicals. Keywords. Cancer risk assessment; risk management; cost-effectiveness analysis; public health context; value-of-information model; social costs. INTRODUCTION The International Life Sciences Institute’s (ILSI) Alterna- tives to Carcinogenicity Testing (ACT) workshop brought together collaborators from many countries in an effort to advance the eld of hazard identication for chemicals. The aims of the ILSI ACT Program may be summarized as follows: 1. Develop and apply new methods for assessment of poten- tial carcinogenic risk to humans from a great variety of chemicals. 2. Stimulate a cooperative scientic effort. 3. Promote consideration of use of new tests and data in risk assessment. The desired outcomes for this effort are to provide a better mechanistic basis for interpretation of short-term tests and rodent lifetime bioassay results and to generate results and interpretations of results more reliably related to risk in hu- mans. I believe we should look forward to a time when new, better understood tests will supplant, not just supplement, rodent lifetime bioassays. We have a large challenge. The public around the world nds scientists’ conicts over the interpretation of toxico- logical and epidemiological scientic evidence bewildering. There is also a common observation that the interpretation by scientists may be highly correlated with employment in in- dustry versus employment in governmental regulatory agen- cies. Surely we can make progress in agreement on the nature of the testing to be done and the analysis of the results, both mechanistically and statistically. The decisions on what to do Address correspondence to: Gilbert S. Omenn, The University of Michigan, 7324 Medical Science I Building, Ann Arbor, MI 48109-0626. with that information rest on larger issues, statutes, policies, and economic interests, discussed later in this paper. As we develop new test strategies and infer risk for hu- mans there is a much neglected biological phenomenon that deserves more emphasis, namely, the crucial inuence of heterogeneity. We should always speak of “cancers” in the plural for there are multiple causes, multiple pathogenetic pathways, and varied responses to treatments and preventive interventions. The phrase “The War on Cancer,” which began in 1970 in the United States, was an illusion, as if there might be a unitary cause and a miraculous cure for all kinds, or at least most kinds, of cancers. Over these decades we have noted the emergence from basic science studies of new signal- ing pathways, many specic receptors, an ever-growing array of molecular targets, and now distinctive mRNA and protein expression patterns. This molecular heterogeneity and the corresponding epidemiological and clinical heterogeneity are highly relevant for research strategies on mechanisms, diag- nosis, treatments, preventive interventions, and testing. In this Workshop, we are focused on the implications for testing. Finally, we should recognize the ramications of analyzing subpopulations with the new tools of pharmaco-genomics. Subpopulations may exhibit variation in biotransformation of pharmaceutical agents and variation in therapeutic or ad- verse effects of those agents at target sites. Many companies are concerned that the US Food and Drug Administration (FDA) and counterpart agencies in other countries might require just as extensive clinical trials in these subgroups as in larger populations, making the studies more difcult and more costly to conduct and possibly limiting the mar- kets to more narrowly dened patient populations. On the other hand, a drug candidate that might be rejected due to infrequent adverse reactions might be approvable and widely used if those at risk for the adverse effect could be reliably 5 0192-6233/01$3.00 $0.00 at UNIV OF MICHIGAN on September 14, 2011 tpx.sagepub.com Downloaded from