Rgearchin NOVEMBER/DECEMBER 1992 VOLUME 5, NUMBER 6 0 Copyright 1992 by the American Chemical Society
Commentary Of Mice and Men: Human Risk Assessment Based on High-Dose Rodent Exposure For the past twenty or so years, the rodent bioassay has been the gold standard for the identification of potential human carcinogens. However, there have always been misgivings about ita use for human risk assessmentbecause of the necessity to extrapolate results from high-dose exposurein mice and rata to low-dose exposure in humans. Are mice or rata appropriate models for human beings; would anyone ever drink lo00 cans a day of a beverage containing saccharin? The assumption of a linear, nonthreshold dose-response as the basis for quantitative risk assessmentleads to an estimate that exposureto low doses of a given compound will lead to x number of deaths annually from a particular cancer. The large size of the human population ensures that virtually any compound that testa positive in the rodent bioassay will be considered a potential human carcinogen at some level of risk. Uncertainties about high-dose-low-dose extrapolation have made the rodent bioassay a frequent source of controversy. Some contend that the linearity of the doseresponse for tumorigenesis is not firmly established and that the assumption of linearity ignores the protective effects of detoxification and repair. Others argue that the testing of chemicals as pure compounds ignores the possible synergistic effects that would result from real-world exposure to complex mixtures. Still others point out that a purely statistical interpretation of the bioassay results ignores potential differences in mechanisms of carcinogenesis that may render extrapolation to humans inappropriate. These concerns are not resolved. In fact, a vigorous debate over the high-dose-low-dose extrapolation has erupted. One major new criticism has emerged with the finding that, at high doses, chemicals induce toxic effects that result in cell proliferation, which is a recognized contributor to the carcinogenic process. At low doses of compound administration, where toxicity doesn't occur, this factor would be unimportant. The second factor that
has rekindled debate is the growing realization that a good deal of DNA adduction occurs from endogenous metabolic processes. The argument goes "What difference do a few more adducts make to carcinogenic risk when there are already substantial numbers of adducts made in a human cell every day from normal metabolism?" The debate over the validity of high-dose animal exposure to human risk assessment has been waged in scientific magazines, in letters to the editor, and at scientific meetings. At times, the arguments have had a personal and/or political tone and their scientific underpinnings have been obscured. It is healthy to challenge established dogma, especially when new information comes to light. Testing and retesting hypotheses is the foundation of the scientific method. However, the outcome of this debate has enormous importance for the health and welfare of the human population, so it is important for the scientific community to understand the experimental data supporting both sides of the issue. This year's Forum, a feature begun in 1990 in Chemical Research in Toxicology, contains articles from three groups actively involved in carcinogenesis testing and risk assessment. Dick Griesemer begins by explaining the protocols of the rodent bioassay, the criteria for selection of compounds, and the information that it provides. He addresses the linearity of the dose-response for carcinogenesis and stresses the importance of understanding mechanism for the development of better and faster bioassays. Sam Cohen and Leon Ellwein discuss the importance of understanding the mechanism of action of carcinogens for extrapolating the results of bioassays to human beings. Characterization of compounds as genotoxic or nongenotoxic and further subdivision of nongenotoxic chemicals into receptor- or non-receptordependent establishes a minimum of three different bases for extension to humans. Finally, Miriam Poirier and Fred
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Beland discuss the use of DNA adducts for risk assessment and human extrapolation. They point out that although steady-state levels of DNA adducts derived from genotoxic chemicals are usually linear with dose, correlation with tumorigenicity does not always occur. The relationship between adduct levels and risk appears simple in some cases, complex in others. Poirier and Beland conclude with a real-world risk assessment for cigarette smoking and human bladder cancer based on DNA adduct levels that is surprising and provocative. These are three well-written articles that effectively convey the scientific basis of the arguments for and against the use of the rodent bioassay for human risk assessment. Although the authors come at the problem
Commentary
from different angles, they all agree on the need for mechanistic information for appropriate interpretation of bioassay results. We think you will find these articles entertaining and extremely informative. The scholarly nature of the authors’ presentations more closely resembles reasoned scientific discourse than election year “factslinging”.’ This is the only way the scientific community can make a lasting contribution to society. Lawrence J. Marnett Editor ‘1 would like to acknowledge President-Elect Bill Clinton (Second Presidential Debate, October15,1992) for this new additionto the political lexicon.
