Thresholds for Carcinogens: A Review of the Relevant Science and Its Implications for Regulatory Policy

Regulation of carcinogens in the United States has been based on a "no threshold" policy. This makes the assumption there exists no level of exposure for which the possibility of causing harm is truly zero. The alternative "threshold" policy assumes that there exists some level of exposure at which no harm will come to anyone in a population so exposed. The no-threshold policy made sense when adopted, thirty or more years ago, since the science then available was not able to distinguish between these two opposing hypotheses, and "no threshold" provides more margin of safety. Since then, our understanding of biological processes related to birth and growth of cancer has greatly expanded. We now understand that two different biological processes can enlarge cancer risk. Increasing the rate at which cells divide is one of these; increasing the rate at which mutations occur, independently of cell division (mitotic) rate, is another. It is known that mitotic rate is under close physiologic control, operated through a complex system including a variety of intercellular messenger molecules. Functions controlled so as to be kept within certain limits in the face of external stressors must by definition exhibit a threshold in their response to small changes in such external stress. It is only necessary to demonstrate the existence of physiologic control to show that the threshold must exist. Thus there will be a threshold in the response to any nonmutagenic ("mitogenic") carcinogens. For classical mutagenesis as well, the weight of evidence favors the conclusion that thresholds exist. Evidence for "no threshold" has almost no weight, either because of the limits on our ability to measure response at very low levels of mutagenic stimulus, or because it springs from an unacknowledged tautology. Conversely, there is evidence of moderate weight, primarily that cancer rates are not elevated in areas of high background radiation flux, that the mutation rate is under active physiologic control. This expanded knowledge allows more reliable guidance for policy makers. First, policy should distinguish between "mitogenic" and "mutagenic" carcinogens, those that act predominantly by increasing the rate at which cells in certain tissues divide, and those that act directly on DNA. Mitogenic carcinogens should receive the same treatment as "noncarcinogens." At EPA, at least, policies are changing to reflect this understanding. Mutagenic carcinogens should be regulated using the "de minimus" approach FDA and EPA use for all cases other than direct food additives and pesticide residues. This approach relies on the concept of a "practical threshold," and provides very adequate protection of public health.