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concerns have arisen that the threats posed by some regulated substances might have been overstated and, conversely, that some unregulated substances might pose greater threats than originally believed. Questions have also been raised about the economic costs of controlling or eliminating emissions of chemicals that might pose extremely small risks. Debates about reducing risks and controlling costs have been fed by the lack of universal agreement among scientists about which methods are best for assessing risk to humans.

Epidemiological studies—typically, comparisons of disease rates between exposed and unexposed populations—are not sufficiently precise to find that a substance poses a carcinogenic risk to humans except when the risk is very high or involves an unusual form of cancer. For this reason, animal studies generally provide the best means of assessing potential risks to humans. However, laboratory animals are usually exposed to toxicants at concentrations much higher than those experienced by humans in the general population. It is not usually known how similar the toxic responses in the test animals are to those in humans, and scientists do not have indisputable ways to measure or predict cancer risks associated with small exposures, such as those typically experienced by most people in the general environment.

Some hypotheses about carcinogens are qualitative. For example, biological data might suggest that any exposure to a carcinogen poses some health risk. Although some scientists disagree with that view or believe that it is not applicable to every carcinogen, its adoption provides at least a provisional answer to a vexing scientific question, namely whether people exposed to low concentrations of substances that are known to be carcinogenic at high concentrations are at some risk of cancer associated with the exposure. The view has dominated policy-making since the 1950s but is not always consistent with new scientific knowledge on the biological mechanisms of chemically induced cancer.

Beginning in the 1960s, toxicologists developed quantitative methods to estimate the risks associated with small exposures to carcinogens. If it were reliable, quantitative risk assessment could improve the ability of decision-makers and to some extent the public to discriminate between important and trivial threats and improve their ability to set priorities, evaluate tradeoffs among pollutants, and allocate public resources accordingly. In short, it could improve regulatory decisions that affect public health and the nation's economy.

During the 1970s and 1980s, methods of risk assessment continued to evolve, as did the underlying science. It became increasingly apparent that the process of carcinogenesis was complex, involving multiple steps and pathways. The concept that all cancer-causing chemicals act through mechanisms similar to those operative for radiation was challenged. Some chemicals were shown to alter DNA directly and hence to mimic radiation. But evidence developed that other chemicals cause cancer without directly altering or damaging DNA, for example, through hormonal pathways, by serving as mitogenic stimuli, or by causing excess cell death with compensatory cell proliferation. Biologically