Implications for the Future: Regulation of Chemicals and Prevention of Cancer

Lifetime feeding studies, when positive for cancer induction, do not provide information to differentiate between primary and secondary mechanisms of cancer induction. So many factors can influence the ultimate risk of incurring cancer in animals or humans that the observation of an increased incidence of cancer in association with exposure to any particular test substance should not lead automatically to the inference that the substance is a carcinogen per se. An increased incidence of cancer can result not only from exposure to “complete” carcinogens, but also from critical exposures to the following factors: those that decrease biological resistance to other independently occurring cancer risk factors, those that cause toxic hyperplasia, or those that act as classical promoters. Both initiation and promotion are prerequisites to cancer induction. Initiation can result independently from the effects of viruses, radiation, chemical initiators, and aging. For example: endogenously-formed nitrosamines are capable of effecting initiation in hepatic cells. Many non-genotoxic hepatic so-called “carcinogens” appear to be “promoters” of cancer induction rather than complete carcinogens. Hepatic cancer induction can be enhanced by classical promotion phenomena, by toxic hyperplasia, or by selective pressures on cell replication created by hormones. Substantial and consistent exposure doses are required to invoke secondary mechanisms of enhancing cancer induction; these secondary events occur in dosage ranges associated with observable histopathologic effects and thus can be detected and measured. By using combinations of in vitro and in vivo techniques, no-adverse-effect dosage levels can be determined whereby the risks for enhancing cancer induction can be avoided.