Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

Nongenotoxic carcinogens are chemicals that induce neoplasia without it or its metabolites reacting directly with DNA. Chemicals classified as nongenotoxic carcinogens have been assumed to act as tumor promoters and exhibit threshold tumor dose-responses. This is in contrast to genotoxic carcinogens that are DNA reactive, act as tumor initiators, and are assumed to exhibit proportional responses at low doses. In this perspective, we examine the basic tenets and utility of this classification for evaluating human cancer risk. Two classes of so-called nongenotoxic chemical carcinogens selected for review include cytotoxic agents that induce regenerative hyperplasia (trihalomethanes and inducers of alpha 2-microglobulin nephropathy) and agents that act via receptor-mediated mechanisms (peroxisome proliferators and dioxin). Major conclusions of this review include: a) many chemicals considered to be nongenotoxic carcinogens actually possess certain genotoxic activities, and limiting evaluations of carcinogenicity to their nongenotoxic effects can be misleading; b) some nongenotoxic activities may cause oxidative DNA damage and thereby initiate carcinogenesis; c) although cell replication is involved in tumor development, cytotoxicity and mitogenesis do not reliably predict carcinogenesis; d) a threshold tumor response is not an inevitable result of a receptor-mediated mechanism. There are insufficient data on the chemicals reviewed here to justify treating their carcinogenic effects in animals as irrelevant for evaluating human risk. Research findings that characterize the multiple mechanisms of chemical carcinogenesis should be used quantitatively to clarify human dose-response relationships, leading to improved scientifically based public health decisions. Excessive reliance on oversimplified classification schemes that do not consider all potential contributing effects of a toxicant can obscure the actual causal relationships between exposure and cancer outcome.