MEASURES OF CELL REPLICATION IN RISK SAFETY ASSESSMENT OF XENOBIOTIC-INDUCED, NONGENOTOXIC CARCINOGENESIS/

The phenomena associated with nongenotoxic carcinogenesis are multifac eted and complex. Nongenotoxic carcinogens stimulate cell replication in the presence or the absence of cytotoxicity. Cell proliferation is pivotal in the neoplastic process, but the extent of its contribution to the development of xenobiotic-induced cancer remains an open questi on. The search for a better understanding of this process has generate d considerable interest and effort, often with the objective of obtain ing useful predictors of the tumourigenic potential of xenobiotics. Al terations in the natural balance of endogenous humoural agents that ma intain replicative homeostasis results in proliferative stimulation (o r inhibition) which may be transient or sustained. The bases for the m olecular interaction of these mediators with cellular receptors, trans -cytoplasmic message conveyance, and subsequent nuclear responses lead ing to xenobiotic-induced mitosis are becoming better understood. Asse ssment of tissue replicative status has now become established and uti lizes biochemical and histological methodology in a routine manner. Th e increasingly challenging international regulatory environment is dem anding greater understanding of the mechanisms that underlie fundament al phenomena and the influences exerted by xenobiotics prior to their registration. While the precise mode of action of an individual xenobi otic may not be known, sound interpretation of toxicological data, inc luding the contribution made by cell replication, creates greater conf idence of its safety in the scientific, regulatory, and commercial com munities. This article offers a view of cell proliferation from molecu lar interactions at the cellular level, through practical assessment o f cell and tissue replicative status to its utility in contributing to the registration of new drugs and chemicals. (C) 1996 Academic Press, Inc.