Measures of Cell Replication in Risk/Safety Assessment of Xenobiotic-Induced, Nongenotoxic Carcinogenesis
The phenomena associated with nongenotoxic carcinogenesis are multifaceted 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 question. The search for a better understanding of this process has generated considerable interest and effort, often with the objective of obtaining useful predictors of the tumourigenic potential of xenobiotics. Alterations in the natural balance of endogenous humoural agents that maintain replicative homeostasis results in proliferative stimulation (or inhibition) which may be transient or sustained. The bases for the molecular interaction of these mediators with cellular receptors, trans-cytoplasmic message conveyance, and subsequent nuclear responses leading to xenobiotic-induced mitosis are becoming better understood. Assessment of tissue replicative status has now become established and utilizes biochemical and histological methodology in a routine manner. The increasingly challenging international regulatory environment is demanding greater understanding of the mechanisms that underlie fundamental phenomena and the influences exerted by xenobiotics prior to their registration. While the precise mode of action of an individual xenobiotic may not be known, sound interpretation of toxicological data, including the contribution made by cell replication, creates greater confidence of its safety in the scientific, regulatory, and commercial communities. This article offers a view of cell proliferation from molecular interactions at the cellular level, through practical assessment of cell and tissue replicative status to its utility in contributing to the registration of new drugs and chemicals.