The low-dose issue and stochastic responses to endocrine disruptors.

The impact of endocrine disruptors, and specifically the low-dose issue, involves interdisciplinary sciences. Thus, in the past these topics have been published widely in the toxicology area. Owing to recent developments in biology, including the whole-genome reading program, the mechanisms underlying the low-dose issue have been clarified. These mechanisms have been found to involve stochastic and probabilistic receptor-mediated adverse effects induced by endocrine disruptors. The effects thought to be induced by low doses of endocrine-disrupting chemicals remain disputed, and the underlying mechanisms remain poorly understood. Three independent factors, each only recently identified and never before encountered in the history of toxicological studies, are associated with what is termed the 'low-dose issue'. First, toxicological risk has been estimated only by extrapolation of adverse phenotypes from high-dose effects and thus provides no reliable information on low-dose effects observed at the right time under experimental paradigm with sufficient sensitivity. Second, toxicity is based on disturbances of homeostatic regulation, a largely unexplored area in toxicology. Third, toxicity is based on stochastic and probabilistic xenobiotic response, a new field of toxicology that is specifically linked to low-dose and less-frequent events. To resolve the low-dose issue whether it causes effects or whether effects observed at low-doses should be considered 'adverse'--or both, each of these factors needs to be addressed.