Commentary on ''Toxicity testing in the 21st century: a vision and a strategy'': stem cells and cell-cell communication as fundamental targets in assessing the potential toxicity of chemicals.

Faced with the reality of our current methods of drug discovery and toxicity assessment of all chemicals is less than perfect, the Report, ''Toxicity Testing in the 21( st) Century: A Vision and a Strategy'', posed a reality check on all scientific efforts to find new conceptual and technical approaches for being better predictors of potential human health effects. This Commentary is a challenge to both the current paradigms and techniques to test chemicals for their potential toxicities. While, clearly, our scientific understanding of the mechanisms of chemical-induced toxicity and of the pathogeneses of all human diseases are not complete, the state of scientific understanding seems not only sufficient to know what we are now doing is not sufficient, but that it is adequate enough to make a new paradigm and technological change. Basically, the challenge includes the opinion that human exposure to chemicals, that are associated with one or more health endpoints (birth defects, cardiovascular diseases, cancer, reproductive and neurological dysfunctions), is the result of epigenetic , not mutagenic or genotoxic, mechanisms. In addition, it is postulated that the adult human stem cell should be considered the ''target'' cell for the important chemical-induced health effects. To test this hypothesis that altering the quantity and quality of adult stem cells by chemical exposures during in utero, neonatal, adolescent, adult and geriatric phases of life can lead to health consequences, it is recommended that 3-D in vitro cultures be used on male and female human adult stem cells from a few major organs (e.g., heart, brain, liver, lung, kidney, breast, prostate ). Altered stem cell biology (e.g., increase or decrease in the stem cell numbers in specific organs; altered apoptotic and differentiation frequencies), as well as measured cell-cell communication, should be seriously considered as toxicity endpoints.