Author(s): Trosko JE, Chang CC
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Abstract Given the reality of the inadequacies of current concepts of the mechanisms of chemical toxicities, of the various assays to predict toxicities from current molecular, biochemical, in vitro and animal bioassays, and of the failure to generate efficacious and safe chemicals for medicines, food supplements, industrial, consumer and agricultural chemicals, the recent NAS Report, "Toxicity Testing in the 21st Century: A Vision and a Strategy", has drawn attention to a renewed examination of what needs to be done to improve our current approach for better assessment of potential risk to human health. This "Commentary" provides a major paradigm challenge to the current concepts of how chemicals induce toxicities and how these various mechanisms of toxicities can contribute to the pathogenesis of some human diseases, such as birth defects and cancer. In concordance with the NAS Report to take "... advantage of the on-going revolution in biology and biotechnology", this "Commentary" supports the use of human embryonic and adult stem cells, grown in vitro under simulated "in vivo niche conditions". The human being should be viewed "as greater than the sum of its parts". Homeostatic control of the "emergent properties" of the human hierarchy, needed to maintain human health, requires complex integration of endogenous and exogenous signaling molecules that control cell proliferation, differentiation, apoptosis and senescence of stem, progenitor and differentiated cells. Currently, in vitro toxicity assays (mutagenesis, cytotoxicity, epigenetic modulation), done on 2-dimensional primary rodent or human cells (which are always mixtures of cells), on immortalized or tumorigenic rodent or human cell lines do not represent normal human cells in vivo [which do not grow on plastic and which are in micro-environments representing 3 dimensions and constantly interacting factors]. In addition, with the known genetic, gender, and developmental state of cells in vivo, any in vitro toxicity assay will need to mimic these conditions in vitro. More specifically, while tissues contain a few stem cells, many progenitor/transit cells and terminally differentiated cells, it should be obvious that both embryonic and adult stem cells would be critical "target" cells for toxicity testing. The ultimate potential for in vitro testing of human stem cells will to try to mimic a 3-D in vitro micro-environment on multiple "organ-specific and multiple genotypic/gender "adult stem cells. The role of stem cells in many chronic diseases, such as cancer, birth defects, and possibly adult diseases after pre-natal and early post-natal exposures (Barker hypothesis), demands toxicity studies of stem cells. While alteration of gene expression ("toxico-epigenomics") is a legitimate endpoint of these toxicity studies, alteration of the quantity of stem cells during development must be serious considered. If the future utility of human stem cells proves to be valid, the elimination of less relevant, expensive and time-consuming rodent and 2-D human in vitro assays will be eliminated. (c) 2009 Elsevier Ireland Ltd. All rights reserved.
This article was published in Toxicology
and referenced in Journal of Bioanalysis & Biomedicine