Predicting future human and environmental health challenges: the Health and Environmental Sciences Institute's scientific mapping exercise.

To predict important strategic issues in product safety during the next 10 years, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute initiated a mapping exercise to evaluate which issues are likely to be of societal, scientific, and regulatory importance to regulatory authorities, the HESI membership, and the scientific community at large. Scientists representing government, academia, and industry participated in the exercise. Societal issues identified include sensitive populations, alternative therapies, public education on the precautionary principle, obesity, and aging world populations. Scientific issues identified include cancer testing, children's health, mixtures and co-exposures, sensitive populations, idiosyncratic reactions, "omics" or bioinformatics, and environmental toxicology. Regulatory issues identified include national and regional legislation on chemical safety, exposure inputs, new technologies, transitioning new science into regulations and guidelines, conservative default factors, data quality, and sensitive populations. Because some issues were identified as important in all three areas (e.g. sensitive populations), a comprehensive approach to assessment and management is needed to ensure consideration of societal, scientific, and regulatory implications. The resulting HESI Combined Challenges Map is not intended to offer a universal description of challenges in safety assessment, nor is it intended to address, advocate, or manage the prioritized issues. Rather, the map focuses on and predicts issues likely to be central to the strategic agendas of individual companies and regulatory authorities in the developed world. Many of these issues will become increasingly important in the future in rapidly developing economies, such as India and China. The scientific mapping exercise has particular value to the toxicology community because it represents the contributions of key scientists from around the world from government, academia, and industry.

The value of DNA methylation analysis in basic, initial toxicity assessments.

DNA methylation is an epigenetic mechanism regulating patterns of gene expression. Our goal was to see if the assessment of DNA methylation might be a useful tool, when used in conjunction with initial, basic in vitro tests, to provide a more informative preliminary appraisal of the toxic potential of chemicals to prioritize them for further evaluation. We sought to give better indications of a compound's toxic potential and its possible mechanism of action at an earlier time and, thereby, contribute to a rational approach of an overall reduction in testing by making improved early decisions. Global and GC-rich patterns of DNA methylation were evaluated along with more traditional cytolethality measurements, e.g., cytolethality and genotoxicity assessments, on rat hepatoma (H4IIE) cells. The relative toxic potential of model compounds camptothecin, 5-fluorouracil, rotenone, and staurosporine was estimated by employing DNA methylation assessments combined with our cytolethality data plus genotoxicity information gleaned from the literature. The overall contribution of the methylation assessment was threefold; it (1) strengthened a ranking based on genotoxicity; (2) provided an indication that a compound might be more potentially problematic than what cytolethality and genotoxicity assessments alone would indicate; and (3) suggested that compounds, particularly nongenotoxins, that are more potent regarding their ability to alter methylation, especially at noncytolethal concentrations, may be more potentially toxic. Altered methylation per se is not proof of toxicity; this needs to be viewed as a component of an evaluation.