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Simon T.W.,Ted Simon LLC | Simons Jr. S.S.,U.S. National Institutes of Health | Preston R.J.,Us Epa National Health And Environmental Effects Research Laboratory | Boobis A.R.,Imperial College London | And 6 more authors.
Critical Reviews in Toxicology | Year: 2014

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs. © 2014 Informa Healthcare USA, Inc. Source


Corton J.C.,U.S. Environmental Protection Agency | Bushel P.R.,National Health Research Institute | Fostel J.,National Health Research Institute | O'Lone R.B.,ILSI Health and Environmental science Institute
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. © 2012. Source


Kim J.H.,ILSI Health and Environmental science Institute
Methods in Molecular Biology | Year: 2013

The current political and societal climate is driving the science of toxicology towards developing non-animal testing methodologies. Though alternative and in vitro tests have always been a mainstay for toxicological testing, technological advances in the last decade have allowed toxicologists to move rapidly towards a better understanding of the relevance of in vitro endpoints for traditional apical endpoints. Non-animal research using new technologies have illuminated toxicologists on the mechanisms of protection and adverse health outcomes. In this context, the "validation" of alternative and in vitro tests has taken on significant importance, particularly in regard to satisfying safety concerns of drugs and chemicals in a regulatory setting. The purpose of this chapter is to briefly review the impetus for the development of alternative and in vitro tests, discuss the projects underway at the ILSI Health and Environmental Sciences Institute (HESI) that are oriented towards this topic, and summarize the processes for formal validation. It should be noted that though there are validated assays and tests, these are under constant evaluation by scientific researchers as our understanding of the underlying biological processes continues to evolve. © 2013 Springer Science+Business Media, LLC. Source


Young J.L.,ILSI Health and Environmental science Institute | Peoples R.,ACS Green Chemistry Institute
Journal of Chemical Education | Year: 2013

As a leader in green chemistry education, the ACS Green Chemistry Institute (ACS GCI) has developed resources for educators, students, and professionals. This communication summarizes one of the invited papers to the ConfChem online conference Educating the Next Generation: Green and Sustainable Chemistry, held from May 7 to June 30, 2010 and hosted by the ACS DivCHED Committee on Computers in Chemical Education (CCCE). The paper, "Educational Resources from the ACS Green Chemistry Institute," discussed May 14-20, 2010 during the conference covered the breadth of educational resources developed by ACS GCI. This communication highlights several new activities since the online conference, including a textbook, online tools and webinars, workshops, student award, and research grant. © 2013 The American Chemical Society and Division of Chemical Education, Inc. Source


Shuey D.,Ford Motor Company | Kim J.H.,ILSI Health and Environmental science Institute
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2011

Since regulatory agencies began implementing the use of standardized developmental toxicology protocols in the mid-1960s, our knowledge base of embryo-fetal development and technologies for experimentation has grown exponentially. These developmental toxicology protocols were a direct result of the thalidomide tragedy from earlier that decade, when large numbers of women were exposed to the drug and over 10,000 cases of phocomelia resulted. In preventing a recurrence of such tragedies, the testing protocols are immensely successful and the field of toxicology has been dedicated to using them to advance safety and risk assessment of chemicals and pharmaceuticals. Recently, our perspectives on toxicity testing have been challenged by a growing awareness that while we have excelled in hazard identification, we are in dire need of improved methodologies for human health risk assessment, particularly with respect to the large numbers of environmental chemicals for which we have little toxicology data and to the growing sentiment that better alternatives to whole animals tests are needed. To provide a forum for scientists, researchers, and regulators, the Developmental and Reproductive Toxicology Technical Committee of the Health and Environmental Sciences Institute organized a 2-day workshop titled "Developmental Toxicology-New Directions" to evaluate lessons learned over the past 30 years and discuss the future of toxicology testing. The following four articles describe different presentations and discussions that were held over the course of those 2 days. © 2011 Wiley Periodicals, Inc. Source

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