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Developmental toxicity testing for safety assessment: new approaches and technologies
KNUDSEN, T. B., R. J. KAVLOCK, G. P. DASTON, D. B. STEDMAN, M. HIXON, AND J. KIM. Developmental toxicity testing for safety assessment: new approaches and technologies. BIRTH DEFECTS RESEARCH PART B: DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY. John Wiley & Sons, Inc, Hoboken, NJ, 92(5):413-420, (2011).
Different scenarios could be tested in a computer simulated system, assuming we build biologically-informed computer models that can be exercised with synthetic data and validated with real data, to predict when environmental disruption will lead to developmental phenotype in human embryos. To link pathway-level response with adverse outcome we need to know major components of the target ‘system’ in terms of key cells and molecules, the relevant interactions among components (network state relations), and the dynamic behavior of components as the system evolves to an endpoint. In the future, virtual tissue models may allow scientists to analyze a simulated embryo for responses across environmental and genetic conditions not practical experimentally, to predict outcomes for targeted testing and further evaluation.
The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled "Developmental Toxicology-New Directions" in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program. Issues discussed include the challenges of anchoring in vitro predictions to relevant in vivo endpoints and the need to validate pathway-based predictions with targeted studies in whole animals. Currently, there are 10,000 to 30,000 chemicals in world-wide commerce in need of hazard data for assessing potential health risks. The traditional animal study designs for assessing developmental toxicity cannot accommodate the evaluation of this large number of chemicals, requiring that alternative technologies be utilized. Though a daunting task, technologies are being developed and utilized to make that goal reachable.