Citation:

Scialli, A., G. Daston, C. Chen, P. Coder, S. Euling, J. Foreman, A. Hoberman, J. Hui, T. Knudsen, S. Makris, L. Morford, A. Piersma, D. Stanislaus, AND K. Thompson. Rethinking Developmental Toxicity Testing: Evolution or Revolution? Birth Defects Research. John Wiley & Sons, Inc., Hoboken, NJ, 110(10):840-850, (2018). https://doi.org/10.1002/bdr2.1212

Impact/Purpose:

This manuscript summarizes the proceedings of a workshop help in April 2017, under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI), and conclusions presented at the 57th annual meeting of the Teratology Society in June, 2017. The proceedings considered design of a prenatal developmental toxicity testing strategy starting over with 21st century knowledge and techniques (revolution) as well as changes to the current protocols that might be recommended to be more predictive for human risk (evolution). Consensus emerged that evolutionary means, such as the use of humanized models or disease models, were temporary measures that would not be entirely satisfactory. A revolutionary transition to the use of human cells, tissue, or computer simulations of human development was generally seen as inevitable, but careful development and validation of new methods of risk assessment would require time and resources to increase confidence in the ability to replace whole mammal studies and improve human risk assessment. There was general optimism that whole animal studies could be eventually replaced with scientifically justified and thoughtful developmental toxicity testing strategies, but that the revolution might be based on incremental, evolutionary change rather than on a cataclysmic retooling of the procedures currently used.

Description:

Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We also considered what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). The revolution could start with hypothesis-driven testing where we take what we know about a compound or close analogs and would answer specific questions using targeted experimental techniques rather than a one-protocol-fits-all approach. Central to the idea of hypothesis-driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach.

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