August 2015

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New NRC report encourages DOD to develop acute toxicity-specific computational models and in vitro test methods

When the US Environmental Protection Agency (EPA) asked the National Resource Council (NRC) to help them develop a cost-effective long-range toxicity testing plan that incorporated advances in biology, computer science, and experimental technologies, the outcome was the NRC’s paradigm-shifting 2007 report, Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. Now, NRC has issued another important strategy report, this time at the request of the Department of Defense (DOD).

The DOD faces a Herculean toxicity testing challenge: evaluating up to 84,000 registered chemicals for their potential to debilitate military personnel in acute exposure situations. Traditional animal-based toxicity testing methods would be far too costly and time-consuming. The DOD enlisted the NRC "to determine the feasibility of developing a toxicity-testing program that uses modern approaches to identify acutely toxic agents rapidly that are relevant to DOD." The results are described in the new NRC report, Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense, which reviews and evaluates computational and high-throughput cell and tissue-based approaches for predicting acute toxicity, and proposes methods for data integration and decision-making.

The new report builds on the framework established in 2007, emphasizing computational models and high-throughput in vitro assays to prioritize and screen chemicals, and limited animal testing (beginning with nonmammalian models where available) when additional information is needed. The committee urges DOD collaborations with established large-scale screening programs such as the EPA’s ToxCast, to tap into their accumulated expertise and resources. It also advises DOD to invest extensively in the development of acute toxicity-predictive computational models and assays. Existing high-throughput (HTS) and medium-throughput (MTS) assays have focused on oral exposure; there is relatively little information on dermal or inhalation exposures, which are more relevant to DOD concerns. Finally, the report proposes ways for DOD to integrate these diverse data streams for effective use in decision-making.

As the report committee acknowledges, traditional acute toxicity tests “are expensive and time-intensive, raise questions about the applicability of results to human populations, raise concerns about animal welfare, and are impractical for evaluating quickly large numbers of chemicals that could be used against deployed forces" (page 3). The approach outlined by the NRC stands to significantly reduce DOD’s use of animals, while greatly improving its capacity for predicting acute toxicity, and expanding the availability and scope of these in silico and in vitro predictive tools for use by other agencies and regulatory bodies.

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