The mission of the Department of Defense (DOD) is “to provide the military forces needed to deter war and to protect the security of our country” (DOD 2014). In support of that mission, DOD must protect the health and capabilities of its personnel—many of whom are deployed overseas—by anticipating and safeguarding against chemical and biological threats. Although many factors, such as availability and dissemination potential, need to be considered in evaluating a potential threat, chemical toxicity is critical in determining whether an agent could pose a threat if used by an adversary. Given the numbers of registered chemicals and new chemicals registered each year, evaluating chemical toxicity is especially daunting, particularly in terms of time and money, if one uses traditional toxicity-testing methods. In light of recent advances in toxicity-testing methods and approaches, DOD would like to determine the feasibility of developing a high-throughput predictive system that could rapidly identify acutely toxic agents and threat potentials. Accordingly, DOD asked the National Research Council (NRC) to determine how DOD could use modern approaches for predicting chemical toxicity in its efforts to prevent debilitating acute exposures of deployed personnel. In response to that request, NRC convened the Committee on Predictive-Toxicology Approaches for Military Assessments of Acute Exposures, which prepared this report.
Toxicity testing reached a turning point in 2007 with the release of the NRC report Toxicity Testing in the 21st Century: A Vision and a Strategy. The report set forth a vision for transforming traditional toxicity testing by incorporating advances in systems biology, epigenetics, toxicogenomics, bioinformatics, and computational toxicology. The new system that was described in the report would be based primarily on in vitro methods that can be used to evaluate changes in biological processes with cells, cell lines, or cellular components, preferably of human origin. The motivation for the new system was to accomplish four important goals: “(1) to provide broad coverage of chemicals, chemical mixtures, outcomes, and life stages, (2) to reduce the cost and time of testing, (3) to use fewer animals and cause minimal suffering in the animals used, and (4) to develop a more robust scientific basis for assessing health effects of environmental agents” (NRC 2007).
On release of the NRC report, several federal agencies embraced the proposed vision. A collaboration that has been informally referred to as Tox21 was formed between the National Toxicology Program of the National Institute of Environmental Health Sciences, the National Center for Computational Toxicology of the US Environmental Protection Agency (EPA), and the Chemical Genomics Center1 of the National Institutes of Health; the US Food and Drug Administration joined the collaboration later. The goal of the collaboration has been to advance the
1The Chemical Genomics Center is now part of the National Center for Advancing Translational Sciences.
vision proposed in the NRC report. EPA launched ToxCast as a separate activity with the goal of developing cost-effective approaches that use high-throughput technologies to predict chemical toxicity. The European Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation encourages companies and other organizations to develop alternative methods that would substitute for traditional methods and has ultimately led to various research initiatives. All those programs and efforts have led to development of new methods and assays for predicting toxicity.
To protect the armed forces and their ability to serve, DOD’s Defense Threat Reduction Agency conducts and sponsors scientific research to predict which chemicals might be used by adversaries as weapons and the toxicity that could occur if such agents were used. To understand potential toxicity at various doses, DOD has largely used in vivo toxicity testing in laboratory animals. However, that approach is time-consuming and expensive, must consider species differences in response, and does not enable DOD to keep up with the pace of new chemical registration. To address the challenge of elucidating the toxicity of more chemicals than can be practically tested in whole-animal assays and to address concerns raised with animal testing, DOD asked the NRC to consider the question of whether the new predictive-toxicology approaches being developed could be used to expedite its evaluation of potential chemical hazard. Specifically, are the new assays and approaches relevant to DOD’s interest in acute toxicity? If not, is there research that would enable DOD to use predictive-toxicology approaches to identify acute chemical threats?
The committee that was convened as a result of DOD’s request included experts in toxicology, computational methods, high-throughput approaches, –omics, physiologically based pharmacokinetic modeling, statistics, model validation, and emergency preparedness (see Appendix A for the committee’s biographical information). As noted, the committee was asked to consider the new predictive-toxicology approaches that have been developed in other fields and to determine whether they could be used to meet DOD’s needs. The committee’s verbatim statement of task is provided in Box 1-1.
To address its task, the committee held four meetings. In an open session during the first meeting, the committee heard presentations from the sponsor on its activities. On the basis of those discussions and the statement of task, the committee focused its attention on approaches that were considered to be most relevant for predicting acute debilitating2 or life-threatening3 effects and on the organ systems that were deemed most likely to be affected. The organ systems of highest concern to DOD included the cardiovascular, respiratory, hepatic, renal, skeletomuscular, immune, and nervous systems, including special senses (vision and hearing). Each organ system was considered by the committee in its deliberations (see Chapter 2, Table 2-1 for further discussion). During the course of its review, the committee sought representative examples that could illustrate nontesting and assay-based approaches to assess acute chemical toxicity; the examples are provided throughout this report. On the basis of its task, the committee excluded from consideration traditional toxicity-testing assays (in vivo rodent assays).
2Acute debilitating effects are defined as ones that cause major irreversible morbidity, such as blindness, loss of limb function, paralysis, and severe hypoxia.
3A life-threatening effect is a disease or condition that makes the likelihood of death high unless the exposure is interrupted.
An ad hoc committee under the auspices of the National Research Council will consider how the Department of Defense (DOD) could use modern approaches for predicting chemical toxicity in its efforts to prevent debilitating acute exposures to deployed personnel.
DOD needs to understand the relative threat of the increasingly long list of registered chemical substances, particularly in terms of potential acute hazard. To help DOD achieve its goal to protect its deployed personnel, this study will consider modern approaches for predicting toxicity and suggest an overall conceptual approach for using such information to evaluate acute hazards. The committee will consider the information provided by predictive-toxicology approaches that is increasingly being generated and used in the environmental health and pharmaceutical sectors to enhance or replace information from traditional, empirical testing of chemical safety in animals. The committee will focus on the assays and approaches that are being developed by the United States and European agencies (for example, for the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) program, the EPA ToxCast effort, and the NIH/EPA/FDA Tox21 program); these might include computational modeling, structure-activity relationship analysis, analysis of physicochemical characteristics, read-across techniques, and high-throughput screening and other in vitro assays. Specifically, the committee will discuss the ability of these approaches to predict acute toxicity at levels relevant to DOD concerns.
In Phase 1 of this study, the committee will comment on the robustness and the relevance of the current approaches to meet DOD's needs. If the approaches being developed by other agencies do not address DOD's concerns about acute toxicity, the committee will broadly describe areas of research that could fill the gaps within the next 5 or 10 years. A second phase of the study, undertaken at the sponsor's request, will provide more detailed recommendations for a research roadmap.
In response to its task to “predict acute toxicity at levels relevant to DOD concerns,” the committee focused its approach on hazard identification, specifically identifying target organ systems and developing toxicity estimates, such as potency estimates. An approach for predicting acute toxicity that involved converting toxicity estimates to human exposure estimates, as has been taken with some chemical-warfare agents (Mioduszewski et al. 2002), was considered beyond the committee’s charge. Furthermore, the committee interpreted DOD’s stated interest in understanding the relative threat of chemicals that could be used by an adversary against deployed US military personnel to mean prioritizing chemicals in terms of their potential to cause acute toxicity. Thus, the committee was not focused on predicting human clinical signs or identifying at-risk populations. And, the committee did not set bounds for its proposed strategy because it recognized the need for DOD to develop policies to set toxicity thresholds relevant to its mission.
During the open session of its first meeting, the committee received a presentation from EPA on the ToxCast program. The committee considered the efforts of that program that were relevant to predicting acute toxicity and, more broadly, the technical approaches that might inform development of a DOD acute-toxicity program. A detailed review of the ToxCast program and its associated assays and methods was considered beyond the scope of the present report.
The committee’s report is organized into six chapters and two appendixes. Chapter 2 describes a conceptual framework and components that would be needed to build an approach based on modern predictive-toxicology methods. Chapter 3 describes the use of nontesting approaches, including quantitative structure–activity relationships, to predict acute chemical toxicity. Chapter 4 provides a brief review of medium-throughput and high-throughput assays that
can be used to predict acute mammalian toxicity. Chapter 5 addresses integration of the biological and chemical data into toxicity predictions. Chapter 6 presents important lessons learned from previous predictive acute-toxicity efforts and the committee’s overall conclusions. The committee also identifies several steps that DOD could begin to take toward developing high-throughput assays and computational approaches to identify chemicals that have the potential to induce life-threatening acute toxicity in deployed personnel. Appendix A contains biographical information on the committee, and Appendix B discusses available toxicity data or databases that one could use to find toxicity data.
DOD (US Department of Defense). 2014. About the Department of Defense. [online]. Available: http://www.defense.gov/about/[accessed March 12, 2015].
Mioduszewski, R., J. Manthei, R. Way, D. Burnett, B. Gaviola, W. Muse, S. Thomson, D. Sommerville, and R. Crosier. 2002. Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats. Toxicol. Sci. 66(2):176-184.
NRC (National Research Council). 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: National Academies Press.