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Review of Acute Human-Toxicity Estimates for Selected Chemical-Warfare Agents



Due to the existence of large stocks of chemical-warfare (CW) agents, their easy producibility from ordinary industrial chemicals, and their potential lethal effects, there is a critical need to determine as precisely as possible the exposure levels at which CW agents cause toxic effects. This information could aid in protecting soldiers in the event of a CW attack.

This report, by the Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents of the National Research Council's Committee on Toxicology, is intended to assist the U.S. Army by assessing the scientific validity of existing human-toxicity estimates for several CW agents. The estimates considered in this report were proposed recently in the Army's Chemical Defense Equipment Process Action Team (CDEPAT) report entitled Review of Existing Toxicity Data and Human Estimates for Selected Chemical Agents and Recommended Human Toxicity Estimates Appropriate for Defending the Soldier (1994). The report was authored by S.A. Reutter, Ph.D., and W.A. Wade, D.V.M.; it is classified "secret" and can be obtained only with permission from the director of the U.S. Army Edgewood Research, Engineering and Development Center, Edgewood, Md.

We gratefully acknowledge Carl Curling, Jerry Glasow, William Klenke, Francis O'Donnell, Forrest Oliverson, Gerald Palmer, Sharon Reutter, Harry Salem, and Sandra Thomson (all from the U.S. Army) for providing background information. We also thank Gail Charnley (Commission on Risk Assessment and Risk Management) and Annetta Watson (Oak Ridge National Laboratory) for making presentations to the subcommittee and providing useful information.

We are grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to this effort are Paul Gilman, executive director of the Commission on Life Sciences; James J. Reisa, director of the Board on Environmental Studies and Toxicology; Carol A. Maczka, program director for toxicology and risk assessment; Ruth E. Crossgrove, editor; Lucy V. Fusco, project assistant, and Catherine M. Kubik, senior program assistant. We especially wish to recognize the major contributions of the project director, Kulbir S. Bakshi, who directed the preparation of the subcommittee's report. His knowledge of the scientific and technical literature and his tireless efforts to obtain information and to organize the study plan, the subcommittee meetings, and the subcommittee's report aided in the successful completion of the project.

Finally, we would like to thank all the members of the subcommittee for their dedicated efforts throughout the development of this report.


Loren D. Koller, Ph.D.
Chair, Subcommittee on Toxicity Values
for Selected Nerve and Vesicant Agents

Rogene F. Henderson, Ph.D.
Chair, Committee on Toxicology


    Contents



    SUMMARY

    1 INTRODUCTION AND BACKGROUND

    2 REVIEWOF ACUTE HUMAN-TOXICITY ESTIMATES FOR GA (TABUN)
      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    3 REVIEW OF ACUTE HUMAN-TOXICITY ESTIMATES FOR GB (SARIN)

      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    4 REVIEW OF ACUTE HUMAN-TOXICITY ESTIMATES FOR GD (SOMAN)
      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    5 REVIEW OF ACUTE HUMAN-TOXICITY ESTIMATES FOR GF
      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    6 REVIEW OF ACUTE HUMAN-TOXICITY ESTIMATES FOR VX
      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    7 REVIEW OF ACUTE HUMAN-TOXICITY ESTIMATES FOR HD
      Percutaneous Vapor Exposure
      Inhalation Vapor Exposure
      Percutaneous Liquid Exposure
      Conclusions and Recommendations

    8 EVALUATION OF THE RISK-ESTIMATION PROCEDURES USED IN THE CDEPAT REPORT
      Use of Log-Probit Analysis
      Use of the ECt50
      Use of Confidence Limits

    REFERENCES

    GLOSSARY

    APPENDIX


    Summary


    No reliable acute-exposure1 standards have been established for the particular purpose of protecting soldiers from toxic exposures to chemical-warfare (CW) agents . Some human-toxicity estimates are available for the most common CW agents—organophosphorus nerve agents and vesicants; however, most of those estimates were developed for offensive purposes (that is, to kill or incapacitate the enemy) and were intended to be interim values only.

    The U.S. Army's original purpose for developing human-toxicity estimates for CW agents was to enable it to predict the number of casualties that would occur during an offensive action in which the goal was to kill or incapacitate a certain fraction of the enemy forces (for example, killing or incapacitating a minimum of 50% of the least-sensitive (most-resistant) individuals). Such an approach would actually result in more than half of the exposed individuals dying (the "bonus effect"), because a certain percentage of those exposed would be expected to be more susceptible than the least-sensitive individual. Thus, exposure under the Army's original estimates would result in substantial "over-kill". These estimates understate the toxicity of the agents and therefore are inappropriate for protecting soldiers.

    Because of the possibility of a chemical attack by a foreign power, the Army's Office of the Surgeon General asked the Army's Chemical Defense Equipment Process Action Team (CDEPAT) to review the toxicity data for the nerve agents GA (tabun), GB (sarin), GD (soman), GF, and VX, and the vesicant agent sulfur mustard (HD) and to establish a set of exposure limits that would be useful in protecting soldiers from toxic exposures to those agents. In the 1994 report entitled Review of Existing Toxicity Data and Human Estimates for Selected Chemical Agents and Recommended Human Toxicity Estimates Appropriate for Defending the Soldier, the team concluded that some of the existing human-toxicity estimates are too high and are inappropriate for use in protecting soldiers. In those cases, CDEPAT proposed new estimates for various routes of exposure-percutaneous vapor, vapor inhalation, and percutaneous liquid exposures. The proposed human-toxicity estimates are only for healthy male military personnel. They must not be used for civilians.

    Before making a decision on acceptance of the human-toxicity estimates proposed by CDEPAT, the Department of the Army requested that the National Research Council (NRC) independently review the CDEPAT report to determine the scientific validity of the proposed estimates. The NRC assigned this project to the Committee on Toxicology (COT) of the Board on Environmental Studies and Toxicology. The COT convened the Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents, which prepared this report. Members of the subcommittee were selected for their recognized expertise in the fields of toxicology, medicine, pathology, biostatistics, and risk assessment. The subcommittee was charged to review the Army's proposed human-toxicity estimates for GA, GB, GD, GF, VX, and HD. Specifically, the subcommittee was charged with the following tasks:


      1. Review the scientific protocols and quality of the toxicity data used in revising the human-toxicity estimates for acute exposures.

      2. Review the toxicity estimates for mild and nonsevere effects and for severe and lethal effects .

      3. Review the methods used in deriving the human-toxicity estimates for acute exposures.

      4. Determine the appropriateness of the assumptions made in deriving the human-toxicity estimates for acute exposures .


    The subcommittee was not asked to recommend new toxicity estimates or to address the policy or operational consequences of lowering the proposed human-toxicity estimates. The subcommittee's evaluations of CDEPAT's proposed estimates for GA, GB, GD, GF, VX, and HD are summarized in Tables 1 through 6.

    The subcommittee's conclusions concerning the scientific validity of the proposed CDEPAT estimates are grouped in four categories: (1) some estimates were judged to be scientifically valid; (2) other estimates were judged adequate to serve as interim estimates until further research is conducted; (3) some estimates need to be lowered; and (4) a few estimates need to be raised.

    The toxicity data that CDEPAT used to derive its proposed estimates were generated primarily from a data base developed from the 1930s to the 1960s. The existing human-toxicity estimates were based on experiments performed 30-40 years ago using various animal species in often poorly controlled studies with vastly different protocols. In reviewing the available toxicity data for the six CW agents, the subcommittee recognized that the quality of the relevant toxicity data is marginal, but it also recognized that the Army needs "best estimates " to protect its troops from exposure. For each chemical agent, data were available for only a few adverse health effects, such as death, incapacitation, cholinesterase (ChE) inhibition, miosis (a decrease in pupil size), and rhinorrhea (running nose), vesication, and erythema. Thus, even though the subcommittee concluded that some of CDEPAT's proposed estimates are scientifically valid, those conclusions are based on a limited toxicity data base. By current standards of toxicology, the toxicity data base for the agents is inadequate, and such inadequacy is a major obstacle to the Army in developing human-toxicity estimates with statistical confidence and in developing risk-management strategies.

    The subcommittee recommends that the Army convene an expert panel to develop a research strategy for deriving more scientifically sound toxicity values for the agents of concern. The panel should first consider the use of such techniques as structure-activity relationships, the uncertainty factors, and in vitro systems for estimating human-toxicity values for CW agents.

    If these approaches do not appear to be useful, animal and human experimentation may be recommended. Although additional research is clearly desirable to provide improved confidence in existing data, such research should not be performed on laboratory animals until expert judgment documents the need on a case-by-case basis. It must be documented that the data to be obtained from laboratory animals is needed to make a significant improvement in the protection of human health.















    The experimental designs should include the following:

  • Define if and when experiments with humans are appropriate.
  • In the absence of human experimentation, define the most appropriate animal model for each specific toxicity value and agent, including the end points to be observed.
  • Define the adequacy of the design in determining the toxicity values for healthy female as well as healthy male military personnel.
  • Define the requirements for observation of reversibility of adverse health effects.
  • Identify adverse health effects at the low end of the dose-response curve to determine threshold exposure levels.
  • Identify confidence limits for the proposed estimates as a measure of the uncertainty of the estimated incidence of toxic effects.
  • Identify potentiation or antagonistic effects from exposures to mixtures of chemical agents .
  • Identify more-sensitive biological markers of exposure and effects for CW agents.

    1A one-time, short-term exposure; for example, <1 hr.
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