Development and Application of Acute Exposure Guideline Levels (AEGLs) for Chemical Warfare Nerve and Sulfur Mustard Agents

Abstract

Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios.

This submission was sponsored by a contractor of the U.S. government under contract DE-AC05-00OR22725. Accordingly, the U.S. government retains a nonexclusive, royalty-free license to publish or reproduce these documents, or to allow others to do so, for U.S. government purposes. These documents may be freely distributed and used for noncommercial, scientific and educational purposes.

ACKNOWLEDGMENTS

This work was prepared by members of the Toxicology and Hazard Assessment Group, Life Sciences Division, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN, in collaboration with staff of the Deployment Environmental Surveillance Program of the U.S. Army Center for Health Promotion and Preventive Medicine. This work was prepared for the U.S. Army Center for Health Promotion and Preventive Medicine, U.S. Department of the Army, under Interagency Agreement 2207-M135-A1. The ORNL is managed and operated by UT-Battelle, LLC, for the U.S. Department of Energy under contract DE-AC05-00OR22725.

The critical advice of the following individuals during development and review of these AEGL values is thankfully acknowledged:

From the Life Sciences Division of ORNL, we thank Sylvia Talmage, Tim Borges, Carol Wood, Marilyn Langston, Lee Ann Wilson, Jennifer Goldberg and Cheryl Bast.

From the National Advisory Committee for Acute Exposure Guidelines for Hazardous Substances, we thank Bill Bress (Vermont Department of Health, Burlington, VT), John Hinz (USAF, Brooks AFB, TX), Loren Koller, (Environmental Health and Toxicology, Corvallis, OR), Glenn Leach (U.S. Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, MD), Mark McClanahan (USDHHS Centers for Disease Control and Prevention, Atlanta, GA) and CAPT Kenneth Still (USN, Naval Health Research Center, Wright-Patterson AFB, OH).

From the National Research Council Committee on Toxicology, Subcommittee on Acute Exposure Guideline Levels, we thank Kulbir Bakshi (Committee on Toxicology, National Research Council, Washington, DC), Edward Bishop (Parsons Corporation, Pasadena, CA), John Doull (University of Kansas Medical Center, Kansas City, KS), David Gaylor (Sciences International, Inc., Little Rock, AR), Daniel Krewski (University of Ottawa, Ottawa, Ontario, Canada), Franz Oesch (University of Mainz, Mainz, GDR), and Frederik de Wolff (Leiden University, Leiden, Netherlands).

Sound technical advice and data interpretation on the subject of miosis and anticholinesterase exposure in multiple laboratory animal and human experimental exposure systems were provided by Drs. Herman van Helden (TNO Prins Maurits Laboratory, the Netherlands), Susan Tattersall (Biomedical Sciences Division, Porton Down, UK), Fred Sidell (HB Publishing, Bel Air, MD), and Timothy Fox (Fox Vision Care, Oliver Springs, TN).

Notes

This submission was sponsored by a contractor of the U.S. government under contract DE-AC05-00OR22725. Accordingly, the U.S. government retains a nonexclusive, royalty-free license to publish or reproduce these documents, or to allow others to do so, for U.S. government purposes. These documents may be freely distributed and used for noncommercial, scientific and educational purposes.

^a Mioduszewski et al., 2000; 2001; 2002a for GB; Anthony et al. 2002, 2003, for GF; 24-h lethality.

^b Callaway and Blackburn, 1954; reported as LCt₅₀ for 1-min exposure duration.

^c EC₅₀ and ECt₅₀ for miosis in these studies represent 50% or more reduction in pupil size relative to baseline in 50% of the exposed population.

^d Mioduszewski et al., 2002b for GB; Benton et al., 2004 for VX; Whalley et al., 2004 for GF.

^a Summary of largely unpublished experimental data.

^a Data from unclassified summary table; remainder of report is classified.

^b ECt₅₀ defined by Mioduszewski et al (2002b) as a postexposure pupil diameter of 50% or less of the preexposure diameter in 50% of the exposed population.

^c Data for agent T2715 (2-methylcyclohexyl methylphosphonfluoridate), analog for agent GF.

^a Undocumented summary of data.

^b Summary of largely unpublished data; GB/GA ratio based on geometric mean of 212 mg-min/m³ for the 2 data points for GA.

^c Lethality after 24 h.

^a Ratio shown in parenthesis based on g/kg.

^a Equivalent concentration estimated from iv dose, using as default values 70 kg body weight, and breathing rate of 0.0138 m³/min (13.8 L/min), and the maximum infusion time listed for the iv dose; for single iv doses, an estimated time of 30 s was used.

^b Values are standardized to 10 min, using linear extrapolation. For a breathing rate of 0.055 m³/min (55 L/min) corresponding to heavy activity, the estimated 10-min equivalent concentrations would be approximately one-fourth of the values listed.

^a Mild miosis defined by Johns, 1952, as “decrease of 1 to 2 mm” in pupil diameter; reversible within 24 h.

^b 95% Confidence limits of 2.15–4.57 mg-min/m³.

^c 95% Confidence limits of 6.00–32.02 mg-min/m³.

^a k Derived from the equation (C/UF) ⁿ × t = k (ten Berge et al., 1986).

^a AEGL estimates are for vapor exposures only.

^b Derived from the experimental data of Whalley et al. (2004) for female SD rats; for comparison purposes only (see text for assumptions used in calculation).

^c Derived from the experimental data of Benton et al. (2004) for female SD rats; for comparison purposes only (see text for assumptions used in calculation).

^a NumberCruncher Statistical System Survival Analysis, Version 5.5 (copyright 1991, Dr. Jerry L. Hintz, Kaysville, UT).

^a Derived from the experimental data of Aas et al. (1985); for comparison purposes only (see text for assumptions used in the calculation).

^a Concentration × exposure time (in this case applied as a simple linear extrapolation).

^b Percutaneous absorption of G agent and VX vapor is known to be an effective route of exposure; nevertheless, percutaneous exposure vapor concentrations needed to produce similar adverse effects are greater than inhalation vapor concentrations by several orders of magnitude. Thus, the AEGLs are values presented are considered protective for both routes of exposure.

^c DA, 2004.

^d DHHS 2003; 8-h value is TWA for repeated chronic occupational exposure; 24-h value is TWA for the general population exposure.

^e Acute threshold effects level; Thacker, 1994 [Note. Ct values derived originally for military casualty estimation were approved by DHHS in 1994 for civilian emergency planning at U.S. Army chemical stockpile sites, but have since been superseded by the Army and FEMA with the AEGLs (CSEPP, 2003).]

^a Values in parentheses are the dilutions as reported by Warthin and Weller (1919).

^b Concentration determinations were limited by the analytical capabilities of the time.

^a LC₅₀ 95% confidence interval 13.5–133.4 mg/m³.

^b 21.2 mg/m³ considered 0.5 × LC₅₀ for female Swiss mice (Kumar & Vijayaraghavan, 1998). Of the 3 challenge concentrations, (0.5, 1.0, 2.0 × LC₅₀), 0.5 × LC₅₀ was only level at which no mortality was observed (7 d), and thus represents an experimentally observed threshold for lethality (accepted as point of departure for AEGL-3 estimations; NRC, 2001).

^c LCt₅₀; 95% confidence interval 700–920 mg-min/m³.

^a Concentration × exposure time (in this case applied as simple linear extrapolation).

^b NRC, 2003.

^c DA, 2004.

^d DHHS, 2004; 8-h chronic value is TWA for occupational exposures; 24-h chronic value is TWA for general population.

^e Acute threshold effect level; Thacker, 1994. [Note. Ct values derived originally for military casualty estimation were approved by DHHS in 1994 for civilian emergency planning near U.S. domestic chemical warfare agent stockpile sites, but have since been superseded by the Army and FEMA with the AEGLs (CSEPP, 2003).]

A. D. Little, Inc. 1985. Pharmacokinetic parameters of selected organophosphate compounds with anticholinesterase activity. AAMRL-TR-85–040 (DTIC AD-A157 923). Prepared for Air Force Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH

Bakshi, K. S., Pang, S. N. J., and Snyder, R., eds. 2000. Review of the U.S. Army's Health Risk Assessments for oral exposure to six chemical-warfare agents. J. Toxicol. Environ. Health. 59:281–526.

Benton, B. J., Matson, K. L., Crouse, C. L., Forster, J. S., Jakubowski, E. M., Anthony, J. S., Scotto, J., Manthei, J. H., Way, R. A., Hulet, S. W., Whalley, C. E., Burnett, D. C., Gavola, B. I., Muse, W. T., Miller, D. B., Mioduszewski, R. J., and Thomson, S. A. 2004. Lowlevel effects of VX vapor exposure on pupil size in rats. Abstract and Poster No. 1728, 43rd Meeting of the Society of Toxicology, 21–25 March 2004, Baltimore, MD. Toxicologist. 78(1–S).

Bowden, E. 1943. Median detectable concentrations by odor of plant run mustard, plant run Lewisite and pilot plant ethyl nitrogen mustard. ADB B969 801, TDMR-615, Chemical Corps Technical Command, Army Chemical Center, MD, April.

Bucci, T. J. and Parker, R. M. 1992. Toxicity studies on agents GB and GD (phase II): 90-Day subchronic study of GB (sarin type II) in CD rats. Final report (DTIC: AD-A248618). E515 and E516. Prepared by the National Center for Toxicological Research, Jefferson, AR, for the U.S. Department. of the Army, Biomedical Research and Development Laboratory, Ft. Detrick, MD.

Bucci, T. J. Parker, R. M., Crowell, J. A., Thurman, J. D., and Gosnell, P. A. 1991. Toxicity studies on agents GB and GD (phase II): 90-Day subchronic study of GB (sarin type I) in CD rats. FDA 224–85–0007 (DTIC: AD-A248617). Prepared by the National Center for Toxicological Research, Jefferson, AR, for the U.S. Department. of the Army, Biomedical Research and Development Laboratory, Ft. Detrick, MD.

Büscher, H. 1932. Green and Yellow Cross: Special pathology and therapy of injuries caused by the chemical war materials of the Green Cross group (phosgene and diphosgene) and of the Yellow Cross group (mustard gas and lewisite)]. Hamburg, Germany: R. Himmelhaber and Co. Translated from the German in 1944 by N. Conway, Kettering Laboratory of Applied Physiology, University of Cincinnati, Cincinnati, OH.

Christensen, M. K., Cresthull, P., and Oberst, F. W. 1958. ICt₉₉ and LCt_1–99 estimates of GB vapor for man at various exposure times. Chemical Warfare Laboratories report 2266. Army Chemical Center. MD: Chemical Warfare Laboratories.

Cohen, B. S., Oberst, F. W., Crook, J. W., and Harris, C. 1954. Effect of repeated exposures of GB vapor on erythrocyte and brain cholinesterase in rats. Army Chemical Center, MD: Medical Laboratories. Research report 297.

Crook, J. W., Hott, P., Owens, E. J., Cummings, E. G., Farrand, R. L., and Cooper, A. E. 1983. The effects of subacute exposures of the mouse, rat, guinea pig, and rabbit, to low-level VX concentrations. Technical report ARCSL-TR-82038. Aberdeen Proving Ground. MD: U.S. Army Armament Research and Development Command, Chemical Systems Laboratory.

Dudley, H. C. and Wells, W. J. H. B. 1938. The detection of HS by odor. ADB 959500, EATR 249 (March 1936). Available through U.S. Army Chemical Biological Center, Aberdeen Proving Ground, MD.

Dutreau, C. W., McGrath, F. P., and Bray, E. H., Jr. 1950. Toxicity studies on GD. 1. Median lethal concentration by inhalation in pigeons, rabbits, rats, and mice. 2. Median detectable concentration by odor for man. MDRR 8, CMLEM-52 (ADE 470029 058). Army Chemical Center, MD: Chemical Corps, Medical Division.

Fuhr, I., and Krakow, E. H. 1945. Median lethal concentrations of H for mice and rats for various exposure times. MDRR-21. Chemical Corps, Army Chemical Center, MD, January

Goldman, M. Wilson, B. W., Kawakami, T. G., Rosenblatt, L. S., Culbertson, M. R., Schreider, J. P., Remsen, J. F., and Shifrine, M. 1988. Toxicity studies on agent VX. Final report (AD A201397). Prepared by the Laboratory for Energy-Related Health Research, University of California, Davis, CA, for the U.S. Department of the Army, Medical Research and Development Command, Fort Detrick, MD.

Harris, C., Koon, W., Christensen, J. W., and Oberst, F. W. 1953. Do pathological lesions develop in dogs repeatedly exposed to low concentrations of GB vapor?. MLRR 155. Army Chemical Center. MD: Medical Laboratories.

Harvey, J. C. 1952. Clinical observations on volunteers exposed to concentrations of GB. Medical Laboratories Research Report 114, Publication Control no. 5030–114 (CMLRE-ML-52). Army Chemical Center. MD: Medical Laboratories.

International Agency for Research on Cancer (IARC). 1987a. Mustard gas (sulphur mustard) (Group 1). In Overall evaluation of carcinogenicity: An updating of IARC Monographs, volumes 1–42. IARC Monogr. Eval. Carcinogen. Risks Hum. suppl. 7, pp. 67, 259–260, 398. Lyons, France: IARC.

Johns, R. J. 1952. The effect of low concentrations of GB on the human eye. Research report 100, Publication control no. 5030–100 (CMLRE-ML-52). Army Chemical Center, MD: Chemical Corps Medical Laboratories.

Kimura, K. K., McNamara, B. P., and Sim, V. M. 1960. Intravenous administration of VX in man. Technical report 3017. Army Chemical Center, MD: U.S. Army Chemical Research and Development Laboratory.

Koon, W. S., Crook, J. W., and Oberst, F. W. 1960. Progress report on the toxicity of VX vapor to mice and goats. TM 24–37. Army Chemical Center: MD. Army Chemical Warfare Laboratories.

Lillibridge, S. 1995. Trip Report (25 April 1995): United States Medical Delegation to Japan. From S. R. Lillibridge, Acting Chief, Disaster Assessment and Epidemiology Section, to R. J. Jackson, Director, National Center for Environmental Health, Centers for Disease Control and Prevention, Department of Health and Human Services, Atlanta, GA.

McGrath, F. P., Von Berg, V. J., and Oberst, F. W. 1953. Toxicity and perception of GF vapor. MLRR 185. Army Chemical Center, MD: Medical Laboratory.

Rosenblatt, D. H. 1987. Recalculation of general population exposure limits and stack detection levels for mustard (unpublished). Fort Detrick, MD: U.S. Army Biomedical Research and Development Laboratory.

Thacker, S. B. Assistant Surgeon General, Acting Director, National Center for Environmental Health, Center for Disease Control and Protection, U.S. Department of Health and Human Services. 1994. Letter dated June 24, 1994, establishing “Recommended Acute Threshold Effects Levels for Determining Emergency Evacuation Distances in the CSEPP Program,” to COL J. M. Coverstone, Deputy for Chemical Demilitarization, Office of the Assistant Secretary (I, L &E), Washington, DC.

U.S. Environmental Protection Agency (USEPA). 2001. National Advisory Committee for Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances; Proposed Values. [Nerve Agents GA, GB, GD, GF, pp. 21944–21948, Nerve agent VX, pp. 21961–21964.]. Fed. Reg. 66(85): 21940–21964

Van Helden, H. P. M. Langenberg, J. P., and Benschop, H. P. 2001. Low level exposure to GB vapor in air: Diagnosis/dosimetry, lowest observable effect levels, and performance incapacitation. Award DAMD17–97–1–7360. Final report (April). Prepared by TNO Prins Maurits Laboratory, Rijswijk, the Netherlands, for the U.S. Army Medical Research and Materiel Command, Fort Detrick, MD.

Van Helden, H. P. M. Trap, H. C., Kuijpers, W. C., Groen, B., Oostdijk, J. P., Vanwersch, R. A. P., Philippens, I. H. C., Langenberg, J. P., and Benschop, H. P. 2002. Low level exposure to GB vapor in air: Diagnosis/dosimetry, lowest observable effect level, and performance-incapacitation. In Operational medical issues in chemical and biological defense. Proceedings of the 75^th Meeting of the Research and Technology Organization (RTO) held in Estoril, Portugal, 14–17 May 2001. RTO-MP-075, AC/323 (HFM-060) TP/37. Neuilly sur Seine CEDEX, France: North Atlantic Treaty Organisation, Research and Technology Organisation.

Wells, C. H. Collins, M. T., Vanderveer, D. E., and Wells, W. A. 1993. Standards for chemical and biological warfare hazard modeling, Volume I. Toxicity of nerve agents and mustard in humans. Abridged edition (unclassified). AL-TR-1993–0026. Prepared by Jaycor, Beavercreek, OH, for the U.S. Air Force, Armstrong Laboratory, Ergonomics Analysis Branch, Wright-Patterson Air Force Base, OH.