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Original Articles

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

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Pages 173-263 | Published online: 24 Feb 2007
 

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.

b CitationCallaway 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.

a Summary of largely unpublished experimental data.

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

b ECt50 defined by CitationMioduszewski 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 CitationJohns, 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 (Citationten Berge et al., 1986).

a AEGL estimates are for vapor exposures only.

b Derived from the experimental data of CitationWhalley 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 CitationBenton 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 CitationAas 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.

d CitationDHHS 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; CitationThacker, 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 (CitationCSEPP, 2003).]

a Values in parentheses are the dilutions as reported by CitationWarthin 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 (CitationKumar & 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; CitationNRC, 2001).

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

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

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

e Acute threshold effect level; CitationThacker, 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 (CitationCSEPP, 2003).]

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