National Research Council Committee
Review of Acute Exposure Guideline
Levels of Selected Airborne Chemicals

This report is the fourteenth volume in the series Acute Exposure Guideline Levels for Selected Airborne Chemicals.

In the Bhopal disaster of 1984, approximately 2,000 residents living near a chemical plant were killed and 20,000 more suffered irreversible damage to their eyes and lungs following accidental release of methyl isocyanate. The toll was particularly high because the community had little idea what chemicals were being used at the plant, how dangerous they might be, or what steps to take in an emergency. This tragedy served to focus international attention on the need for governments to identify hazardous substances and to assist local communities in planning how to deal with emergency exposures.

In the United States, the Superfund Amendments and Reauthorization Act (SARA) of 1986 required that the U.S. Environmental Protection Agency (EPA) identify extremely hazardous substances (EHSs) and, in cooperation with the Federal Emergency Management Agency and the U.S. Department of Transportation, assist local emergency planning committees (LEPCs) by providing guidance for conducting health hazard assessments for the development of emergency response plans for sites where EHSs are produced, stored, transported, or used. SARA also required that the Agency for Toxic Substances and Disease Registry (ATSDR) determine whether chemical substances identified at hazardous waste sites or in the environment present a public health concern.

As a first step in assisting the LEPCs, EPA identified approximately 400 EHSs largely on the basis of their immediately dangerous to life and health values, developed by the National Institute for Occupational Safety and Health. Although several public and private groups, such as the Occupational Safety and Health Administration and the American Conference of Governmental Industrial Hygienists, have established exposure limits for some substances and some exposures (e.g., workplace or ambient air quality), these limits are not easily or directly translated into emergency exposure limits for exposures at high levels but



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National Research Council Committee Review of Acute Exposure Guideline Levels of Selected Airborne Chemicals This report is the fourteenth volume in the series Acute Exposure Guide- line Levels for Selected Airborne Chemicals. In the Bhopal disaster of 1984, approximately 2,000 residents living near a chemical plant were killed and 20,000 more suffered irreversible damage to their eyes and lungs following accidental release of methyl isocyanate. The toll was particularly high because the community had little idea what chemicals were being used at the plant, how dangerous they might be, or what steps to take in an emergency. This tragedy served to focus international attention on the need for governments to identify hazardous substances and to assist local communities in planning how to deal with emergency exposures. In the United States, the Superfund Amendments and Reauthorization Act (SARA) of 1986 required that the U.S. Environmental Protection Agency (EPA) identify extremely hazardous substances (EHSs) and, in cooperation with the Federal Emergency Management Agency and the U.S. Department of Transpor- tation, assist local emergency planning committees (LEPCs) by providing guid- ance for conducting health hazard assessments for the development of emergen- cy response plans for sites where EHSs are produced, stored, transported, or used. SARA also required that the Agency for Toxic Substances and Disease Registry (ATSDR) determine whether chemical substances identified at hazard- ous waste sites or in the environment present a public health concern. As a first step in assisting the LEPCs, EPA identified approximately 400 EHSs largely on the basis of their immediately dangerous to life and health val- ues, developed by the National Institute for Occupational Safety and Health. Although several public and private groups, such as the Occupational Safety and Health Administration and the American Conference of Governmental Industrial Hygienists, have established exposure limits for some substances and some ex- posures (e.g., workplace or ambient air quality), these limits are not easily or directly translated into emergency exposure limits for exposures at high levels 3

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4 Acute Exposure Guideline Levels but of short duration, usually less than 1 hour (h), and only once in a lifetime for the general population, which includes infants (from birth to 3 years of age), children, the elderly, and persons with diseases, such as asthma or heart disease. The National Research Council (NRC) Committee on Toxicology (COT) has published many reports on emergency exposure guidance levels and space- craft maximum allowable concentrations for chemicals used by the U.S. De- partment of Defense (DOD) and the National Aeronautics and Space Admin- istration (NASA) (NRC 1968, 1972, 1984a,b,c,d, 1985a,b, 1986a, 1987, 1988, 1994, 1996a,b, 2000a, 2002a, 2007a, 2008a). COT has also published guidelines for developing emergency exposure guidance levels for military personnel and for astronauts (NRC 1986b, 1992, 2000b). Because of COT’s experience in rec- ommending emergency exposure levels for short-term exposures, in 1991 EPA and ATSDR requested that COT develop criteria and methods for developing emergency exposure levels for EHSs for the general population. In response to that request, the NRC assigned this project to the COT Subcommittee on Guide- lines for Developing Community Emergency Exposure Levels for Hazardous Substances. The report of that subcommittee, Guidelines for Developing Com- munity Emergency Exposure Levels for Hazardous Substances (NRC 1993), provides step-by-step guidance for setting emergency exposure levels for EHSs. Guidance is given on what data are needed, what data are available, how to evaluate the data, and how to present the results. In November 1995, the National Advisory Committee (NAC)1 for Acute Exposure Guideline Levels for Hazardous Substances was established to identi- fy, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. The NRC’s previous name for acute exposure levels—community emergency exposure levels (CEELs)—was replaced by the term AEGLs to re- flect the broad application of these values to planning, response, and prevention in the community, the workplace, transportation, the military, and the remedia- tion of Superfund sites. AEGLs represent threshold exposure limits (exposure levels below which adverse health effects are not likely to occur) for the general public and are ap- plicable to emergency exposures ranging from 10 minutes (min) to 8 h. Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five expo- sure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: 1 NAC completed its chemical reviews in October 2011. The committee was composed of members from EPA, DOD, many other federal and state agencies, industry, academia, and other organizations. From 1996 to 2011, the NAC discussed over 300 chemicals and developed AEGLs values for at least 272 of the 329 chemicals on the AEGLs priority chemicals lists. Although the work of the NAC has ended, the NAC-reviewed technical support documents are being submitted to the NRC for independent review and finaliza- tion.

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NRC Committee Review of Acute Exposure Guideline Levels 5 AEGL-1 is the airborne concentration (expressed as ppm [parts per mil- lion] or mg/m3 [milligrams per cubic meter]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening adverse health effects or death. Airborne concentrations below AEGL-1 represent exposure levels that can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic nonsensory adverse effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as in- fants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experi- ence the effects described at concentrations below the corresponding AEGL. SUMMARY OF REPORT ON GUIDELINES FOR DEVELOPING AEGLS As described in Guidelines for Developing Community Emergency Expo- sure Levels for Hazardous Substances (NRC 1993) and the NRC guidelines re- port Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001a), the first step in establishing AEGLs for a chemical is to collect and review all relevant published and un- published information. Various types of evidence are assessed in establishing AEGL values for a chemical. These include information from (1) chemical- physical characterizations, (2) structure-activity relationships, (3) in vitro toxici- ty studies, (4) animal toxicity studies, (5) controlled human studies, (6) observa- tions of humans involved in chemical accidents, and (7) epidemiologic studies. Toxicity data from human studies are most applicable and are used when availa- ble in preference to data from animal studies and in vitro studies. Toxicity data from inhalation exposures are most useful for setting AEGLs for airborne chem- icals because inhalation is the most likely route of exposure and because extrap-

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6 Acute Exposure Guideline Levels olation of data from other routes would lead to additional uncertainty in the AEGL estimate. For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data for animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, data from the most sensi- tive animal species are used. Uncertainty factors are commonly used when ani- mal data are used to estimate risk levels for humans. The magnitude of uncer- tainty factors depends on the quality of the animal data used to determine the no- observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmacokinetic data on tissue doses are consid- ered for interspecies extrapolation. For substances that affect several organ systems or have multiple effects, all end points (including reproductive [in both genders], developmental, neuro- toxic, respiratory, and other organ-related effects) are evaluated, the most im- portant or most sensitive effect receiving the greatest attention. For carcinogenic chemicals, excess carcinogenic risk is estimated, and the AEGLs corresponding to carcinogenic risks of 1 in 10,000 (1  10-4), 1 in 100,000 (1  10-5), and 1 in 1,000,000 (1  10-6) exposed persons are estimated. REVIEW OF AEGL REPORTS As NAC began developing chemical-specific AEGL reports, EPA and DOD asked the NRC to review independently the NAC reports for their scien- tific validity, completeness, and consistency with the NRC guideline reports (NRC 1993, 2001a). The NRC assigned this project to the COT Committee on Acute Exposure Guideline Levels. The committee has expertise in toxicology, epidemiology, occupational health, pharmacology, medicine, pharmacokinetics, industrial hygiene, and risk assessment. The AEGL draft reports were initially prepared by ad hoc AEGL devel- opment teams consisting of a chemical manager, chemical reviewers, and a staff scientist of the NAC contractors—Oak Ridge National Laboratory and subse- quently Syracuse Research Corporation. The draft documents were then re- viewed by NAC and elevated from “draft” to “proposed” status. After the AEGL documents were approved by NAC, they were published in the Federal Register for public comment. The reports were then revised by NAC in response to the public comments, elevated from “proposed” to “interim” status, and sent to the NRC Committee on Acute Exposure Guideline Levels for final evaluation. The NRC committee’s review of the AEGL reports prepared by NAC and its contractors involves oral and written presentations to the committee by the authors of the reports. The NRC committee provides advice and recommenda-

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NRC Committee Review of Acute Exposure Guideline Levels 7 tions for revisions to ensure scientific validity and consistency with the NRC guideline reports (NRC 1993, 2001a). The revised reports are presented at sub- sequent meetings until the committee is satisfied with the reviews. Because of the enormous amount of data presented in AEGL reports, the NRC committee cannot verify all of the data used by NAC. The NRC committee relies on NAC for the accuracy and completeness of the toxicity data cited in the AEGL reports. Thus far, the committee has prepared thirteen reports in the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2001b, 2002b, 2003, 2004, 2007b, 2008b, 2009, 2010a,b, 2011, 2012a,b,c). This report is the fourteenth volume in that series. AEGL documents for BZ (2-quinuclidinyl benzilate), ethyl phosphorodichloridate, hexane, methanesulfonyl chloride, nitric acid, propargyl alcohol, and vinyl acetate monomer are each published as an ap- pendix in this report. The committee concludes that the AEGLs developed in these appendixes are scientifically valid conclusions based on the data reviewed by NAC and are consistent with the NRC guideline reports. AEGL reports for addi- tional chemicals will be presented in subsequent volumes. REFERENCES NRC (National Research Council). 1968. Atmospheric Contaminants in Spacecraft. Washington, DC: National Academy of Sciences. NRC (National Research Council). 1972. Atmospheric Contaminants in Manned Space- craft. Washington, DC: National Academy of Sciences. NRC (National Research Council). 1984a. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press. NRC (National Research Council). 1984b. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press. NRC (National Research Council). 1984c. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 3. Washington, DC: National Academy Press. NRC (National Research Council). 1984d. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: National Academy Press. NRC (National Research Council). 1985a. Emergency and Continuous Exposure Guid- ance Levels for Selected Airborne Contaminants, Vol. 4. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 1985b. Emergency and Continuous Exposure Guid- ance Levels for Selected Airborne Contaminants, Vol. 5. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 1986a. Emergency and Continuous Exposure Guid- ance Levels for Selected Airborne Contaminants, Vol. 6. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 1986b. Criteria and Methods for Preparing Emergen- cy Exposure Guidance Level (EEGL), Short-Term Public Emergency Guidance Level (SPEGL), and Continuous Exposure Guidance level (CEGL) Documents. Washington, DC: National Academy Press.

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8 Acute Exposure Guideline Levels NRC (National Research Council). 1987. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 7. Washington, DC: National Academy Press. NRC (National Research Council). 1988. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 8. Washington, DC: National Academy Press. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maxi- mum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press. NRC (National Research Council). 1996a. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press. NRC (National Research Council). 1996b. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 3. Washington, DC: National Academy Press. NRC (National Research Council). 2000a. Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academy Press. NRC (National Research Council). 2000b. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2001a. Standing Operating Procedures for Develop- ing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. NRC (National Research Council). 2001b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 1. Washington, DC: National Academy Press. NRC (National Research Council). 2002a. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. NRC (National Research Council). 2002b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol 2. Washington, DC: The National Academies Press. NRC (National Research Council). 2003. Acute Exposure Guideline Levels for Selected Airborne Chemical, Vol. 3. Washington, DC: The National Academies Press. NRC (National Research Council). 2004. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The National Academies Press. NRC (National Research Council). 2007a. Emergency and Continuous Exposure Guid- ance Levels for Selected Submarine Contaminants, Vol. 1. Washington, DC: The National Academies Press. NRC (National Research Council). 2007b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 5. Washington, DC: The National Academies Press. NRC (National Research Council). 2008a. Emergency and Continuous Exposure Guid- ance Levels for Selected Submarine Contaminants, Vol. 2. Washington, DC: The National Academies Press. NRC (National Research Council). 2008b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 6. Washington, DC: The National Academies Press. NRC (National Research Council). 2009. Acute Exposure Guideline Levels for Selected

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NRC Committee Review of Acute Exposure Guideline Levels 9 Airborne Chemicals, Vol. 7. Washington, DC: The National Academies Press. NRC (National Research Council). 2010a. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 8. Washington, DC: The National Academies Press. NRC (National Research Council). 2010b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 9. Washington, DC: The National Academies Press. NRC (National Research Council). 2011. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 10. Washington, DC: The National Academies Press. NRC (National Research Council). 2012a. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 11. Washington, DC: The National Academies Press. NRC (National Research Council). 2012b. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 12. Washington, DC: The National Academies Press. NRC (National Research Council). 2012c. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 13. Washington, DC: The National Academies Press.

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