Standing Operating Procedures

for Developing

Acute Exposure Guideline Levels

for Hazardous Chemicals

Subcommittee on Acute Exposure Guideline Levels

Committee on Toxicology

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

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v 

SUBCOMMITTEE ON ACUTE EXPOSURE GUIDELINE LEVELS

DANIEL KREWSKI, (Chair), University of Ottawa, Ottawa, Ontario

EDWARD C. BISHOP, Parsons Engineering Science, Inc., Fairfax, Virginia

JAMES V. BRUCKNER, University of Georgia, Athens

JOHN DOULL, University of Kansas Medical Center, Kansas City

DONALD E. GARDNER, Inhalation Toxicology Associates, Inc., Raleigh,

North Carolina

DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson,

Arkansas

FLORENCE K. KINOSHITA, Hercules Incorporated, Wilmington, Delaware

STEPHEN U. LESTER, Center for Health, Environment and Justice, Falls

Church, Virginia

HARIHARA MEHENDALE, University of Louisiana, Monroe

RICHARD B. SCHLESINGER, New York University School of Medicine,

Tuxedo

CALVIN C. WILLHITE, State of California, Berkeley

Staff

KULBIR S. BAKSHI, Project Director 

RUTH E. CROSSGROVE, Editor

AIDA NEEL, Administrative Assistant 

Sponsor: U.S. Department of Defense
vi 

COMMITTEE ON TOXICOLOGY

BAILUS WALKER, JR. (Chair), Howard University Medical Center and

American Public Health Association, Washington, D.C.

MELVIN E. ANDERSEN, Colorado State University, Denver

GERMAINE M. BUCK, National Institute of Health, Washington, D.C.

ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia

WILLIAM E. HALPERIN, National Institute for Occupational Safety and

Health, Cincinnati, Ohio

CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace

Biomedical and Environmental Research Institute, Albuquerque,

New Mexico

SAM KACEW, University of Ottawa, Ottawa, Ontario

NANCY KERKVLIET, Oregon State University, Corvallis

MICHAEL J. KOSNETT, University of Colorado Health Sciences Center,

Denver

MORTON LIPPMANN, New York University School of Medicine, Tuxedo

ERNEST E. MCCONNELL, ToxPath, Inc., Raleigh, North Carolina

THOMAS E. MCKONE, Lawrence Berkeley National Laboratory and

University of California, Berkeley

HARIHARA MEHENDALE, University of Louisiana, Monroe

DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Maryland

LAUREN ZEISE, California Environmental Protection Agency, Oakland

Staff

KULBIR S. BAKSHI, Program Director 

SUSAN N.J. MARTEL, Program Officer

ABIGAIL E. STACK, Program Officer

RUTH E. CROSSGROVE, Publications Manager

AIDA NEEL, Administrative Assistant

JESSICA BROCK, Project Assistant
vii 

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

GORDON ORIANS (Chair), University of Washington, Seattle

JOHN DOULL, University of Kansas Medical Center, Kansas City

DAVID ALLEN, University of Texas, Austin

INGRID C. BURKE, Colorado State University, Fort Collins

THOMAS BURKE, Johns Hopkins University, Baltimore, Maryland

GLEN R. CASS, Georgia Institute of Technology, Atlanta

WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta

CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford,

California

JOHN GERHART, University of California, Berkeley

J. PAUL GILMAN, Celera Genomics, Rockville, Maryland

DANIEL S. GREENBAUM, Health Effects Institute, Cambridge,

Massachusetts

BRUCE D. HAMMOCK, University of California, Davis

ROGENE HENDERSON, Lovelace Respiratory Research Institute,

Albuquerque, New Mexico

CAROL HENRY, American Chemistry Council, Arlington, Virginia

ROBERT HUGGETT, Michigan State University, East Lansing

JAMES F. KITCHELL, University of Wisconsin, Madison

DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario

JAMES A. MACMAHON, Utah State University, Logan

CHARLES O’MELIA, Johns Hopkins University, Baltimore, Maryland

WILLEM F. PASSCHIER, Health Council of the Netherlands, The Hague

ANN POWERS, Pace University School of Law, White Plains, New York

KIRK SMITH, University of California, Berkeley

TERRY F. YOSIE, American Chemistry Council, Arlington, Virginia

Senior Staff

JAMES J. REISA, Director

DAVID J. POLICANSKY, Associate Director and Senior Program Director for

Applied Ecology 

RAYMOND A. WASSEL, Senior Program Director for Environmental

Sciences and Engineering

KULBIR BAKSHI, Program Director for the Committee on Toxicology

ROBERTA M. WEDGE, Program Director for Risk Analysis

JOHN HOLMES, Senior Staff Officer
viii 

COMMISSION ON LIFE SCIENCES

MICHAEL T. CLEGG (Chair), University of California, Riverside

PAUL BERG (Vice Chair), Stanford University, Stanford, California

FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington,

D.C.

JOANNA BURGER, Rutgers University, Piscataway, New Jersey

JAMES E. CLEAVER, University of California, San Francisco

DAVID S. EISENBERG, University of California, Los Angeles

NEAL L. FIRST, University of Wisconsin, Madison

DAVID J. GALAS, Keck Graduate Institute of Applied Life Science,

Claremont, California

DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, California

ARTURO GOMEZ-POMPA, University of California, Riverside

COREY S. GOODMAN, University of California, Berkeley

JON W. GORDON, Mount Sinai School of Medicine, New York

DAVID G. HOEL, Medical University of South Carolina, Charleston

BARBARA S. HULKA, University of North Carolina, Chapel Hill

CYNTHIA J. KENYON, University of California, San Francisco

BRUCE R. LEVIN, Emory University, Atlanta, Georgia

DAVID M. LIVINGSTON, Dana-Farber Cancer Institute, Boston,

Massachusetts

DONALD R. MATTISON, March of Dimes, White Plains, New York

ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena

ROBERT T. PAINE, University of Washington, Seattle

RONALD R. SEDEROFF, North Carolina State University, Raleigh

ROBERT R. SOKAL, State University of New York, Stony Brook

CHARLES F. STEVENS, The Salk Institute for Biological Studies, La Jolla,

California

SHIRLEY M. TILGHMAN, Princeton University, Princeton, New Jersey

RAYMOND L. WHITE, DNA Sciences, Inc., Mountain View, California

Staff

WARREN R. MUIR, Executive Director

JACQUELINE K. PRINCE, Financial Officer

BARBARA B. SMITH, Administrative Associate

LAURA T. HOLLIDAY, Senior Program Assistant
ix 

OTHER REPORTS OF THE

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

A Risk-Management Strategy for PCB-Contaminated Sediments (2001)

Toxicological Effects of Methylmercury (2000)

Strengthening Science at the U.S. Environmental Protection Agency:

Research-Management and Peer-Review Practices (2000)

Scientific Frontiers in Developmental Toxicology and Risk Assessment

(2000)

Modeling Mobile-Source Emissions (2000)

Toxicological Risks of Selected Flame-Retardant Chemicals (2000)

Copper in Drinking Water (2000)

Ecological Indicators for the Nation (2000)

Waste Incineration and Public Health (1999)

Hormonally Active Agents in the Environment (1999)

Research Priorities for Airborne Particulate Matter: I. Immediate Priorities

and a Long-Range Research Portfolio (1998); II. Evaluating

Research Progress and Updating the Portfolio (1999)

Ozone-Forming Potential of Reformulated Gasoline (1999)

Risk-Based Waste Classification in California (1999)

Arsenic in Drinking Water (1999)

Brucellosis in the Greater Yellowstone Area (1998)

The National Research Council’s Committee on Toxicology: The First 50

Years (1997)

Toxicologic Assessment of the Army’s Zinc Cadmium Sulfide Dispersion

Tests (1997)

Carcinogens and Anticarcinogens in the Human Diet (1996)

Upstream: Salmon and Society in the Pacific Northwest (1996)

Science and the Endangered Species Act (1995)

Wetlands: Characteristics and Boundaries (1995)

Biologic Markers (5 reports, 1989-1995)

Review of EPA's Environmental Monitoring and Assessment Program (3

reports, 1994-1995)

Science and Judgment in Risk Assessment (1994)

Ranking Hazardous Waste Sites for Remedial Action (1994)

Pesticides in the Diets of Infants and Children (1993)

Issues in Risk Assessment (1993)

Setting Priorities for Land Conservation (1993)

Protecting Visibility in National Parks and Wilderness Areas (1993)

Dolphins and the Tuna Industry (1992)

Hazardous Materials on the Public Lands (1992)
x OTHER REPORTS

Science and the National Parks (1992)

Animals as Sentinels of Environmental Health Hazards (1991)

Assessment of the U.S. Outer Continental Shelf Environmental Studies

Program, Volumes I-IV (1991-1993)

Human Exposure Assessment for Airborne Pollutants (1991)

Monitoring Human Tissues for Toxic Substances (1991)

Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991)

Decline of the Sea Turtles (1990)

Copies of these reports may be ordered from

the National Academy Press

(800) 624-6242

(202) 334-3313

www.nap.edu
xi 

OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY 

Evaluating Chemical and Other Agent Exposures for Reproductive and

Developmental Toxicity (2001)

Acute Exposure Guideline Levels for Selected Airborne Contaminants,

Volume 1 (2000)

Review of the U.S. Navy’s Human Health Risk Assessment of the Naval

Air Facility at Atsugi, Japan (2000)

Methods for Developing Spacecraft Water Exposure Guidelines (2000)

Review of the U.S. Navy Environmental Health Center’s Health-Hazard

Assessment Process (2000)

Review of the U.S. Navy's Exposure Standard for Manufactured Vitreous

Fibers (2000)

Re-Evaluation of Drinking-Water Guidelines for Diisopropyl

Methylphosphonate (2000)

Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: 

HFC-236fa, HFC-23, and HFC-404a (2000)

Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to

Six Chemical-Warfare Agents (1999)

Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2

(1999), Volume 3 (1999)

Assessment of Exposure-Response Functions for Rocket-Emission

Toxicants (1998)

Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123

(1996)

Permissible Exposure Levels for Selected Military Fuel Vapors (1996)

Spacecraft Maximum Allowable Concentrations for Selected Airborne

Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3

(1996), Volume 4 (2000)
1

As defined pursuant to the Superfund Amendments and Reauthorization Act of

1986.

xiii 

Preface

Extremely hazardous substances (EHSs)1 can be released accidentally as a

result of chemical spills, industrial explosions, fires, or accidents involving

railroad cars and trucks transporting EHSs. The people in communities surrounding industrial facilities where EHSs are manufactured, used, or stored

and in communities along the nation’s railways and highways are potentially

at risk of being exposed to airborne EHSs during accidental releases. Pursuant

to the Superfund Amendments and Reauthorization Act of 1986, the U.S.

Environmental Protection Agency (EPA) has identified approximately 400

EHSs on the basis of acute lethality data in rodents.

As part of its efforts to develop acute exposure guideline levels for EHSs,

EPA and the Agency for Toxic Substances and Disease Registry (ATSDR)

requested in 1991 that the National Research Council (NRC) develop guidelines for establishing such levels. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for

Hazardous Substances in 1993.

Using the 1993 NRC guidelines report, the National Advisory Committee

(NAC) on Acute Exposure Guideline Levels for Hazardous Substances—

consisting of members from EPA, the Department of Defense (DOD), the

Department of Energy (DOE), the Department of Transportation, other federal

and state governments, the chemical industry, academia, and other organiza-
xiv PREFACE

tions from the private sector—has developed acute exposure guideline levels

(AEGLs) for approximately 80 EHSs.

In 1998, EPA and DOD requested that the NRC independently review the

AEGLs developed by NAC. In response to that request, the NRC organized

within its Committee on Toxicology the Subcommittee on Acute Exposure

Guideline Levels, which prepared this report. This report evaluates the NAC’s

Standing Operating Procedures (SOP) document for its scientific validity,

completeness, and for conformance to the 1993 NRC guidelines report. The

report will be useful to EPA, DOD, ATSDR, and other federal, state, and local

agencies, and industry in developing toxicologic risk assessments for hazardous chemicals.

This report has been reviewed in draft form by individuals chosen for their

diverse perspectives and technical expertise, in accordance with procedures

approved by the NRC's Report Review Committee. The purpose of this

independent review is to provide candid and critical comments that will assist

the institution in making its published report as sound as possible and to ensure

that the report meets institutional standards for objectivity, evidence, and

responsiveness to the study charge. The review comments and draft manuscript

remain confidential to protect the integrity of the deliberative process. We

wish to thank the following individuals for their review of this report: Gary

Carlson (Purdue University), Charles Feigley (University of South Carolina),

and Ralph Kodell (National Center for Toxicological Research).

Although the reviewers listed above have provided many constructive

comments and suggestions, they were not asked to endorse the conclusions or

recommendations nor did they see the final draft of the report before its

release. The review of this report was overseen by Mary Vore (University of

Kentucky), appointed by the Commission on Life Sciences, who was responsible for making certain that an independent examination of this report was

carried out in accordance with institutional procedures and that all review

comments were carefully considered. Responsibility for the final content of

this report rests entirely with the authoring committee and the institution.

The subcommittee gratefully acknowledges the valuable assistance provided by the following persons: Roger Garrett, Paul Tobin, and Ernest Falke

(all from EPA); George Rusch (Honeywell, Inc.); Po Yung Lu, Sylvia

Talmage, Robert Young, and Cheryl Bast (all from Oak Ridge National

Laboratory), and Karl Rozman (University of Kansas Medical Center). Aida

Neel was the project assistant. Ruth Crossgrove edited the report. We are

grateful to James J. Reisa, director of the Board on Environmental Studies and

Toxicology (BEST), and David Policansky, associate director of BEST, for
PREFACE xv 

their helpful comments. The subcommittee particularly acknowledges Kulbir

Bakshi, project director for the subcommittee, for bringing the report to

completion. Finally, we would like to thank all members of the subcommittee

for their expertise and dedicated effort throughout the development of this

report.

Daniel Krewski, Chair

Subcommittee on Acute Exposure 

Guideline Levels

Bailus Walker, Chair

Committee on Toxicology

xvii 

Contents

INTRODUCTION ............................................. 1

ROSTER OF THE NATIONAL ADVISORY COMMITTEE FOR ACUTE

EXPOSURE GUIDELINE LEVELS (NAC/AEGL COMMITTEE) FOR

HAZARDOUS SUBSTANCES ................................. 7

APPENDIX: STANDING OPERATING PROCEDURES FOR DEVELOPING

ACUTE EXPOSURE GUIDELINE LEVELS FOR HAZARDOUS CHEMICALS15

PREFACE ................................................. 17

1. OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE . 19

History, 19

Purpose and Objectives of the AEGL Program and the NAC/AEGL

Committee, 21

Committee Membership and Organizational Structure, 23

Selection of Chemicals for AEGL Development, 24

Scientific Credibility of AEGL Values, 25

The AEGL Development and Peer-Review Process, 26

Operation of the NAC/AEGL Committee, 28

Value of a Collaborative Effort in the AEGL Program, 30

Applications of the AEGL Values, 31

2. DERIVATION OF AEGL VALUES ........................... 34
xviii CONTENTS

2.1 Characterization of AEGLs, 34

2.2 Empirical Toxicologic Endpoints and Methods for Determining

Exposure Concentrations Used to Derive AEGLs 1,2, and 3, 35

2.3 Guidelines and Criteria for the Search Strategy, Evaluation,

Selection, and Documentation of Key Data and Supporting Data

Used for the Derivation of AEGL Values, 46

2.4 Dosimetry Corrections from Animal to Human Exposures, 57

2.5 Guidelines and Criteria for Selection of Uncertainty Factors to

Address the Variability Between Animals and Humans and Within

the Human Population, 62

2.6 Guidelines and Criteria for Selection of Modifying Factors, 91

2.7 Guidelines and Criteria for Time Scaling, 92

2.8 Guidelines and Criteria for Addressing Short-Term Exposure

Known and Suspect Carcinogens, 111

2.9 Guidelines and Criteria for Miscellaneous Procedures and Methods,

122

3. FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS . 124

Editorial Conventions, 124

3.1 Format and Content of Technical Support Documents, 125

3.2 Graphic Description of Data, 131

4. CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES

FOR THE DEVELOPMENT OF AEGL VALUES .............. 139

4.1 Committee Membership and Organizational Structure, 140

4.2 The AEGL Development and Peer-Review Process, 141

4.3 Operation of the NAC/AEGL Committee, 144

4.4 Role of the Director of the AEGL Program, 146

4.5 Role of the Designated Federal Officer, 147

4.6 Role of the NAC/AEGL Committee Chair, 147

4.7 Classification of the Status of AEGL Values, 148

4.8 Function of AEGL Development Teams, 148

4.9 Role of NAC/AEGL Committee Members, 151

4.10 Role of the Organization That Drafts TSDs, 152

5. REFERENCES .......................................... 154

APPENDIX A. PRIORITY LISTS OF CHEMICALS. ................ 165

APPENDIX B. DIAGRAM OF THE AEGL DEVELOPMENT PROCESS . 173
CONTENTS xix 

APPENDIX C. GLOSSARY OF ACRONYMS, ABBREVIATIONS,

AND SYMBOLS ......................................... 175

APPENDIX D. EXAMPLE OF A TABLE OF CONTENTS OF A 

TECHNICAL SUPPORT DOCUMENT ......................... 179

APPENDIX E. EXAMPLE OF A SUMMARY OF A TECHNICAL 

SUPPORT DOCUMENT ................................... 182

APPENDIX F. EXAMPLE OF THE DERIVATION OF AEGL VALUES 

APPENDIX IN A TECHNICAL SUPPORT DOCUMENT ............ 186

APPENDIX G. EXAMPLE OF TIME-SCALING CALCULATIONS 

APPENDIX IN A TECHNICAL SUPPORT DOCUMENT ............ 190

APPENDIX H. EXAMPLE OF A CARCINOGENICITY ASSESSMENT 

APPENDIX IN A TECHNICAL SUPPORT DOCUMENT ............ 194

APPENDIX I. EXAMPLE OF THE AEGL DERIVATION SUMMARY 

APPENDIX IN A TECHNICAL SUPPORT DOCUMENT ............ 196

APPENDIX J. LIST OF EXTANT STANDARDS AND GUIDELINES IN A 

TECHNICAL SUPPORT DOCUMENT ......................... 201

LIST OF TABLES

TABLE 2-1 Values of n from Ten Berge et al. (1986). ........... 94

TABLE 3-1 Grouping Data into Categories for Plotting ......... 132

TABLE A-1 Priority List of Chemicals . . . . . . . . . . . . . . . . . . . . . . 168

LIST OF FIGURES

FIGURE 1-1 Hazard assessment .......................... 33

FIGURE 2-1 Decision tree for the selection of key and 

supporting data ............................ 55

FIGURE 2-2 Effects of varying n in the equation Cn

 × t = k . . . 104

FIGURE 3-1 Plot of categories of data . . . . . . . . . . . . . . . . . . . . 137

FIGURE 4-1 The AEGL development process .............. 142
Standing Operating Procedures

for Developing

Acute Exposure Guideline Levels

for Hazardous Chemicals

1

Introduction

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, and what steps

to take in case of 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 the U.S. Environmental Protection Agency (EPA)

to identify extremely hazardous substances (EHSs) and, in cooperation with

the Federal Emergency Management Agency and the Department of Transportation, to 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 the Agency for Toxic Substances and

Disease Registry (ATSDR) to 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”

(IDLH) values developed by the National Institute for Occupational Safety and

Health in experimental animals. 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
2 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

1

NAC is composed of members from EPA, DOD, many other federal and state

agencies, industry, academia, and other organizations. The roster of NAC is shown

on page 7.

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 of short duration, usually less

than 1 hr, and only once in a lifetime for the general population, which includes infants, children, the elderly, and persons with diseases, such as asthma,

heart disease, or lung disease.

The National Research Council (NRC) Committee on Toxicology (COT)

has published many reports on emergency exposure guidance levels and

spacecraft maximum allowable concentrations for chemicals used by the

Department of Defense (DOD) and the National Aeronautics and Space

Administration (NASA) (NRC 1968; 1972; 1984a,b,c,d; 1985a,b; 1986a,b;

1987; 1988, 1994, 1996a,b; 2000a,b). COT has also published guidelines for

developing emergency exposure guidance levels for military personnel and for

astronauts (NRC 1986b, 1992). Because of the experience of COT in recommending emergency exposure levels for short-term exposures, EPA and

ATSDR in 1991 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 Guidelines for Developing Community Emergency Exposure Levels

for Hazardous Substances. The report of that subcommittee, Guidelines for

Developing Community 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 them, and how to present the results. 

In November1995, the National Advisory Committee for Acute Exposure

Guideline Levels for Hazardous Substances (NAC1

) was established to identify, 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 reflect the broad application of these values to planning, response,

and prevention in the community, the workplace, transportation, the military,

and the remediation of Superfund sites.

AEGLs represent threshold exposure limits for the general public and

are applicable to emergency exposures ranging from 10 min to 8 h. Three

levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five
INTRODUCTION 3 

exposure 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:

AEGL-1 is the airborne concentration (expressed as ppm (parts per

million) 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 susceptible 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 susceptible individuals, could experience life-threatening

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 effects. With

increasing airborne concentrations above each AEGL, there is a progressive

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 infants, children, the elderly, persons with asthma, and those with other

illnesses, it is recognized that individuals, subject to unique or idiosyncratic

responses, could experience the effects described at concentrations below the

corresponding AEGL.

REVIEW OF THE NAC DOCUMENT

STANDING OPERATING PROCEDURES ON ACUTE EXPOSURE

GUIDELINE LEVELS FOR HAZARDOUS SUBSTANCES

Before developing AEGLs for individual chemicals, the NAC developed
4 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

the guidelines document Standing Operating Procedures of the National

Advisory Committee on Acute Exposure Guideline Levels for Hazardous

Substances (referred to as the SOP manual), which documents the procedures,

methods, criteria, and other guidelines used by NAC in the development of the

AEGL values. The information contained in the SOP document is based on

the guidance provided by the NRC in its guidelines report (NRC 1993). The

SOP document contains further details and clarification of specific procedures,

methods, criteria, and guidelines interpreted from the NRC report.

In 1998, EPA and DOD asked the NRC to review the NAC’s SOP document and AEGL reports for their scientific validity, completeness, and conformance to the 1993 NRC guidelines report. The NRC assigned this project to

the COT Subcommittee on Acute Exposure Guideline Levels. The subcommittee members were chosen for their expertise in toxicology, epidemiology,

pharmacology, medicine, industrial hygiene, biostatistics, risk assessment, and

risk communication. The subcommittee’s review of the SOP document

prepared by the NAC involved oral and written presentations to the subcommittee by the authors of the report. The subcommittee provided advice and

recommendations for revisions to ensure scientific validity and consistency

with the NRC (1993) guidelines report. The authors of the SOP document

presented their revised report at subsequent meetings until the subcommittee

was satisfied with the revisions. The subcommittee concludes that the revised

SOP document presented in the Appendix of this report is scientifically valid,

complete, and consistent with the 1993 NRC guidelines report.

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

Spacecraft. 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
INTRODUCTION 5 

Needs and Priorities. Washington, DC: National Academy Press.

NRC (National Research Council). 1985a. Emergency and Continuous Exposure

Guidance Levels for Selected Airborne Contaminants, Vol. 4. Washington, DC:

National Academy Press.

NRC (National Research Council). 1985b. Emergency and Continuous Exposure

Guidance Levels for Selected Airborne Contaminants, Vol. 5. Washington, DC:

National Academy Press.

NRC (National Research Council). 1986a. Emergency and Continuous Exposure

Guidance Levels for Selected Airborne Contaminants, Vol. 6. Washington, DC:

National Academy Press.

NRC (National Research Council). 1986b. Criteria and Methods for Preparing

Emergency Exposure Guidance Level (EEGL), Short-Term Public Emergency

Guidance Level (SPEGL), and Continuous Exposure Guidance level (CEGL)

Documents. Washington, DC: National Academy Press.

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

Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press.

NRC (National Research Council). 1993. Guidelines for Developing Community

Emergency Exposure Levels for Hazardous Substances. Washington, DC:

National Academy Press.

NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 1. Washington, DC: National

Academy Press.

NRC (National Research Council). 1996a. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 2. Washington, DC: National

Academy Press.

NRC (National Research Council). 1996b. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 3. Washington, DC: National

Academy Press.

NRC (National Research Council). 2000a. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 4. Washington, DC: National

Academy Press.

NRC (National Research Council). 2000b. Acute Exposure Guideline Levels for

Selected Airborne Chemicals, Vol. 1. Washington, DC: National Academy Press.

7

Roster

National Advisory Committee for Acute

Exposure Guideline Levels (NAC/AEGL

Committee) for Hazardous Substances

COMMITTEE MEMBERS

George Rusch

Chair, NAC/AEGL Committee

Honeywell International, Inc.

Morristown, NJ

Ernest Falke

Chair, SOP Workgroup

U.S. Environmental Protection Agency

Washington, DC

George Alexeeff

California EPA

Oakland, CA

Steven Barbee

Arch Chemicals, Inc.

Norwalk, CT
8 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Lynn Beasley

U.S. Environmental Protection Agency

Washington, DC

David Belluck

Minnesota Department of Transportation

Oakdale, MN

Robert Benson

U.S. Environmental Protection Agency

Denver, CO

Jonathan Borak

American College of Occupational and Environmental Medicine

and Yale University

New Haven, CT

William Bress

Vermont Department of Health

Burlington, VT

George Cushmac

U.S. Department of Transportation

Washington, DC

Larry Gephart

ExxonMobil Biomedical Sciences, Inc.

Annandale, NJ

Doan Hanson

Brookhaven National Laboratory

Upton, NY

John P. Hinz

U.S. Air Force

Brooks Air Force Base, TX

James Holler

Agency for Toxic Substances and Disease Registry

Atlanta, GA
ROSTER OF THE NAC/AEGL COMMITTEE 9 

Thomas C. Hornshaw

Illinois Environmental Protection Agency

Springfield, IL

Nancy K. Kim

New York State Department of Health

Troy, NY

Loren Koller

Oregon State University

Corvallis, OR

Glenn Leach

U.S. Army

Aberdeen Proving Grounds, MD

Mark A. McClanahan

Centers for Disease Control & Prevention

Doraville, GA

John Morawetz

International Chemical Workers Union

Cincinnati, OH

Richard Niemeier

National Institute for Occupational Safety and Health

Cincinnati, OH

Marinelle Payton

Harvard Medical School

Boston, MA

Zarena Post

Texas Natural Resource Conservation Commission

Austin, TX

George Rodgers

American Association of Poison Control Centers

University of Louisville

Louisville, KY
10 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Robert Snyder

Environmental and Occupational Health Sciences Institute

Piscataway, NJ

Thomas J. Sobotka

U.S. Food and Drug Administration

Laurel, MD

Kenneth Still

U.S. Navy

Wright-Patterson Air Force Base, OH

Judy Strickland

U.S. Environmental Protection Agency

Research Triangle Park, NC

Richard Thomas

International Center for Environmental Technology

McLean, VA

Thomas Tuccinardi

U.S. Department of Energy

Germantown, MD

Past Committee Members

Kyle Blackman

Federal Emergency Management Agency

Washington, DC

Luz Claudio

Mount Sinai Medical Center

New York, NY

Benjamin Jackson

Consultant

Washington, DC
ROSTER OF THE NAC/AEGL COMMITTEE 11 

William Pepelko

U.S. Environmental Protection Agency

Washington, DC

Michelle Schaper

Mine Safety and Health Administration

Arlington, VA

Patricia Talcott

University of Idaho

Moscow, ID

Participants from Cooperative Partner Countries

Peter Griem

Forschungs- und Beratungsinstitut Gefarhstoffe

Freiburg, Germany

Ursula Gundert-Remy

Federal Institute for Consumer Health Protection and Veterinary Medicine

Berlin, Germany

Fritz Kalberlah

Forschungs- und Beratungsinstitut Gefarhstoffe

Freiburg, Germany

Marc Ruijten

Medical Emergency Preparedness and Planning Office

Rotterdam, The Netherlands

Ursula Stephan

Head, German Toxicology Expert Group for AEGLs

Berlin, Germany

Marcel van Raaij

RIVM Center for Chemical Risk Assessment

Rotterdam, The Netherlands
12 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Other Participants

Surender Ahir

Occupational Safety and Health Administration

Washington, DC

Annick Pichard

Institut National de l’Environment Industriel et des Risques

Paris, France

Oak Ridge National Laboratory Staff

Po-Yung Lu

Manager, AEGL Project 

Oak Ridge National Laboratory

Oak Ridge, TN

Cheryl B. Bast

Oak Ridge National Laboratory

Oak Ridge, TN

Kowetha Davidson

Oak Ridge National Laboratory

Oak Ridge, TN

Carol S. Forsyth

Oak Ridge National Laboratory

Oak Ridge, TN

Sylvia Milanez

Oak Ridge National Laboratory

Oak Ridge, TN

Robert H. Ross

Oak Ridge National Laboratory

Oak Ridge, TN

Sylvia Talmage

Oak Ridge National Laboratory

Oak Ridge, TN
ROSTER OF THE NAC/AEGL COMMITTEE 13 

Claudia M. Troxel

Oak Ridge National Laboratory

Oak Ridge, TN

Annetta Watson

Oak Ridge National Laboratory

Oak Ridge, TN

Robert A. Young

Oak Ridge National Laboratory

Oak Ridge, TN

AEGL Program Senior Staff

Roger Garrett

Director, AEGL Program

U.S. Environmental Protection Agency

Washington, DC

Paul S. Tobin

Designated Federal Officer, AEGL Program

U.S. Environmental Protection Agency

Washington, DC

Letty Tahan

Senior Scientist

U.S. Environmental Protection Agency

Washington, DC

Appendix

Standing Operating Procedures

for Developing

Acute Exposure Guideline Levels

for Hazardous Chemicals

1

NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC:

National Academy Press.

17

Preface

The National Advisory Committee for Acute Exposure Guideline Levels for

Hazardous Substances (NAC/AEGL Committee) was established to develop

scientifically credible short-term exposure limits for approximately 400 to 500

acutely toxic substances. These short-term exposure limits, referred to as acute

exposure guideline levels, or AEGLs, are essential for emergency planning,

response, and prevention of accidental releases of chemical substances.

Further, it is important that the values developed be scientifically credible so

that effective planning, response, and prevention can be accomplished.

To ensure scientific credibility, six major elements have been integrated

into the AEGL development process. These elements are (1) adherence to the

National Research Council (NRC) report Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances,1

 with changes or

additions described in this Standing Operating Procedures Manual (SOP

manual); (2) consideration of other NRC guidelines for developing short-term

exposure limits; (3) the use of scientifically acceptable processes and methodologies to ensure consistent and scientifically credible AEGL values; (4) a

comprehensive search and review of relevant data and information from both

published and unpublished sources; (5) the extensive evaluation of the data

and the development of AEGLs by a committee of scientific and technical
18 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

experts from both the public and private sectors; and (6) a multi-tiered peerreview process culminating with final review and concurrence by the NRC.

With the recent participation of certain member-countries of the Organization for Economic Cooperation and Development (OECD), it is anticipated

that the AEGL program will be expanded to include the international community. That should result in increased scientific and technical support, a broader

scope of the review process, and an even greater assurance of scientifically

credible AEGL values.

This SOP manual represents the NAC/AEGL Committee’s SOP Workgroup documentation of the procedures, methodologies, criteria, and other

guidelines used by the NAC/AEGL Committee in the development of the

AEGL values. The information contained herein is based on the guidance

provided by the NRC (1993) guidelines report. This manual contains additions and further details and clarification of specific procedures, methodologies, criteria, and guidelines interpreted from the NRC guidelines that have

been determined by the NAC/AEGL Committee to be a necessary supplement

to the NRC guidelines. Procedures and methodologies included in this manual

have been reviewed by the NAC/AEGL Committee and numerous OECD

member countries and have received a review and concurrence by the NRC.

New or modified procedures and methodologies that are developed and

adopted by the NAC/AEGL Committee are classified as “proposed.” Such

procedures and methodologies will be submitted from time to time to the NRC

for review and concurrence. Upon concurrence by the NRC, they will be considered final and will serve as a supplement to the 1993 NRC guidelines and

to this manual.

It is believed that adherence to a rigorous AEGL development process in

general and the use of scientifically sound procedures and methodologies in

particular will provide the most scientifically credible exposure limits that are

reasonably possible to achieve. This document is considered a “living document” and the various procedures and methodologies, including those classified as “final,” are subject to change as deemed necessary by the NAC/AEGL

Committee and the NRC Subcommittee on Acute Exposure Guideline Levels.

As new data become available and new scientific procedures and methodologies become accepted by a majority of the relevant scientific community, the

NAC/AEGL Committee, and the NRC, they will be integrated into the AEGL

development process and the SOP manual. With this approach, both the

scientific credibility of the AEGL values and the reduction in risk to the

general population will be ensured.
19

1. Overview of AEGL Program

and NAC/AEGL Committee

HISTORY

The concerns of the U.S. Environmental Protection Agency (EPA), other U.S.

federal agencies, state and local agencies, private industry, and other organizations in the private sector regarding short-term exposures due to chemical

accidents became sharply focused following the accidental release of methyl

isocyanate in Bhopal, India in December of 1984. In November 1985, as part

of EPA’s National Strategy for Toxic Air Pollutants, EPA developed the

Chemical Emergency Preparedness Program. This voluntary program identified a list of more than 400 acutely toxic chemicals and provided this information, together with interim technical guidance, for the development of emergency response plans at the local community level. At that time, EPA adopted

the National Institute for Occupational Safety and Health (NIOSH) immediately dangerous to life and health (IDLH) exposure values, or an approximation of those values in instances where IDLH values were not published, to

serve as the initial airborne concentrations of concern for each chemical.

During this same period, the U.S. Chemical Manufacturers Association

(CMA) (now known as American Chemistry Council) developed and implemented the Community Awareness and Emergency Response Program. This

program encouraged chemical plant managers to assist community leaders in

preparing for potential accidental releases of acutely toxic chemicals. The

program was intended to provide local communities with information on

existing chemicals and chemical processes, technical expertise to assist in
20 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

emergency planning, notification, and response, as well as in training emergency-response personnel.

In October 1986, as part of the reauthorization of Superfund, Congress

wrote into law an emergency planning program under the Superfund Amendments and Reauthorization Act (SARA Title III). Under this act, states were

required to have emergency response plans for chemical accidents developed

at the local community level. EPA subsequently adjusted the level-of-concern

values to one-tenth of the IDLH values or their equivalents as an approach to

improving the safety of the levels used for the general public. Since that time,

the agency and other organizations, including private industry, have been

interested in adopting more rigorous methodologies for determining values

that would be deemed safe for the general public. During this period, the

American Industrial Hygiene Association (AIHA) established a committee, the

Emergency Response Planning Guidelines (ERPG) Committee to develop

ERPGs and pioneered the concept of developing three different airborne

concentrations for each chemical that would reflect the thresholds for important health-effect endpoints. That committee was later renamed the Emergency Response Planning (ERP) Committee. Although constrained by limited

resources, the ERP Committee has developed 1-h exposure limits for more

than 70 chemicals during the past 10 years.

At a workshop hosted by EPA in 1987, it was proposed by EPA that the

ERP Committee and scientists from federal and state agencies as well as

scientists and clinicians from academia and public interest groups pool their

technical and financial resources and form a single committee comprising

scientists from both the public sector and the private sector to develop AEGL

values. EPA conceived the idea to formulate general guidance for developing

short-term exposure limits and together with the Agency for Toxic Substances

and Diseases Registry (ATSDR) subsequently requested that the National

Research Council (NRC) develop guidance on the use of procedures and

methodologies to establish emergency exposure guideline levels for the

general public. The NRC convened the Subcommittee on Acute Exposure

Guideline Levels within the Committee on Toxicology (COT) to address the

project.

Since the 1940s, COT has developed emergency exposure levels for

numerous chemicals of concern to the U.S. Department of Defense (DOD).

These values are referred to as “emergency exposure guidance levels”

(EEGLs). Although the EEGLs were developed for use for military personnel,

the NRC also developed emergency exposure levels for the general public,

termed “short-term public emergency guidance levels” (SPEGLs). On the

basis of this extensive experience and the high level of scientific and technical
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 21 

expertise continually available to the NRC, this organization was considered

the most qualified entity to develop guidance on the methodologies and

procedures used to establish short-term exposure limits for acutely toxic

chemicals.

The NRC guidance document Guidelines for Developing Community

Emergency Exposure Levels for Hazardous Substances was published in 1993.

The community emergency exposure levels (CEELs) and the acute exposure

guideline levels (AEGLs) represent the identical short-term emergency exposure levels. The NRC CEELs has been replaced by AEGLs to convey the

broad applications of these values for planning, response, and prevention in the

community, the workplace, transportation, the military, and the remediation

of Superfund sites. A discussion of how AEGLs might be used for emergency

planning, response, and prevention appears later in this chapter.

The efforts to mobilize the federal and state agencies and organizations in

the private sector to form the committee began shortly after the release of the

NRC (1993a) report. In October 1995, the National Advisory Committee on

Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL

Committee) was formally chartered and the charter filed with the U.S. Congress under the Federal Advisory Committee Act (FACA) with approval by

the Office of Management and Budget (OMB) and concurrence by the General

Services Administration (GSA). Due to EPA budgetary constraints, the first

meeting of the NAC/AEGL Committee was not held until June 1996. This

meeting represented the culmination of the efforts to solicit stakeholders,

identify committee members, form the committee, obtain the technical support

of the Oak Ridge National Laboratories (ORNL), and begin the development

of the AEGL values.

PURPOSE AND OBJECTIVES OF THE

AEGL PROGRAM AND THE NAC/AEGL COMMITTEE

The primary purpose of the AEGL program and the NAC/AEGL Committee is to develop guideline levels for once-in-a-lifetime, short-term exposures

to airborne concentrations of acutely toxic, high-priority chemicals. AEGLs

are needed for a wide range of applications—planning, response, and prevention. These applications may include EPA’s SARA Title III Section 302-304

emergency planning program, the U.S. Clean Air Act Amendments (CAAA)

Section 112(r) accident prevention program, and the remediation of Superfund

sites program; the Department of Energy’s (DOE’s) environmental restoration,

waste management, waste transport, and fixed facility programs; the Depart-
22 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

ment of Transportation’s (DOT’s) emergency waste response program; the

Department of Defense’s (DOD’s) environmental restoration, waste management, and fixed facility programs; ATSDR’s health consultation and risk

assessment programs; NIOSH’s and the Occupational Safety and Health

Administration’s (OSHA’s) regulations and guidelines for workplace exposure; state CAA Section 112(b) programs and other state programs; and

private-sector programs, such as the AIHA-ERPG and the American Chemistry Council’s Chemtrec programs.

A principal objective of the NAC/AEGL Committee is to develop scientifically credible, acute (short-term) once-in-a-lifetime exposure guideline levels

within the constraints of data availability, resources, and time. That objective

requires highly effective and efficient efforts in data gathering, data evaluation,

and data summarization; fostering the participation of a large cross-section of

the relevant scientific community; and the adoption of procedures and methodologies that facilitate consensus-building for AEGL values within the committee.

Another principal objective of the committee is to develop AEGL values

for approximately 400 to 500 acutely hazardous substances within the next 10

years. Therefore, the near-term objective is to increase the level of production

of AEGL development to approximately 40 to 50 chemicals per year without

exceeding budgetary limitations or compromising the scientific credibility of

the values developed.

Further, in addition to determining AEGL values for three health-effect

endpoints, it is intended to derive exposure values for the general public that

are applicable to emergency (accidental), once-in-a-lifetime exposure periods

ranging from 10 min to 8 h. Therefore, exposure limits will be developed for

a minimum of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h). Each

AEGL tier is distinguished by varying degrees of severity of toxic effects, as

initially conceived by the ERP Committee and further defined in Guidelines

for Developing Community Emergency Exposure Levels for Hazardous

Substances (NRC 1993a) and further defined by the NAC/AEGL Committee.

The AEGL-1, AEGL-2, and AEGL-3 definitions are presented in the Introduction and in Section 2.1 of this standing operating procedures (SOP) manual.

As stated in the NRC guidelines (NRC 1993a) and described in the AEGL

definitions, these exposure limits are intended to protect most individuals in

the general population, including those that might be particularly susceptible

to the deleterious effects of the chemicals. However, as stated in the guidelines and the definitions, it is recognized that certain individuals, subject to

unique and idiosyncratic responses, could experience effects at concentrations

below the corresponding AEGLs.
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 23 

An important objective of the NAC/AEGL Committee is the establishment

and maintenance of a comprehensive SOP manual that adheres to the NRC

guidelines (NRC 1993a) and supplements, clarifies, interprets, or defines those

guidelines with regard to the specific use of certain procedures and methodologies, such as selection of no-observed-adverse-effect levels (NOAELs) or the

lowest-observed-adverse-effect levels (LOAELs), and the use of uncertainty

factors, modifying factors, interspecies and intraspecies extrapolation methods,

time scaling, carcinogenic risk assessment, and other methods and procedures

relevant to the development of AEGL values.

COMMITTEE MEMBERSHIP AND 

ORGANIZATIONAL STRUCTURE

The NAC/AEGL Committee comprises representatives of federal, state

and local agencies and organizations in the private sector that derive programmatic or operational benefits from the AEGL values. The membership includes

federal representatives from EPA, ATSDR, DOE, NIOSH, OSHA, DOT,

DOD, the Centers for Disease Control and Prevention (CDC), the Food and

Drug Administration (FDA), and the Federal Emergency Management Agency

(FEMA). States providing committee representatives include New York, New

Jersey, Texas, California, Minnesota, Illinois, Connecticut, and Vermont.

Private companies with representatives include Honeywell, Inc., ExxonMobil,

and Arch Chemicals, Inc. The American Industrial Hygiene Association

(AIHA), the American College of Occupational and Environmental Medicine

(ACOEM), the American Association of Poison Control Centers (AAPCC),

and the American Federation of Labor and Congress of Industrial Organizations (AFL-CIO) are represented, as are other private-sector organizations. The

committee also includes individuals from academia and a representative of

environmental justice. A current list of the NAC/AEGL Committee members

and their affiliations is shown on page 7. At present, the committee has 30

members.

Recently, the Organization of Economic Cooperation and Development

(OECD) and various OECD member countries have expressed an interest in

the AEGL program. Several OECD member countries, such as Germany and

The Netherlands, have been participating in the committee’s activities and

actively pursuing formal membership on the NAC/AEGL Committee. It is

envisioned that the committee and the AEGL program in general will progressively expand its scope and participation to include the international community.
24 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

The program director of the AEGL program has the overall responsibility

for the entire AEGL program and the NAC/AEGL Committee and its activities. A designated federal officer (DFO) is responsible for all administrative

matters related to the committee to ensure that it functions properly and

efficiently. These individuals are not voting members of the committee. The

NAC/AEGL committee chair is appointed by EPA and is selected from the

committee members. In concert with the program director and the DFO, the

chair coordinates the activities of the committee and also directs all formal

meetings of the committee. From time to time, the members of the committee

serve as chemical managers and chemical reviewers in a collaborative effort

with assigned scientist-authors (noncommittee members) to develop AEGLs

for a specific chemical. These groups of individuals are referred to as the

AEGL development teams and their function is discussed in Section 4.8 of this

manual.

SELECTION OF CHEMICALS FOR AEGL DEVELOPMENT

A master list of approximately 1,000 acutely toxic chemicals was initially

compiled through the integration of individual priority lists of chemicals

submitted by each U.S. federal agency. The master list was subsequently

reviewed by individuals from certain state agencies and representatives from

organizations in the private sector and modified as a result of comments and

suggestions received. The various priority chemical lists were compiled

separately by each federal agency on the basis of their individual assessments

of the hazards, potential exposure, risk, and relevance of a chemical to their

program needs. A list of approximately 400 chemicals representing the

higher-priority chemicals was tentatively identified from the original master

list. It was acknowledged that this list was subject to change based on the

changing needs of the stakeholders.

On May 21, 1997, a list of 85 chemicals was published in the Federal

Register. This list identified those chemicals from the list of approximately

400 chemicals considered to be of highest priority across all U.S. federal

agencies and represented the selection of chemicals for AEGL development

by the NAC/AEGL Committee for the first 2-3 years of the program. The

committee has addressed these chemicals, and they are in the “draft,” “proposed,” “interim,” or “final” stages of development. Certain chemicals did not

have an adequate database for AEGL development and, consequently, are on

hold pending decisions regarding further toxicity testing. The initial highestpriority list of 85 chemicals is shown in Appendix A. 

A second “working list” of priority chemicals is being selected from (1)
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 25 

the original master list, (2) the intermediate list of approximately 400 chemicals (which is a subset of the master list), and (3) the list of new, high-priority

candidate chemicals submitted by U.S. agencies and organizations and OECD

member countries that are planning to participate in the AEGL program.

Although working lists will be published in the Federal Register and elsewhere from time to time to indicate the NAC/AEGL Committee’s agenda, the

priority of chemicals addressed, and, hence, the “working list,” is subject to

modification if priorities of the NAC/AEGL Committee or individual stakeholder organizations, including international members, change during that

period.

SCIENTIFIC CREDIBILITY OF AEGL VALUES

The scientific credibility of the AEGL values is based on adherence to the

NRC guidelines (NRC 1993a) for the development of short-term exposure

limits, the comprehensive nature of data collection and evaluation, the consistency of the methodologies and procedures used to develop the values, the

potential of acute toxicity testing in cases of inadequate data, and the adoption

of the most comprehensive peer-review process ever used to establish shortterm exposure limits for acutely toxic chemicals.

The comprehensive data-gathering process involves literature searches for

all relevant published data and the mobilization of all relevant unpublished

data. Data and information from unpublished sources is obtained through

individual companies in the private sector and the cooperation of trade associations. The completeness of the data searches is enhanced through the oversight and supplemental searches conducted by individual committee members

and interested parties during the peer-review process.

Data evaluation and data selection are performed by scientists with expertise in toxicology and related disciplines from staff at the organization that

drafts “technical support documents” and from assigned members of the

NAC/AEGL Committee. Additionally, input on data evaluation and selection

is provided by interested parties who participate in the open meetings of the

committee or who formally comment on the Federal Register notices of

proposed AEGL values.

The work of the NAC/AEGL Committee adheres to Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances

(NRC 1993a). Since this guidance document represents a more general

guidance for methodologies and procedures, the NAC/AEGL Committee

interprets and develops greater detail related to the methodologies and procedures that it follows. These standing operating procedures (SOPs) are docu-
26 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

mented by the SOP Workgroup and represent a consensus or a two-thirds

majority vote of the NAC/AEGL Committee. SOPs also represent concurrence

of the NRC Subcommittee on Acute Exposure Guideline Levels (NRC/AEGL

Subcommittee). Therefore, each step of the AEGL development process

follows specific methodologies, criteria, or other guidelines to ensure consistent, scientifically sound values.

In those instances where adequate data are not available in the judgment

of the NAC/AEGL Committee, AEGLs will not be developed. The AEGL

program is committed to ensuring that AEGL values are derived from adequate

data and information based on a consensus or a two-thirds majority vote of the

NAC/AEGL Committee and concurrence of the NRC/AEGL Subcommittee.

To further assure the scientific credibility of the AEGL values and their

supporting rationale, the most comprehensive peer-review process ever used

in the development of short-term exposure limits has been established (see

next section). This review process has been designed to effectively, yet efficiently, encourage and enable the participation of the scientific community and

other interested parties from the public and private sectors in the development

of AEGLs. Further, the review process utilizes the NRC/AEGL Subcommittee

as the final scientific reviewer. Hence, the final judgment of scientifically

credible values rests with the United States’ National Academy of Sciences’

National Research Council. A detailed summary of the AEGL development

process is presented in the next section.

THE AEGL DEVELOPMENT AND PEER-REVIEW PROCESS

The process that has been established for the development of the AEGL

values is the most comprehensive ever used for the determination of short-term

exposure limits for acutely toxic chemicals. A summary of the overall process

is presented in diagram form in Appendix B. The process consists of four

basic stages in the development and status of the AEGLs, and they are identified according to the review level and concurrent status of the AEGL values.

They include (1) draft AEGLs, (2) proposed AEGLs, (3) interim AEGLs, and

(4) final AEGLs. The entire development process can be described by individually describing the four basic stages in the development of AEGL values.

Stage 1: Draft AEGLs

This first stage begins with a comprehensive search of the published

scientific literature. Attempts are made to mobilize all relevant unpublished
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 27 

data through industry-trade associations and from individual companies in the

private sector. A more detailed description of the published and unpublished

sources of data and information utilized is provided in Section 2.3 of this

document, which addresses search strategies. The data are evaluated by

following the published NRC guidelines (NRC, 1993a) and this SOP manual,

and selected data are used as the basis for the derivation of the AEGL values

and the supporting scientific rationale. Data evaluation, data selection, and

development of a technical support document (TSD) are all performed as a

collaborative effort among the staff scientists at the organization drafting the

TSDs, the chemical manager, and two chemical reviewers. This group is

called the AEGL Development Team. Specific NAC/AEGL Committee members are assigned to a team for each chemical under review. Hence, a separate

team comprising different committee members is formed for each chemical

under review. The product of this effort is a TSD that contains draft AEGLs.

The draft TSD is subsequently circulated to all other NAC/AEGL Committee

members for review and comment prior to a formal meeting of the committee.

Revisions to the initial TSD and the draft AEGLs are made up to the time of

the NAC/AEGL Committee meeting scheduled for formal presentation and

discussion of the AEGL values and the documents. At the committee meeting,

the committee deliberates and, if a quorum is present, attempts to reach a

consensus or a two-thirds majority vote to elevate the draft AEGLs to "proposed" status. A quorum of the NAC/AEGL Committee is defined as 51% or

more of the total NAC/AEGL Committee membership. If agreement cannot be

reached, the committee conveys its issues and concerns to the AEGL Development Team and further work is conducted by this group. After completion of

additional work, the chemical is resubmitted for consideration at a future

meeting. If a consensus or a two-thirds majority vote of the committee cannot

be achieved because of inadequate data, no AEGL values will be developed

until adequate data become available.

Stage 2: Proposed AEGLs

Once the NAC/AEGL Committee has reached a consensus or a two-thirds

majority vote on the AEGL values and supporting rationale, they are referred

to as “proposed” AEGLs and are published in the Federal Register for a 30-

day review and comment period. Following publication, the committee reviews the public comments, addresses and resolves relevant issues, and seeks

a consensus or a two-thirds majority vote of those present on the original or

modified AEGL values and the accompanying scientific rationale.
28 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Stage 3: Interim AEGLs

Following resolution of relevant issues raised through public review and

comment and subsequent approval of the committee, the AEGL values are

classified as "interim." The interim AEGL status represents the best efforts of

the NAC/AEGL Committee to establish exposure limits, and the values are

available for use as deemed appropriate on an interim basis by federal and state

regulatory agencies and the private sector. The interim AEGLs, the supporting

scientific rationale, and the TSD, are subsequently presented to the

NRC/AEGL Subcommittee for its review and concurrence. If concurrence

cannot be achieved, the NRC/AEGL Subcommittee will submit its issues and

concerns to the NAC/AEGL Committee for further work and resolution. 

Stage 4: Final AEGLs

When concurrence by the NRC/AEGL Subcommittee is achieved, the

AEGL values are considered "final" and published by the NRC. Final AEGL

values may be used on a permanent basis by all federal, state and local agencies, and private organizations. It is possible that new data will become

available from time to time that challenges the scientific credibility of final

AEGLs. If that occurs, the chemical will be resubmitted to the NAC/AEGL

Committee and recycled through the review process.

OPERATION OF THE NAC/AEGL COMMITTEE

The NAC/AEGL Committee meets formally four times each year for 21⁄2

days each. The meetings are scheduled for each quarter of the calendar year

and are generally held in the months of March, June, September, and December. Because of overall cost considerations, the meetings are generally held

in Washington, D.C. However, committee meetings may be held from time

to time at other locations for justifiable reasons.

At least 15 days before the committee meetings, a notice of the meeting is

published in the Federal Register together with a list of the chemicals and

other matters to be addressed by the committee. The notice provides dates,

times, and location of the meetings. The agenda is finalized and distributed to

committee members approximately 1 week before the meeting. The agenda

is also available to other interested parties at that time, upon request, through

the DFO.
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 29 

All NAC/AEGL Committee meetings are open to the public, and interested parties may schedule individual presentations of relevant data and

information by contacting the DFO to establish a date and time. Relevant data

and information from interested parties also may be provided to the committee

through the DFO during the period of development of the draft AEGLs so that

the data can be considered during the early stages of development. Data and

information also may be submitted when the document is in the proposed and

interim stages.

The NAC/AEGL Committee meetings are conducted by the chair, who is

appointed by EPA in accordance with the Federal Advisory Committee Act

(FACA). At the time of the meeting, the chair and the other committee members will have received the initial draft and one or more revisions of the TSD

and the draft, proposed, or interim AEGL values for each chemical on the

agenda. Reviews, comments, and revisions are continuous up to the time of

the meeting, and committee members are expected to be familiar with the

draft, proposed, or interim AEGLs, the supporting rationale, and other data and

information in each TSD, and to participate in the resolution of residual issues

at the meeting. Procedures for the AEGL Development Teams and the other

committee members regarding work on proposed or interim AEGLs are similar

to those for draft AEGLs.

All decisions of the NAC/AEGL Committee related to the development of

draft, proposed, interim, and final AEGLs and their supporting rationale are

made by consensus or a two-thirds majority of a quorum of the committee

members present.

The highlights of each meeting are recorded by the scientists who draft the

TSDs, and written minutes are prepared, ratified, and maintained in the committee’s permanent records. Deliberations of each meeting are also tape-recorded

when possible and stored in the committee’s permanent records by the DFO

for future reference as necessary.

All proposed AEGL values and supporting scientific rationale are published in the U.S. Federal Register. Review and comment by interested parties

and the general public are requested and encouraged. The committee’s response to official comments on Federal Register notices on proposed AEGL

values consists of an evaluation of the comments received, discussions and

deliberations that take place at committee meetings regarding the elevation of

AEGLs from proposed to interim status, and changes to the TSDs as deemed

appropriate by the NAC/AEGL Committee. This information is reflected on

the tapes and in the minutes of the meetings and will be maintained for future

reference. As previously mentioned, the SOP Workgroup, established in

March 1997, documents, summarizes, and evaluates the various procedures,
30 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

methodologies, and guidelines used by the committee in the gathering and

evaluation of scientific data and information and the development of the

AEGL values. The SOP Workgroup performs a critical function by providing

the committee with detailed information on the committee’s interpretation of

the NRC guidelines and the approaches the committee has taken in the derivation of each AEGL value for each chemical addressed. This documentation

enables the NAC/AEGL Committee to continually document and assess the

basis for its decision-making, ensure consistency with the NRC guidelines, and

maintain the scientific credibility of the AEGL values and the accompanying

scientific rationale. This ongoing effort is continually documented and is

identified for further revisions in the SOP manual.

VALUE OF A COLLABORATIVE EFFORT IN THE

AEGL PROGRAM

The value of a collaborative effort in the AEGL program is related primarily to the pooling of substantial resources of the various stakeholders and the

direct or indirect involvement of a significant portion of the relevant scientific

community from both the public and private sectors. These factors, in turn,

promote greater productivity, efficiency, and cost effectiveness of such an

effort and greatly enhance the scientific credibility of the AEGLs that are

developed by the committee.

The formation of the NAC/AEGL Committee, which consists of approximately 30 to 35 members has provided an important forum for scientists,

clinicians, and others to develop AEGLs and resolve related scientific issues.

The composition of the committee represents a balanced cross-section of the

relevant scientific disciplines and a balance of U.S. federal and state agencies,

academia, the medical community, private industry, public interest groups,

and other organizations in the private sector. This mutual participation of

stakeholders, including the regulators and the regulated community, in the

development of the AEGLs promotes the acceptance of the AEGLs by all

parties involved. Additionally, the diverse composition of the committee

represents the nucleus of a broad network of scientists, clinicians, and other

technical personnel that fosters information and data exchange and the resolution of relevant scientific and technical issues well beyond the committee

membership. This network also facilitates the identification of national and

international experts with particular expertise that may provide important data,

information, or insight on a specific chemical or scientific issue.

The collaborative effort also results in greater scientific credibility of the

exposure values developed. The pooling of resources enables a comprehen-
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 31 

sive gathering and evaluation effort of both published and unpublished data

and information. Collaboration provides a broad base of relevant scientific

knowledge and expertise that is highly focused on the chemicals and issues

addressed by the committee. This approach provides sufficient scientific and

technical resources for the SOP Workgroup to document and evaluate procedures and methodologies that instill rigor and consistency into the process and

the resultant AEGL values. The documentation of these procedures and

methodologies is contained in this SOP manual. Finally, the collaborative

effort has enabled the establishment of the most comprehensive peer-review

process ever implemented for the development of short-term exposure limits.

The AEGL program has extended invitations to all OECD member countries to participate on the NAC/AEGL Committee and in program activities in

general. To date, Germany and The Netherlands have commitments for participation. It is believed that expanding the scope of the AEGL program to include

the international community will be of great benefit. Its participation will

provide even greater resources, further broaden the base of scientific and

technical expertise, provide new toxicologic data and insights, and foster the

harmonization of emergency exposure limits at the international level.

In summary, the establishment of a collaborative effort, with its pooling

of resources, represents the most productive, efficient, and cost-effective

approach to the development of exposure guideline levels. Further, the effort

results in the development of uniform values for a wide range of applications.

This approach eliminates inconsistencies and confusion among individuals and

organizations involved in emergency planning, response, and prevention of

chemical accidents. In global terms, the NAC/AEGL Committee represents

an approach to unifying the international community in the development and

use of chemical emergency exposure limits. In the interests of multinational

companies seeking uniform operating parameters and federal agencies having

mandates to achieve international harmonization of standards and guidelines,

the participation of the international community in the AEGL program represents an important goal of the AEGL program.

APPLICATIONS OF THE AEGL VALUES

It is anticipated that the AEGL values will be used for regulatory and

nonregulatory purposes by U.S. federal and state agencies and possibly the

international community in conjunction with chemical emergency response,

planning, and prevention programs. More specifically, the AEGL values will

be used for conducting various risk assessments to aid in the development of

emergency preparedness and prevention plans, as well as real-time emergency
32 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

response actions, for accidental chemical releases at fixed facilities and from

transport carriers. The AEGL values, which represent defined toxic endpoints,

are used in conjunction with various chemical-release and dispersion models

to determine geographical areas, or “vulnerable zones,” associated with accidental or terrorist releases of chemical substances. By determining these

geographical areas and the presence of human populations and facilities within

those zones, the potential risks associated with accidental chemical releases

can be estimated. For example, the release and dispersion models, which take

into account the quantity and rate of release of the chemical, the volatility of

the substance, the wind speed and wind stability at the time of the release, and

the topographical characteristics in the area of the release, will define the

geographical areas exposed and, quantitatively, the airborne concentration of

the "plume" or the chemical cloud as it is dispersed. By comparing the projected airborne concentrations of the chemical substance in question with the

exposed populations, human health risks associated with a chemical release

can be estimated. Using these risk estimates, emergency-response personnel

can make effective risk-management and risk-communication decisions to

minimize the adverse impact of the release on human health. Figure 1-1 is a

summary diagram that indicates the overall effects that are expected to occur

above each of the three AEGL threshold tiers as well as the sensory and

nonsensory or asymptomatic effects that are expected to occur below the

AEGL-1 threshold. Figure 1-1 also indicates the expected increase in occurrence and severity of the various adverse health effects as the airborne concentration increases beyond each of the three AEGLs.

Because of the complex nature of chemical accidents, the populations at

risk, the variable capabilities among emergency response units, and many

other considerations related to a specific event, it is beyond the scope of this

document to discuss or speculate on specific actions that should or could be

taken at any point in time or at a given level of exposure to a specific chemical. However, emergency responders and planners know that various options

are available, depending upon the circumstances, for reducing or even preventing the adverse impacts of chemical releases. In general, they include public

notification and instruction, sheltering-in-place, evacuation procedures to

enable or facilitate medical attention, or a combination of these options. Decisions on these options are important and are best left to local emergency

planners and responders to be addressed on a case-by-case basis. Further,

information regarding the applications of short-term exposure limits such as

AEGLs may be obtained in Technical Guidance for Hazards Analysis (EPA

1987).
OVERVIEW OF AEGL PROGRAM AND NAC/AEGL COMMITTEE 33 

Increasing

likelihood of death

AEGL-3

DEATH

DISABLING

DISCOMFORT

DETECTABILITY

Effects

-Impairment of ability to escape

-Increasing severity of

irreversible or other serious

long-lasting effects

-Increase in notable discomfort

-increasing severity of

reversible effects (with or

without signs/symptoms)

Increasing complaints of

objectionable odor, taste,

sensory irritation or other

mild, non-sensory or

asymptomatic effects

Threshold

Levels

AEGL-1

AEGL-2

FIGURE 1-1 Hazard assessment.
34

2. Derivation of AEGL Values

2.1 CHARACTERIZATION OF AEGLs

Three tiers of AEGL severity levels represent short-term exposure values that

are a threshold for specific biologic effects for the general public and are

applicable to specified exposure durations of 10 min, 30 min, 1 h, 4 h, and 8

h. The values for these specified durations are maximum airborne concentrations above which there is an increasing likelihood of the adverse effects

associated with the respective AEGL tiers. Therefore, to avoid the onset of

these adverse effects, the values should not be exceeded during the specified

exposure durations. Three tiers of AEGLs distinguished by varying degrees

of severity of toxic effects are developed for each of the five exposure durations. Ten-minute AEGLs for the four chemicals included in the first publication of AEGLs by the National Research Council (NRC 2000b) will be developed at a future date.

Under the authority of the Federal Advisory Committee Act (FACA) P.L.

92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been

established to identify, review, and interpret relevant toxicologic and other

scientific data and develop AEGLs for high-priority acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are

applicable to emergency exposure periods ranging from 10 min to 8 h. AEGL2 and AEGL-3, and AEGL-1 values as appropriate, will be developed for each

of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the
DERIVATION OF AEGL VALUES 35 

recommended exposure levels are applicable to the general population including infants and children, and other individuals who may be susceptible. The

three AEGLs have been defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or

milligrams per cubic meter (ppm or mg/m3

)) 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

susceptible individuals, could experience irreversible or other serious, longlasting 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

susceptible individuals, could experience life-threatening health effects or

death.

Airborne concentrations below the 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 effects.

With increasing airborne concentrations above each AEGL, there is a progressive 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 infants, children, the elderly, persons with asthma, and those with other

illnesses, it is recognized that individuals, subject to unique or idiosyncratic

responses, could experience the effects described at concentrations below the

corresponding AEGL.

2.2 EMPIRICAL TOXICOLOGIC ENDPOINTS AND METHODS

FOR DETERMINING EXPOSURE CONCENTRATIONS USED TO

DERIVE AEGLs 1, 2, AND 3

The selection of the biologic endpoints that serve as the thresholds for

each of the AEGL severity levels are based on the definitions for the community emergency exposure levels (CEELs) that were published in the NRC

guidelines for developing short-term exposure limits (NRC 1993a). The

AEGLs address the same defined population as the NRC CEELs. The NRC
36 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

definitions of the three CEEL tiers have been modified slightly by the

NAC/AEGL Committee to improve only the clarity of description of the

threshold levels. Hence, the defined threshold levels for CEELs and AEGLs

are the same.

The NRC guidelines describe CEELs as exposure limits applicable to

emergency exposures to hazardous substances (NRC 1993a). The NRC

guidance states the CEELs must be set low enough to protect most of the

population that may be exposed, including those with increased susceptibilities, such as children, pregnant women, persons with asthma, and persons with

other specific illnesses (NRC 1993a). The NRC definition of CEELs for each

of the three tiers of adverse health effects states that the adverse effects for

each CEEL tier are not likely to occur below that level for a specified exposure

duration but are increasingly likely to occur at concentrations above that level

in a general population, including susceptible individuals. For this reason, the

NRC also refers to the CEELs as threshold levels (NRC 1993a).

Because the data and methodologies used to derive AEGLs or any other

short-term exposure limits are not sufficiently precise to make a distinction

between a ceiling value and a threshold value, no distinction has been made

with respect to AEGL values. No fine line can be drawn to precisely differentiate between a ceiling level, which represents the highest exposure concentration for which an effect is unlikely to occur, and a threshold level, which

represents the lowest exposure concentration for the likelihood of onset of a

given set of effects. Hence, AEGLs are not true effect levels. Rather, they are

considered threshold levels that represent an estimated point of transition and

reflect the best efforts to establish quantitatively a demarcation between one

defined set of symptoms or adverse effects and another defined set of symptoms or adverse effects. Therefore, in the development of AEGLs, the

NAC/AEGL Committee selects the highest exposure level from animal or

human data where the effects used to define a given AEGL tier are not observed.

2.2.1 Selection of the Highest Exposure Level at Which the Effects

That Define an AEGL Are Not Observed 

Traditionally, when setting acceptable (typically considered “safe”) levels

of exposure, the risk assessor will select the highest experimental exposure that

does not cause an adverse effect (no-observed-adverse-effect level (NOAEL))

in an experiment that demonstrated a graded exposure response from no effect

to adverse effects. In standard risk-assessment practice (NRC 1993a), the
DERIVATION OF AEGL VALUES 37 

exposure level identified as the NOAEL would then be divided by appropriate

uncertainty factors and modifying factors to derive an acceptable exposure

level for humans. However, there are a number of limitations in this method.

It does not consider the number of animals used in the experiment and the

associated statistical uncertainty around the experimental exposure level

chosen. It does not consider the slope of the exposure-response relationship

and subjects the risk assessor to using the possibly arbitrarily selected exposure levels chosen in the face of an unknown exposure-response relationship.

Under some conditions, especially when only a small number of animals are

exposed per exposure, the NOAEL could be a level associated with significant

adverse health effects (Leisenring and Ryan 1992). In recent years, Crump

and Howe (1984), Barnes et al. (1995), the U.S. Environmental Protection

Agency (EPA 1995a), Faustman et al. (1994), Gaylor et al. (1998, 1999), and

Fowles et al. (1999) addressed these problems by using the concept of analyzing all the data to estimate statistically a benchmark concentration (BMC). The

BMC is a statistical estimate of an exposure that will cause a specified incidence of a defined adverse health effect. The BMC is commonly defined as

the 95% lower confidence limit (LCL) on the exposure level causing a specified level of response (typically 1% to 10%). This exposure level is intended

to replace the NOAEL and is used like the NOAEL when setting acceptable

exposure levels.

The BMC method has a number of advantages over the traditional

NOAEL approach. The BMC is derived from a statistical analysis of the

exposure-response relationship and is not subject to investigator selection of

exposure levels. It is a reflection of the exposure-response curve. Although

the number of animals used in a study will affect the NOAEL and BMC

estimates, the BMC, when compared with the maximum likelihood estimate

(MLE), will explicitly reflect the variability in the study and the uncertainty

around the number of subjects. The greater the variability and uncertainty, the

greater the difference between the BMC and the MLE. The BMC calculation

allows for the statistical estimation of a BMC in the absence of an empirical

NOAEL.

The data most relevant to the development of AEGL-3 values and most

amenable to a BMC analysis are inhalation LC50 (lethal concentration for 50%

of the animals) data. Fowles et al. (1999) analyzed 120 inhalation animal

lethality data sets by using the BMC method. The analysis provides the basis

for the application of the BMC approach used by the NAC/AEGL Committee

in the development of AEGL values. BMCs (95% LCL) and MLEs were

developed for the 1%, 5%, and 10% response levels using log probit and

Weibull models. Species tested included rats, mice, guinea pigs, hamsters,
38 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

rabbits, and dogs. Exposure times ranged from 5 min to 8 h. Each data set

consisted of at least four data points. The BMC and MLE values were compared with the empirical NOAEL (highest exposure that did not cause death

in the experiment) and LOAEL (lowest exposure that killed at least one

animal). The curve generated by the statistical models was subjected to a chisquared goodness of fit test (p > 0.05). For statistical and data presentation

reasons, 100 studies were analyzed with the probit analysis and 93 with the

Weibull model. Most of the studies reported NOAELs (81/100 considered for

the probit analysis and 74/93 considered for the Weibull analysis).

The BMCs were generally lower than the NOAELs when analyzed with

either statistical estimate. The mean NOAEL/BMC ratios for the 1%, 5%, and

10% response were 1.60, 1.16, and 0.99, respectively, when using a probit

analysis, and 3.59, 1.59, and 1.17, respectively, when using the Weibull

analysis. It is interesting to note that comparable means from a Weibull

analysis of developmental toxicity data were considerably greater, the developmental toxicity means of the NOAEL/BMC ratios were 29, 5.9, and 2.9 (Allen

et al. 1994).

The proportion of times that the NOAEL exceeded the BMC for the 1%,

5%, and 10% response was 89%, 65%, and 42%, respectively, for the probit

analysis and 95%, 80%, and 54%, respectively, for the Weibull analysis. In

all cases, the LOAEL/BMC ratio exceeded 1 for the probit and Weibull

analysis of the 1% and 5% response but not always for the 10% response

(99%). For this reason, the BMC10 may be too high a response rate to use to

predict a NOAEL. In contrast, the corresponding 1% and 5% response ratios

were always greater than 1.

The ratios of the MLE/BMC were not great, ranging from a mean of 1.39

for a probit analysis of the 10% response to 3.02 for a Weibull analysis of the

10% response. It is important to note that when using the probit analysis, the

LOAEL/MLE ratios were equal to or greater than 1 in 99%, 94%, and 71% of

the cases for the 1%, 5%, and 10% responses, respectively. The MLE would

probably be protective at the 1% response level but not for the 5% and 10%

response levels. Similar numbers of 99%, 97%, and 76% were observed for

the Weibull analysis.

The BMC approach can provide a more refined assessment of the prediction of the empirical NOAEL. It must be emphasized that even the empirical

NOAEL may represent a response level that is not detected. When 5 to10

animals are used in an experiment, a 10-20% response can be missed

(Leisenring and Ryan 1992) and even a BMC10 is similar to a LOAEL with

dichotomized data (Gaylor 1996). It is expected that the BMC is less than the

empirical LOAEL. In the Fowles et al. (1999) analysis of the data, the BMC05
DERIVATION OF AEGL VALUES 39 

and BMC01 values were always below the empirical LOAEL for the studies

analyzed. The probit analysis of the data by Fowles et al. (1999) provided a

better fit with the data as measured by the “chi-squared goodness-of-fit test,

mean width of confidence intervals, and number of data sets amenable to

analysis by the model.”

It is interesting to note that the BMC05 is very close to the MLE01 in the

Fowles et al. (1999) evaluation of inhalation acute toxicity data. Through

1999, the NAC/AEGL Committee has used the MLE01 to estimate the highest

exposure at which lethality is not likely to be observed in a typical acute

exposure study. Given the analysis by Fowles et al. (1999) and for the above

reasons, the NAC/AEGL Committee will generally use the BMC05 (lower 95%

confidence limit (LCL) of the exposure required to produce a 5% response to

exposure to chemicals) in the future for this estimate, although the MLE01 will

also be calculated and considered. This approach incorporates the uncertainties due to the number of animals used in an experiment and the experimental

variability observed; it utilizes all the data and the slope of the exposureresponse curve and provides for a reasonable estimate of a predicted experimental NOAEL. In all cases, the MLE and BMC at specific response levels

will be considered when setting AEGL values. Statistical models in addition

to the log-probit will also be considered. Since goodness-of-fit tests consider

an average fit, they may not be valid predictors of the fit in the low-exposure

region of interest. In this case, the output of the different models will be

plotted and compared visually with the experimental data in selection of the

most appropriate model.

It should be emphasized that these methods will generally be considered

for an acute lethal endpoint. Their use to set AEGL-1 and AEGL-2 values will

be considered on a chemical-by-chemical basis. Different endpoints may

require the use of different data sets in different or the same species, a different

benchmark dose approach, or identification of a different response level.

These factors will be considered for specific chemicals and toxicologic endpoints.

The preferred approach will be to use the BMC approach to identify the

highest exposure at which the toxicologic effects used to define an AEGL tier

were not observed. If the data are insufficient for a meaningful statistical

analysis to use that approach, then the level will be determined empirically

from experimental data.

2.2.2 Selection of Health-Effect Endpoints for AEGL-1,

AEGL-2, and AEGL-3

In addition to the working definitions of the three AEGL tiers, this section
40 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

includes a summary of the specific biologic endpoints used to establish the

AEGL values for individual chemicals. Also included are general principles

for selection of AEGL health-effect endpoints that have been derived from the

committee’s selections on a chemical-by-chemical basis. Since ideal data sets

for certain chemicals are not available, extrapolation methods and the committee’s scientific judgment are often used to establish threshold values. In the

absence of adequate data, the committee can decide that no AEGL value be

established. The basis for this decision is the failure to achieve a minimum

two-thirds majority of a quorum of the committee that is in favor of establishing a value or a formal decision by two-thirds of the committee not to establish

a value.

Under ideal circumstances, the specific health effects would be identified

that determine each of the AEGLs. A search of the published literature for

data on the chemical would be performed, and AEGLs would be generated

from those data. However, data relating exposure and effect do not always

follow an ideal paradigm and may lead to apparent inconsistences in the use

of endpoints to set AEGLs. The general principles laid down in the NRC

(1993a) guidance for evaluating data and selecting appropriate health effects,

combined with professional judgment, are used to establish AEGLs. From the

evaluations of the first four chemicals in the subcommittee’s first full report

(NRC 2000b) and experience with data sets on chemicals currently under

review, the following refinements to the NRC guidelines have been adopted

by the NAC/AEGL Committee to set AEGLs.

For reasons discussed earlier in this chapter, the NAC/AEGL Committee

generally selects the highest experimental concentration that does not elicit the

symptoms or effects defined by the AEGL tier in question. This concentration

represents the starting point for AEGL development. In instances in which

appropriate data are available, the BMC method may be considered and used

to select the AEGL endpoints.

2.2.2.1 AEGL-1 Endpoints

The NRC (1993a) guidelines discuss the definition of the CEEL-1 (AEGL1) endpoint on pages 10, 12, and 21 of that report. Above the AEGL-1 value,

discomfort becomes increasingly likely. Below the AEGL-1 value

(detectability), “Exposure insufficient to cause discomfort or adverse health

effects may be perceived nevertheless by means of smell, taste, or sensations

(mild sensory irritation) that are not uncomfortable. The awareness of exposure may lead to anxiety and complaints and constitutes what is termed here

detectability.” (NRC 1993a, p. 21).
DERIVATION OF AEGL VALUES 41 

Thus, below the AEGL-1 values, there may be specific effects, such as the

perception of a disagreeable odor, taste, or other sensations (mild sensory

irritation). In some people, that exposure level could result in mild lacrimation

or coughing. Since there is a continuum in which it is difficult to judge the

appearance of “discomfort” in animal studies and human experiences, the

NAC/AEGL Committee has used its best judgment on a case-by-case basis to

arrive at appropriate and reasonable AEGL-1 values.

One additional factor to consider is that the three tiers of AEGL values

“provide much more information than a single value because the series indicates the slope of the dose-response curve” (NRC 1993a). If an accident occurs

and people smell or otherwise “detect” a chemical, the extent of the concentration range between AEGL-1 and AEGL-2 values provides useful information

and insight into the estimated margin of safety between a level of detection or

mild sensory irritation (AEGL-1) and a level that may impair escape or lead to

a serious long-term or irreversible health effect (AEGL-2). In cases in which

the biologic criteria for the AEGL-1 value would be close to, or exceed, the

AEGL-2 value, the conclusion is reached that it is “not recommended” (NR) to

develop AEGL-1 values. In these cases, “detectability” by itself would indicate

that a serious situation exists. In instances in which the AEGL-1 value approaches or exceeds the AEGL-2 value, it may erroneously be believed that

people experiencing mild irritation are not at risk when in fact they have

already been exposed to extremely hazardous or possibly lethal concentrations.

Since a comparison of the AEGL-1 and AEGL-2 values indicates the slope

of the dose-response curve that may be of value in emergency response, planning, or prevention, the NAC/AEGL Committee also attempts to establish

AEGL-1 endpoints for adverse effects that are asymptomatic or nonsensory.

Examples of such effects include significant (measurable) levels of methemoglobin, elevated blood enzyme levels, or other biologic markers related to

exposure to a specific chemical. By establishing an AEGL-1 value in these

instances, important information on the toxicologic behavior of a specific

chemical is available to emergency responders and planners.

The following criteria have been used by the NAC/AEGL Committee to

select endpoints for use in setting the AEGL-1 values.

2.2.2.1.1 No Value Established—AEGL-1 Is Close to or Exceeds

AEGL-2

1. State what aspects of the chemical toxicity profile make it inadvisable

to recommend an AEGL-1 value.

For example, the AEGL-1 value is not established, because levels that are
42 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

“detectable” are close to, or exceed, an AEGL-2 value. These materials have

poor warning properties.

2.2.2.1.2 No Value Established—Insufficient Data

Insufficient data were available to establish AEGL-1.

2.2.2.1.3 Highest Experimental Exposure Without an AEGL-1 Effect

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

For example, the highest experimental exposure levels that did not cause

(a) sensory irritation, (b) altered pulmonary function, and (c) narcosis in humans have been used to set AEGL-1 values.

2.2.2.1.4 Effect Level for a Response

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

For example, levels for odor detection in humans, mild sensory irritation,

asymptomatic or nonsensory effects, such as methemoglobin formation (22%)

and altered pulmonary function (transient changes in clinically insignificant

pulmonary functions of a susceptible individual), have been used as AEGL-1

endpoints.

2.2.2.2 AEGL-2 Endpoints

NRC (1993a) discussed the CEEL-2 (AEGL-2) definition on pages 10, 12,

and 21 of its report. The AEGL-2 has been defined as the threshold between

reversible effects that cause discomfort and serious or irreversible health

effects or effects that impair escape. Above the AEGL-2 value, there is an

increasing likelihood that people may become disabled or are increasingly

likely to experience serious or irreversible health effects. “The term disability

is used here to indicate the situation where persons will require assistance or

where the effects of exposure will be more severe or prolonged without assistance” (NRC 1993a, p. 21). In developing AEGL-2 values, the NAC/AEGL
DERIVATION OF AEGL VALUES 43 

Committee estimates a NOAEL for serious or irreversible effects or effects

that impair escape. It must be emphasized that reversible clinical toxicity may

be observed below the AEGL-2 value. If minor reversible effects are seen at

one level of exposure and disabling effects at a higher exposure, the former is

used to set the AEGL-2 value. If the exposure associated with disabling effects cannot be determined from experimental data, then the highest level

causing reversible effects and discomfort may be used to set the AEGL-2

value.

The following criteria have been used by the NAC/AEGL Committee to

select endpoints for use in setting the AEGL-2 values.

2.2.2.2.1 Highest Experimental Exposure Without an AEGL-2 Effect

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

The highest experimental exposure levels that did not cause decreased

hematocrit, kidney pathology, behavioral changes, or lethality (effects observed at higher exposures were above the definition for AEGL-2) have been

used as the basis for determining AEGL-2 values.

2.2.2.2.2 Effect Level for a Toxic Response That Was Not 

Incapacitating or Not Irreversible

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

For example, overt ocular and/or respiratory tract irritation, dyspnea,

pulmonary function changes, provocation of asthma episodes, pathology

(respiratory tract), mild narcosis, and methemoglobin formation (approximately 40%) have been used as a basis for AEGL-2 values.

2.2.2.2.3 A Fraction of the AEGL-3 Value

1. State the rationale for using a fraction of the AEGL-3.

2. State why the specific fraction chosen is scientifically justified.

In the absence of specific data used to determine an AEGL-2 value, onethird of the AEGL-3 value has been used to establish the AEGL-2 value. This
44 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

approach can only be used if the data indicate a steep exposure-based relationship based on data for effects below the AEGL-2 value and lethal-effect value.

2.2.2.3 AEGL-3 Endpoints

NRC (1993a) discussed the CEEL-3 (AEGL-3) definition on pages 10, 12,

and 21 of its report. The AEGL-3 tier has been defined as the threshold

exposure level between serious long-lasting or irreversible effects or effects

that impair escape and death or life-threatening effects. Above the AEGL-3,

there is an increasing likelihood of death or life-threatening effects occurring.

In determining AEGL-3 values, the NAC/AEGL Committee defined the

highest exposure level that does not cause death or life-threatening effects. It

must be emphasized that severe toxicity will be observed at levels exceeding

the AEGL-3. In cases in which data to determine the highest exposure level

that does not cause life-threatening effects are not available, levels that cause

severe toxicity without producing death have been used.

The following criteria have been used by the NAC/AEGL Committee to

date to select endpoints for use in setting the AEGL-3 values.

2.2.2.3.1 Highest Exposure Level That Does Not Cause Lethality—

Experimentally Observed Threshold (AEGL-3 NOAEL)

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

When experimental lethality data are insufficient to determine statistically

a BMC, the highest experimental exposure that did not cause lethality in an

experiment in which death was observed was used to set the AEGL-3 value.

2.2.2.3.2 Highest Exposure Level That Does Not Cause Lethality—

Estimated Lethality Threshold—One-Third of the LC50

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

3. If an exposure that does not produce death is estimated by dividing an

LC50 value by 3 (or some other divisor), then give the slope of the

exposure response curve or enough data points to support the division

by 3 (or some other divisor).
DERIVATION OF AEGL VALUES 45 

When experimental lethality data have been insufficient to determine

statistically an LC01 value, but an LC50 value was determined and all exposure

levels caused lethality, a fraction of the LC50 value is used to estimate the

threshold for lethality. In all cases, the exposure-response curve was steep,

and the LC50 value was divided by 3. Fowles et al. (1999) analyzed 120 published inhalation animal lethality data sets using the BMC method. Their

analyses of inhalation toxicity experiments revealed that for many chemicals

the ratio between the LC50 and the experimentally observed nonlethal level was

on average a factor of approximately 2, the 90th percentile was 2.9, and the

95th percentile was 3.5. There was a range of ratios from 1.1 to 6.5.

2.2.2.3.3 Highest Exposure Level That Does Not Cause Lethality—

Benchmark Exposure Calculation of the 5% and 1% 

Response

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

3. State the statistical method used to derive a BMC05 and the MLE01.

When sufficient information is available, the preferred method through

1999 utilized probit analyses (Finney 1971; Litchfield and Wilcoxon 1948;

and the Number Cruncher Statistical System - Version 5.5) to determine the

LC01 and the MLE was used for the LC01 value.

In the future, the BMC05 and MLE01 for lethality will be determined, presented, and discussed. Results from the above models will be compared with

the log probit EPA (2000) benchmark dose software (http://www.epa.gov/

ncea/bmds.htm). In all cases, the MLE and BMC at specific response levels

will be considered. Other statistical models such as the Weibull may also be

considered. Since goodness-of fit-tests consider an average fit, they may not

be valid predictors of the fit in the low-exposure region of interest. In this

case, the output of the different models will be plotted and compared visually

with the experimental data to determine the most appropriate model. The

method that results in values consistent with the experimental data and the

shape of the exposure-response curve will be selected for AEGL derivations.

Because of uncertainties that may be associated with extrapolations

beyond the experimental data, the estimated values are compared with the

empirical data. Estimated values that conflict with empirical data will generally not be used.
46 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.2.2.3.4 Effect Level for a Response

1. State the species, effect, concentration, and exposure time to cause the

effect.

2. Describe the toxicologic endpoint of concern.

When data are insufficient to estimate the highest exposure that does not

cause lethality, exposure levels that cause severe toxicity in the absence of

lethality are used in the selection of exposure levels to set AEGL-3 values.

The endpoints of concern include decreased hematocrit, methemoglobin

formation (70-80%), cardiac pathology, and severe respiratory pathology.

2.3 GUIDELINES AND CRITERIA FOR THE SEARCH

STRATEGY, EVALUATION, SELECTION, AND

DOCUMENTATION OF KEY DATA AND SUPPORTING

DATA USED FOR THE DERIVATION OF AEGL VALUES 

2.3.1 Search Strategy

The literature search strategy focuses on three general sources of information: (1) electronic databases, primarily peer-reviewed journals, and government databases; (2) published books and documents from the public and

private sectors of the United States and foreign countries, including references

on toxicology, regulatory initiatives, and general chemical information; (3)

data from private industry or other private organizations. The search strategy

also includes the use of search terms to enhance the relevance of the electronic

databases identified and retrieved.

(1) Electronic Database Coverage

The following databases are searched:

TOXLINE database (1981-current) from the U.S. National Library of 

Medicine's TOXNET

TOXLINE covers the toxicologic effects of chemicals, drugs, and physical

agents on living systems. Among the areas covered are adverse drug

reactions, carcinogenesis, mutagenesis, developmental and reproductive

toxicology, environmental pollution, and food contamination.
DERIVATION OF AEGL VALUES 47 

TOXLINE 65 database (1965-1980)

Subject coverage is identical to TOXLINE for time periods that precede

that of TOXLINE.

HAZARDOUS SUBSTANCES DATA BANK (HSDB) (Current) from

TOXNET

HSDB is a comprehensive factual and numeric chemical profile. Each

chemical profile is peer reviewed for completeness and accuracy to reflect

what is known about the chemical. 

PUBLIC MEDLINE (PUBMED)

PUBMED includes MEDLINE and PREMEDLINE. MEDLINE, the U.S.

National Library of Medicine's premier bibliographic database, covers

medicine, nursing, dentistry, veterinary medicine, health-care systems, and

the preclinical sciences. The above-mentioned TOXLINE searches include

MEDLINE citations. PREMEDLINE, also produced by NLM, provides

citation and abstract information before full records are added to MEDLINE. For a short period of time, this information is only available in

PUBMED.

REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES

(RTECS)

RTECS, compiled by NIOSH (U.S. National Institute for Occupational

Safety and Health), is a comprehensive database of basic toxicity information and toxic-effects data on more than 100,000 chemicals.

U.S. NATIONAL TECHNICAL INFORMATION SERVICE (NTIS)

The NTIS database provides access to the results of U.S. government-sponsored research, development and engineering, plus analyses

prepared by federal agencies, their contractors, or grantees. It is a means

through which unclassified, publicly available, unlimited distribution

reports are made available from such U.S. agencies as National Aeronautics and Space Administration (NASA), Department of Energy (DOE),

Department of Housing and Urban Development (HUD), Department of

Transportation (DOT), and some 600 other agencies. In addition, some

state and local government agencies contribute their reports to the database. NTIS also provides access to the results of government-sponsored

research and development from other countries.
48 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

U.S. INTEGRATED RISK INFORMATION SYSTEM (IRIS)

IRIS contains data from EPA in support of human health risk assessment,

focusing on hazard identification and dose-response assessment for specific chemicals.

U.S. FEDERAL RESEARCH IN PROGRESS (FEDRIP)

FEDRIP provides access to information about ongoing U.S. governmentfunded research projects in the fields of physical sciences, engineering,

and life sciences.

U.S. DEFENSE TECHNICAL INFORMATION CENTER (DTIC)

DTIC is the central U.S. Department of Defense facility for access to

scientific and technical information. The DTIC database includes technical reports, independent research and development summaries, technology

transfer information, and research and development descriptive summaries. The scope of the DTIC collection includes areas normally associated

with defense research, such as military sciences, aeronautics, missile

technology, and nuclear science. The collection also includes information

on biology, chemistry, environmental sciences, and engineering.

ORNL (U.S. Oak Ridge National Laboratory) IN-HOUSE DATABASES

CHEMICAL UNIT RECORD ESTIMATES (CURE)

The CURE database contains selected information from the EPA

Office of Health and Environmental Assessment documents and

Carcinogen Risk Assessment Verification Effort (CRAVE) and Reference Dose (RfD) work groups. Although the groups are not currently

active, this database is a valuable compilation of historic information.

TOXICOLOGY AND RISK ANALYSIS (TARA) DOCUMENT LIST

This database lists all types of documents written by TARA staff over

the past 15 years. These range from toxicity summaries to journal

articles. This list provides good references for chemicals that overlap

the AEGL priority list.

(2) Published Books and Documents from the Public and Private Sectors

GENERAL REFERENCES FOR TOXICOLOGY AND CHEMICAL 

INFORMATION
DERIVATION OF AEGL VALUES 49 

ATSDR (U.S. Agency for Toxic Substances and Disease Registry) Toxicological Profiles.

Chemfinder, Chemical Searching and Information Integration by CambridgeSoft Corporation

Current Contents, Life Sciences edition

HEAST (Health Effects Assessment Summary Tables)

Kirk-Othmer Encyclopedia of Chemical Technology

IARC (International Agency for Research on Cancer) Monographs on the

Evaluation of the Carcinogenic Risk of Chemicals to Humans

Low-Dose Extrapolation of Cancer Risks, S. Olin et al. (editors)

Merck Index

NTP (U.S. National Toxicology Program) Division of Toxicology Research and Testing, published reports.

Patty’s Industrial Hygiene and Toxicology

Respiratory System, Monographs on the Pathology of Laboratory Animals, T.C. Jones et al. (editors)

Synthetic Organic Chemicals, U.S. International Trade Commission

Toxicology of the Nasal Passages, C.S. Barrow (editor)

U.S. Air Force Installation Restoration Program Toxicology Guide

GENERAL REFERENCES FOR REGULATORY INFORMATION AND

STANDARDS

AIHA (American Industrial Hygiene Association) Emergency Response

Planning Guidelines (ERPGs) and Workplace Exposure Level Guides

(WEELs)

ACGIH (American Conference of Government and Industrial Hygienists)

Threshold Limit Values for Chemical Substances and Physical Agents

and Biological Exposure Indices

ACGIH Documentation of Threshold Limit Values

NAAQS (U.S. National Ambient Air Quality Standards)

NIOSH (U.S. National Institute for Occupational Safety and Health)

Documentation of IDLH’s (immediately dangerous to life and health)

NIOSH Pocket Guide to Chemical Hazards

NIOSH Recommendations for Occupational Safety and Health, Compendium of Policy Documents and Statements

OSHA (U.S. Occupational Safety and Health Administration) Limits for

Air Contaminants

SMACs (Spacecraft Maximum Allowable Concentrations for Selected

Airborne Contaminants), Committee on Toxicology, sponsored by

the National Research Council

EPA Health Effects Documents
50 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

(3) Unpublished Data from Private Industry and Other Private Sector

Organizations of All Nations

These data consist of reports and data that are not published in peerreviewed scientific journals but are relevant to the development of AEGLs.

Most often, the data represent acute toxicity data from controlled inhalation

exposure studies available from private industry or other organizations in the

private sector of all nations that may or may not be published in a peer-reviewed journal.

Search Terms

The U.S. Chemical Abstract Services (CAS) Registry number of the

chemical is used as the first choice. Chemical nomenclature or common

chemical names and synonyms are used if the CAS Registry number is unknown.

The CAS Registry number alone is used as the first step. If there are

approximately 300 citations, then all are retrieved for review. If less than

approximately 300 references are found, searches are conducted using chemical nomenclature and common chemical names in addition to the CAS number.

Searches by chemical name or names also should be made if few data of high

quality are found, irrespective of the number of citations found.

If more than 300 citations are found using any form of chemical identification, the references may be enriched in relevance and quality by adding any

number of the following characterizations of the desired data to the search

strategy:

short-term

threshold limit

permissible exposure limit

acute toxicity

ocular terms

inhalation terms

dermal terms

If the number or quality of single-exposure toxicity studies found is not

deemed to be adequate, multiple exposure studies may be considered but may

not achieve a consensus of the NAC/AEGL Committee. If a consensus or twothird majority of the committee cannot agree on the adequacy of the data, the

chemical may be placed on the list for future acute toxicity testing.
DERIVATION OF AEGL VALUES 51 

2.3.2 Evaluation, Selection, and Documentation of

Key and Supporting Data

As a detailed interpretation and supplementation of the NRC (1993a)

guidelines, the NAC/AEGL Committee has developed guidelines for evaluating the quality of studies to be used in the calculation of proposed AEGL

values. The proposed evaluation and documentation procedure created by the

NAC/AEGL Committee is intended to provide technical-support-document

writers, reviewers, committee members, interested parties, and the public with

a clear and consistent list of elements that must be considered in their evaluations. The proposed evaluation and documentation system will add technical

validity and administrative credibility to the process by providing a transparent, logical, and consistent methodology for selecting key studies used to

calculate an AEGL value. Additionally, the system will allow the proper

selection of uncertainty factors and modifying factors in a consistent and

logical manner. The process is designed to allow maximum flexibility in

professional judgment while promoting scientific uniformity and consistency

and providing a sound administrative foundation on which committee members can function.

Many toxicology studies used in the development of an AEGL were not

designed to meet current regulatory guidelines and are not necessarily consistent in protocol or scientific methodology. As a result, these valuable investigations cannot be judged solely on the basis of currently accepted experimental design criteria for such studies. Current guidelines from EPA (1998) and

the Organization for Economic Cooperation and Development (OECD 1993)

are used as the basis for conducting future studies on behalf of the

NAC/AEGL Committee, but lack of consistency of older studies requires

evaluation and qualification of each data set for scientific validity within the

context of AEGL documentation. A study can be valuable in the derivation

of AEGLs without conforming completely to a standard of detailed methodology, data analysis, and the results reported. The aim of the subject procedure

is to provide specific criteria in the selection and use of specific data sets for

development of defensible values, yet retain the ability to use logical scientific

thinking and competent professional judgment in the data-selection process.

If a study or some portion of a study uses scientifically valid methods, contains

adequate and reliable data, and presents defensible conclusions relevant to the

AEGL process, it may be included in the technical support document (TSD)

and used to support the AEGLs. 

It is important to emphasize that only toxicity data obtained directly from

a primary reference source are used as the basis for “key” toxicity studies from

which the AEGL values are derived. Additionally, all supporting data and
52 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

information important to the derivation of an AEGL value are obtained solely

from the primary references. These data include those used to provide a

“weight-of-evidence” rationale in support of the AEGL value derived. Secondary references may be used to provide data and information on commercial

uses, production volumes, chemical and physical properties, and other nontoxicologic or epidemiologic information on a chemical. Secondary references

also may be used to present background information on the toxicity of a

chemical. Any other information not important or directly relevant to the

actual derivation of the AEGL values may be used to provide supporting

rationale for the AEGL values. Data and information from secondary references should not be included in data summary tables presented in the TSDs

The credibility of evaluation guidelines is enhanced when they are drawn

from a widely accepted prescription for study protocol design. The guidelines

for a study evaluation should be based on the scientific methodologies but not

be so restrictive that it precludes competent professional judgment. Current

Good Laboratory Practice (GLP) guidelines provide a basis for selection of a

robust list of study elements that, in concert with the professional experience

and judgment of the AEGL Development Team and NAC/AEGL Committee

members in general, are used to qualify the data which support the AEGLs. 

Consequently the NAC/AEGL Committee has used the NRC guidelines

(1993a), the OECD Guidelines for the Testing of Chemicals (OECD 1993),

and the EPA Health Effects Test Guidelines (EPA 1998) as a basis for selection. 

The NRC (1993a) guidance provides general insight on the use of toxicologic data for AEGL derivation from routes of exposure other than inhalation. The NRC (1993a) guidance states that the bioavailability and differences

in the pharmacokinetics from different exposure routes of the chemical in

question must be considered. Because of these complex biologic phenomena

and the paucity of data to enable credible evaluation and consideration, the

NAC/AEGL Committee to date has selected and used only inhalation toxicity

data to derive AEGL values. Further, toxicity data on other exposure routes

will not be included in discussions in the TSDs unless those data are considered important for the support of relevant pharmacokinetic or metabolism data

or mechanisms of toxicity. In the absence of inhalation data to derive an

AEGL value, the NAC/AEGL Committee may use toxicity data from other

exposure routes if there are adequate data to perform scientifically credible

route-to-route extrapolations. In the absence of acceptable data, the committee

will refer the chemical for toxicity testing.

Each key and supporting study is evaluated using all listed “elements for

evaluation” as guidance. A “key study” is defined as the human and/or animal

study from which a toxicologic value is obtained for use in AEGL calcula-
DERIVATION OF AEGL VALUES 53 

tions. “Supporting studies” include those human and/or animal studies used

to support the toxicologic findings and values obtained from the key study, and

their use is consistent with the weight-of-evidence approach to scientific

credibility. While all elements for evaluation listed below are considered

when evaluating a study, only elements for evaluation from key and supporting studies that are relevant to the derivation of the AEGL values will be

discussed in the TSD as they impact the derivation. In evaluating a study, a

variety of endpoints are preferred. However, a study measuring, for example,

only one endpoint may be selected for development of an AEGL if other

studies have shown that other known inhalation toxicology endpoints are less

sensitive, provided the data are considered reliable. The list of elements for

evaluation is used for initial review of all studies evaluated for possible

inclusion in the TSD in instances in which they are germane to the selection

of studies.

The NAC/AEGL Committee is dependent upon existing clinical, epidemiologic, and case report studies published in the literature for data on humans.

Many of these studies do not necessarily follow current guidelines on ethical

standards that require effective, documented, informed consent from participating humans subjects. Further, recent studies that followed such guidelines

may not include that fact in the publication. Although human data may be

important in deriving AEGL values that protect the general public, utmost care

must be exercised to ensure first of all that such data have been developed in

accordance with ethical standards. No data on humans known to be obtained

through force, coercion, misrepresentation, or any other such means will be

used in the development of AEGLs. The NAC/AEGL Committee will use its

best judgment to determine whether the human studies were ethically conducted and whether the human subjects were likely to have provided their

informed consent. Additionally, human data from epidemiologic studies and

chemical accidents may be used. However, in all instances described here,

only human data, documents, and records will be used from sources that are

publicly available or if the information is recorded by the investigator in such

a manner that subjects cannot be identified directly or indirectly. These

restrictions on the use of human data are consistent with the “Common Rule”

published in the Code of Federal Regulations (Protection of Human Subjects,

40 CFR 26, 2000).

In addition to the discussion of the elements for evaluation in the individual studies section of the TSD, a section entitled "Data Adequacy and Research Needs" is included in the text of the TSD. A summary of the dataadequacy discussion is also included in the derivation summary tables in the

appendix of the TSD and in the summary section of the TSD. The text of the

TSD relates the studies used to derive or support the derivation of the AEGL
54 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

values to the discussion of the adequacy of the available data. Brief summaries of this discussion are included in the summary and derivation summary

tables. The data-adequacy section also presents and integrates the weight of

evidence by considering all information as a whole for each AEGL developed.

In addition to considering the elements for evaluation as relevant in the discussion, a number of other factors must be considered. They include repeatability

of experiments between laboratories, consistency of data between experiments

and laboratories, types and number of species tested, variability of results

between species, and comparison of AEGL values with the valid human and

animal data. Every data set is a unique, chemical-specific source of information that reflects the investigations conducted on the chemical and the properties of the chemical. This section reflects a “best professional judgment”

approach in the evaluation of the data adequacy and future research needs.

Figure 2-1 contains a diagram of the decision process for the selection of

key studies and supporting studies. A summary of the elements or criteria

used to select key studies and supporting studies and to evaluate their adequacy in deriving AEGL values follows.

Elements for the Evaluation of Key and Supporting Data and Studies

1. Only toxicity data and information obtained directly from a primary

reference source may be used as the basis for “key” toxicologic studies.

All other studies important to the derivation of an AEGL value or that

serve as a weight-of-evidence rationale are obtained from a primary

source.

2. Secondary references may be used for nontoxicologic data, such as physical and chemical properties, production locations, quantities, and background information on the toxicity of a chemical, provided the information

is not directly used in the derivation of the AEGL values. 

3. Only human data from studies that meet the ethical standards discussed in

the “Evaluation, Selection, and Documentation of Key and Supporting

Data” section of this SOP manual will be used in the derivation of AEGL

values.

4. The inhalation route of exposure is preferred. When the endpoint of

concern is systemic toxicity and the hepatic first-pass effect is not significant, oral exposure may be considered. In the absence of scientifically

sound inhalation data and with high confidence in a valid route-to-route

extrapolation, routes of exposure other than inhalation will not be used for

AEGL derivation.
DERIVATION OF AEGL VALUES 55 

Identification and

Selection of Relevant

Data / Information

Incorporation in Whole

or in Part into TSD?

Consider for AEGL

Derivation?

Selected as Key Study

Not Included in TSD Evaluate Data and

Information

Background Information

Supporting Study

Derivation of one or more

Acute Exposure Guideline Levels

Retain

Yes

Yes

Non-published,

Non-peer Reviewed

Industry Data

Published

Literature

Search

Other

Data / Information

Sources

Special Toxicity

Studies

Reject based on major

deficiencies in specific

selection criteria

No

Does not represent the

best key or supporting

studies based on

adherence to specific

selection criteria

No

Good supporting data

but does not represent

the best key studies

FIGURE 2-1 Decision tree for the selection of key and supporting studies.

5. Scientifically credible exposure concentration and exposure duration for

the study are provided.

6. Analytical procedures are used to determine chamber concentration for

inhalation exposure in controlled studies, and detailed, scientifically
56 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

credible methods, procedures, and data are used to measure chemical

concentration in epidemiologic or anecdotal cases (accidental chemical

releases). For oral exposure, dose may be determined from the amount of

test chemical placed into the subject. 

7. The number of subjects is not rigid; e.g., a general rule uses 5-10 rodents/sex/group as a valid measure, but as few as 2-3 primates or dogs/sex/

group may be used. The acceptable number of subjects per group is

influenced by the relationship between the within-group variability and the

degree of change that is considered to be detrimental. Smaller numbers

per group may be acceptable by increasing the number of treatment

groups.

8. Humans are the most relevant species studied. Rats, mice, rabbits, guinea

pigs, ferrets, dogs, or monkeys are acceptable. Other species require evaluation on a case-by-case basis. It is important to use a species for which

there are historical control data and relevance to humans.

9. A concurrent control group is composed of the same species as that in the

treatment groups. The control subjects should be housed and cared for in

the same manner as exposed animals.

10. Concentration or dose selection establishes a clear dose-response relationship.

11. The observation period is variable based on the time of onset of the toxic

effect. If it is rapid (minutes to 2-3 h) and associated with quick recovery,

an observation period of 3-4 days may be sufficient. For effects that are

slow in onset (2-3 days) and delayed in time, a minimum observation

period of 14 days is recommended.

12. Signs and symptoms of toxicity are noted during and after exposure and

reported separately by sex and concentration or dose.

13. For animal studies, body weights should be recorded throughout the study.

14. For repeated concentration or dose studies, the highest estimated or experimental (empirical) level of no effect is established for the specific AEGL

endpoint of concern.

15. Toxicity data from routes of exposure other than inhalation generally will

not be used as key or supporting data. Data from alternate routes are

considered in the absence of inhalation data if sufficient data are available

to perform a credible route-to-route extrapolation.

16. Number of concentrations or doses used are given.

17. If a NOAEL is selected or derived as the endpoint for an AEGL severity

level of concern, identifying both the highest dose at which the effect is

not seen and the lowest dose at which it is seen for each AEGL severity

level strengthens the confidence in the study.

18. Time of death is recorded if applicable.
DERIVATION OF AEGL VALUES 57 

19. For animal studies, necropsy is conducted with at least gross examination

results noted.

20. As available, data (e.g. histopathologic changes, clinical chemistry, and

hematology) may reduce uncertainty.

21. Recovery group included in the study and data generated are sufficient to

determine the degree of reversibility.

22. There is statistical treatment of data generated from study.

23. An evaluation of all relevant data should be performed and summarized

in the TSDs to present an integrated weight-of-evidence picture for all

information considered as a whole.

2.3.3 Elements for Discussion on Data Adequacy and Research Needs

The adequacy of the key and supporting data selected for AEGL derivation

should be discussed in Section 8.3 of the TSD (“Data Adequacy and Research

Needs”). Because of the different toxic endpoints used for the three AEGL

tiers and the use of different data or studies for each tier, the data adequacy

should be addressed separately for AEGL-1, -2, and -3 values. In addition to

any discussion regarding the elements for evaluating key and supporting studies listed in this section of the TSD, the discussion should consider in general

terms: (1) repeatability of experiments between laboratories, (2) consistency

of data between experiments and laboratories, (3) types and number of species

tested, and, (4) comparisons of the AEGLs with valid human and animal data.

A summary of the discussion in the TSD section “Data Adequacy and

Research Needs” also should be included in the summary of the AEGL document and the derivation summary tables. The summary statements should

address the adequacy of the data by AEGL tier.

2.4 DOSIMETRY CORRECTIONS FROM ANIMAL TO

HUMAN EXPOSURES

When extrapolating from observed responses in animals to predicted

human responses, the relationship between nominal exposure concentration

and delivered dose to the target tissue is of concern. For inhaled toxicants, the

target tissue is either a component of the respiratory system and/or other tissue

or organ (systemic). A number of methods have been proposed to adjust for

differences in the dose to target tissue in the respiratory system (EPA 1994)

and those tissues located systemically (NRC 1993a; EPA 1994). The concern

has been the lack of validated methodologies that would provide scientifically
58 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

sound values for gases, vapors, and aerosols. That concern is particularly true

when the methodology may predict levels for humans that may not be sufficiently protective. Both methodologies referenced above have not been validated for gases with experimental data, especially in the high-dose ranges

required to produce toxicity with acute exposures. Another possible dosimetry

correction, using the inhaled dose against the body weight raised to the 3/4

power, has support based on an analysis of chronic toxicity studies (EPA

1992). However, this adjustment may not be relevant for acute lethality studies

(Rhomberg and Wolff 1998). Therefore, no dosimetry adjustments have been

made to date by the NAC/AEGL Committee for attaining human-equivalent

doses in the development of AEGLs for gases, vapors, and aerosols.

If AEGL values are developed for particulates, the methodology developed by EPA and validated with experimental data on particulate matter will

be reviewed and applied on the basis of the individual material (EPA 1994).

When specific data and validated models are available for chemicals inhaled

as gases, a dosimetry correction will be made by the NAC/AEGL Committee.

2.4.1 Discussion of Potential Dosimetry Correction

Methodologies for Gases

2.4.1.1 The Respiratory System As a Target Organ

The RfC (reference concentration) method for chronic exposure to gases

was proposed by EPA (1994) as an approach to the dosimetry correction for

effects on the respiratory system. This method has not been used by the

NAC/AEGL Committee for the following reasons: (1) the RfC dosimetry

corrections from animal to man are based on theoretical constructs that have

not been confirmed and validated with experimental data; (2) some of the RfC

assumptions are questionable and can have a significant impact upon the calculated dosimetry correction between animals and humans. Below is a discussion of two key examples and their impact upon the dosimetry adjustment.

The assumptions are the requirement of uniform deposition in compartments

and equivalent percent of deposition in animals and humans.

For Category 1 gases (highly water soluble and/or rapidly irreversibly

reactive), the RfC method assumes that for each respiratory compartment

(extrathoracic, tracheobronchial, and pulmonary), the deposition of chemical

is equivalent throughout the compartment. This assumption fails to take into

account major differences in anatomical structure and deposition (dose) as the

gas, vapor, or aerosol progresses from proximal to distal regions within any
DERIVATION OF AEGL VALUES 59 

one compartment. The dosimetric adjustment from rodent to man for the

extrathoracic region predicts a 5-fold higher delivered dose to humans compared with rodents at equivalent exposures. However, a number of investigators have shown that treating the entire extrathoracic region as a single homogeneous compartment is incorrect. The use of sophisticated computational

fluid dynamics computer modeling, correlated with analysis of patterns of

lesions induced by chemical exposure, demonstrate that the degree of deposition of chemicals varies greatly in different extrathoracic regions in rats

(Kimbell et al. 1993, 1997a,b) and the monkey (Kepler et al. 1998). Specific

areas such as the olfactory epithelium will receive different regional doses in

the rat and humans because of differences in surface area, susceptible location,

and degree of ventilation (Frederick et al. 1998). A recent estimate of a dosimetric adjustment for vinyl acetate toxicity to the olfactory epithelium was

performed using multiple compartments and a physiologically based pharmacokinetic model (PBPK). Bogdanffy et al. (1999) predicted that a time-adjusted exposure at 8.7 ppm in the rat would result in the same damage in a human

exposed at 10 ppm. In this case, the application of the RfC method overestimates the risk to humans.

In the RfC method, the proportion deposited in each region for Category

1 gases is assumed to be the same in animals and humans. When the deposition is less than 100%, this assumption is incorrect when one considers a rodent breathing at 100 times a minute vs 15 breaths a minute for a human. The

residence time for the chemical in a rodent lung is approximately 0.6 seconds

and is approximately 4 seconds in a human, or about 6 times as long. All

things being equal, the longer residence time in the human respiratory system

will mean that the human extracts a greater percent of inspired chemical per

breath than a rodent. Another factor to consider is that at high exposure levels

a steady state can be rapidly achieved in which relatively little chemical is

deposited in each breath so that the concentration becomes the determining

factor.

Of concern is the fact that when dosimetry adjustments are made between

rodents and humans for toxicity to the pulmonary region, the delivered dose

to the human is predicted to be about 3 times less than the mouse for an equivalent nominal exposure concentration. Using this method in the absence of

supporting empirical data could seriously underestimate human sensitivity.

For example, at lethal concentrations, fluorine toxicity is due to pulmonary

intoxication in all species tested (Keplinger and Suissa 1968). Further, the

empirically derived LC50 values for the mouse, rat, rabbit, and guinea pig are

essentially identical. However, the minute-volume-to-surface-area ratio for the

pulmonary region of the guinea pig closely resembles the human. If the RfC
60 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

dosimetry procedure were correct, the LC50 for the guinea pig should be 2-3

times higher than that observed for the rat and mouse, yet the empirical data

were essentially identical for all three species. Using the RfC method to extrapolate a dosimetric correction to humans in this case would seriously underestimate the risk by a factor of 3 from the mouse data. This problem is compounded by the fact that the RfC method calls for the use of a lower interspecies uncertainty factor when the dosimetry correction is used.

2.4.1.2 Systemic Toxicity

Most systemic toxicants would fall under the definition of a Category 2

gas in the EPA methodology (EPA 1994). Category 2 gases are moderately

water soluble and intermediate in their reactivity; thus, they would be distributed throughout the respiratory tract and absorbed readily into the

bloodstream. In the case of Category 2 gases, the RfC dosimetry procedure

predicts that the human receives a dose ranging from 6,000 to 50,000 times

higher than a rodent (depending upon the species) for an equivalent exposure.

These numbers do not appear to be biologically reasonable or scientifically

credible. Because of the potential errors, the methodology for Category 2

gases has not been used. When a corrected methodology is published, it will

be evaluated for use by the NAC/AEGL Committee.

For systemic toxicants, the NRC (1993a), proposed that dosimetry correction be conducted by adjusting for minute-volume-to-body-weight ratios. It

is assumed for this calculation that 100% of the chemical or equal percentages

of the chemical are absorbed. Given that assumption, the correction is a reasonable approach and may be valid for low concentrations of chemicals. Most

animal-to-human extrapolation is done using mouse or rat data. Using certain

typical minute-volume and body-weight parameters, it is possible to calculate

an adjustment factor or multiplier to derive an equivalent dose in a human

from animal data. The multiplier is approximately 6 for the mouse and 3.5 for

the rat. Thus, if the exposure of interest in mice or rats is 100 ppm, an equivalent internal dose in humans would be predicted to be induced by exposure to

600 ppm and 350 ppm from these two species, respectively. Therefore, to

induce an acutely toxic systemic effect in humans, people would have to be

exposed to a concentration 6 times greater and 3.5 times greater than the nominal exposure required to induce the effect in mice or rats, respectively.

If less than 100% of the inspired chemical is absorbed with each breath,

the human and animal would absorb a different fraction of the chemical in

each minute (see discussion above). As the percent absorbed approaches 0, the
DERIVATION OF AEGL VALUES 61 

multiplier would approach 1. In the example above, the multiplier for human

dosimetry correction would decrease from 6 to 1 in the case of mice and 3.5

to 1 in the case of rats as the percent absorbed approaches 0.

AEGL-2 and AEGL-3 values represent relatively high exposure concentrations where absorption may not be complete. If the minute-volume-to-bodyweight correction for dosimetry, which assumes 100% absorption, were used

in these cases, the estimated human exposure equivalent to the rodent would

be too high, leading to an underestimate of the toxicity and the derivation of

AEGL values that are not protective of the human population.

Another approach to dosimetry correction may be that used by EPA when

extrapolating from animal cancer bioassays to theoretical excess human cancer

risk levels for lifetime exposures (EPA 1992). The cross species scaling factor

used is based on an equivalence of mg/kg3/4/day. There is reasonable scientific

support for utilizing this approach based on an analysis of a number of multiple exposure studies across a number of animal species (EPA 1992). One

might assume that the total amount of chemical inhaled is equivalent to the

dose (NRC 1993a) and adjust that across species using the equivalence of

mg/kg3/4/day. However, Vocci and Farber (1988) point out that the power law

of (body weight)3/4 holds for the ventilation rate, such that on a weight-toweight basis, the rat receives about 4 times the delivered dose of a human for

the same exposure concentration. When this adjustment for breathing rate is

combined with the adjustment for toxicity (EPA 1992), the two cancel each

other out and one is left with the conclusion that equivalent exposure concentrations result in equivalent outcomes in animals and humans.

The situation is further complicated by an analysis of oral acute toxicity

experiments by Rhomberg and Wolff (1998) using pair-wise comparisons of

LD50 values for different species for a large number of chemicals on the

RTECS database. Their findings contrast with those of EPA (1992), which

largely evaluated multiple exposure studies, in that the best correspondence of

toxicity across species for LD50 values was found when doses were expressed

as milligrams per kilogram. This finding might argue for the NRC (1993a)

recommendation to scale doses across species based on minute-volume-tobody-weight ratios. However, this conclusion would be based on an evaluation of oral toxicity studies, most of which were conducted by gavage. Bolus

doses result in a high peak body dose, in contrast to the inhalation of a chemical over a number of hours with a more constant body burden over time. The

question then becomes, does inhalation exposure on the order of hours mimic

the toxic response seen with multiple exposures (EPA 1992) or the acute oral

bolus doses used in the Rhomberg and Wolff (1998) analysis? If the former

situation prevails, then the rationale by Vocci and Farber (1988) would argue
62 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

for no dosimetry corrections being made. On the other hand, the latter case

would argue for the use of the NRC (1993a) methodology.

2.4.2 Current Approach of the NAC/AEGL Committee to

Dosimetry Corrections

Given the uncertainty surrounding this issue, and the fact that the use of

no dosimetry corrections for gases across species would be the most conservative public-health approach, the NAC/AEGL Committee concluded it would

not use dosimetry corrections across species. As the science surrounding this

issue progresses, the NAC/AEGL Committee will re-evaluate that practice.

If data are available on a chemical-by-chemical basis that scientifically support

dosimetry corrections for gases in the development of AEGLs, they will be

used.

As AEGLs are developed for particulates, the methodology developed by

EPA and validated with experimental data on particulate matter will be reviewed and applied on the basis of the individual material (EPA 1994).

2.5 GUIDELINES AND CRITERIA FOR SELECTION OF

UNCERTAINTY FACTORS TO ADDRESS THE VARIABILITY

BETWEEN ANIMALS AND HUMANS AND WITHIN

THE HUMAN POPULATION

2.5.1 Introduction

The variation in the toxicologic response of organisms to chemical exposures is well known. This variability is observed across species and among

individuals within the same species. Lack of knowledge about the range of

variability introduces uncertainties into any estimate of AEGL values based

on biologic data. To account for known and unknown variability in response,

the value derived from experimental data is adjusted by a value that reflects the

degree of uncertainty. This value is referred to here and by most agencies and

organizations as the uncertainty factor (UF). If an extrapolation is being made

from animal data to humans, the total UF is a composite of an interspecies UF

to account for possible differences between animal and human response to the

chemical and an intraspecies UF to account for differences in response to the

chemical within the human population. The intraspecies UF is needed to

account for possible variabilities in response by “those at either extreme of
DERIVATION OF AEGL VALUES 63 

age, those with poor nutritional status, those with preexisting diseases, such as

certain heart diseases, that are fairly widespread in the general population,

those with enhanced hereditary susceptibility, or those who are overexposed

because of unusual physical exertion.” (NRC 1993a, p. 88).

Interspecies and intraspecies UFs have been used in the development of

“safe” or threshold exposure levels for chronic, noncancer toxicity by health

organizations throughout the world. Examples include the acceptable daily

intake (ADI) (Lu 1988; Truhaut 1991; Lu and Sielken 1991), the tolerable

daily intake (TDI) or tolerable concentration (TC) (Meek et al. 1994; IPCS

1994), the minimal risk level (MRL) (Pohl and Abadin 1995), the reference

dose (RfD) (Barnes and Dourson 1988; Dourson 1996), and the reference

concentration (RfC) (EPA 1994; Jarabek et al. 1990). The importance of using

distribution-based analyses to assess the degree of variability and uncertainty

in risk assessments has been emphasized in recent trends in risk analysis. This

will enable risk managers to make more informed decisions and better inform

the public about possible risks and the distribution of those risks among the

population (Hattis and Anderson 1999). These techniques can be used to

assess variability from differences in individual exposure and susceptibility for

specific risk assessments to reduce the uncertainty in estimating the real variability that exists in a population (Hattis and Burmaster 1994; Hattis and

Barlow 1996).

The use of UFs in the development of AEGL values is designed to protect

the general public, including susceptible subpopulations, from short-term

exposures to acutely toxic chemicals. However, it is recognized that certain

individuals, subject to unique or idiosyncratic responses, could experience

adverse effects at concentrations below the corresponding AEGL value. “In

the case of CEEL-2 [AEGL-2], UFs must be balanced against the inherent risk

associated with actions, such as evacuation, that may be taken as a result of

application of CEELs [AEGLs]. Large UFs, which may be appropriate with

chronic exposure limits, such as PELs, may be associated with increased risk

to the community in the application of CEEL-2 [AEGL-2].” (NRC 1993a).

For short-term exposure limits such as AEGLs, the NRC (1993a) recommended that UFs ranging from 1 to 10 generally be applied to account for

interspecies and intraspecies variability. The selection of any UF should be

based on the quality and quantity of data available for the chemical under

consideration. Based on the data set at hand, and professional judgment, UFs

between 1 and 10 are applied to account for interspecies and intraspecies

variability in the derivation of AEGL values (NRC 1993a). 
64 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.2 Background

The concept of “safety factors,” more recently referred to as “uncertainty

factors,” is thought to have evolved from studies (Bliss 1935a,b) whose mathematical treatise of the statistical variations inherent in the calculation of the

dosage-mortality curve indicated a range of uncertainty often found in toxicologic predictions (Calabrese 1983). Barnes and Denz (1954) observed that this

same uncertainty may also occur for toxicologic predictions using data from

animals. They suggested that food additives should show no adverse effect in

test animals fed levels 100 times the levels used in food for humans. Although

they considered this 100-fold margin of safety reasonable, they acknowledged

at the time that there was no rigorous scientific basis for a value of 100.

Bigwood (1973) credits the Joint Food and Agriculture OrganizationWorld Health Organization Expert Committee on Food Additives with developing the concept of “acceptable daily intake” (ADI) in the late 1950s. However, Lehman and Fitzhugh (1954) from the U.S. Food and Drug Administration (FDA) appear to be the first to suggest that ADIs be derived from chronic

animal NOAELs expressed in milligrams per kilogram of diet through the use

of a 100-fold factor. Bigwood (1973) criticized a WHO report published in

1967 on ADIs that states that an arbitrary factor of 100 has been widely accepted for determining maximum safe dietary levels but that the margin of

safety may vary from 10- to 500-fold. Although acknowledging that the

100-fold safety factor (SF) is an approximation, Bigwood justified the value

on the basis of (1) differences in body size of animals and humans, (2) differences in food requirements that vary with age, sex, physical exertion, and

environmental conditions, (3) differences in water balance between the body

and its environment, (4) differences in balance of hormonal functions (and its

effect on food intake), and (5) differences in the susceptibility of various animal species to the toxic effect of a given additive. Further, he suggested that

a SF slightly larger than 60 would cover the first four parameters and concluded that a SF of 100 would address all five parameters with an acceptable

degree of validity. The WHO Expert Committee for pesticide residues used

a similar approach (Lu 1979). Vettorazzi (1977, 1980) also supported the use

of a 100-fold factor based on differences between animals and humans in

susceptibility to toxicants, variations in response among humans, the size of

the test population versus the exposed human population, the difficulty in

estimating human intake, and possible synergistic actions of various chemicals

in the human diet.

The FDA modified its original approach to ADI derivations using a 100-

fold SF by accepting subchronic animal NOAELs with an additional 10-fold
DERIVATION OF AEGL VALUES 65 

SF in the absence of chronic data (Kokoski 1976, as cited in Dourson and

Stara 1983). The NRC (1977) recommended a similar approach with two

significant changes: (1) the measurement of a NOAEL in milligrams per

kilogram of body weight per day rather than milligrams per kilogram of diet,

and (2) the use of a 10-fold factor when valid data on prolonged ingestion by

humans were available. Also, several reports published during this time suggested that in certain instances the 100-fold SF could be divided into two

10-fold factors to describe separately the interspecies and intraspecies variabilities (Bigwood 1973; Klaassen and Doull 1980; Food Safety Council 1982).

On the basis of the NRC approach, EPA (1980) also recommended SFs for

estimating ADIs for ambient water quality criteria. The ADIs were intended

to protect individuals on the basis of chronic contaminant exposure. An additional SF of 1- to 10-fold was included to estimate NOAELs when only

LOAEL data were available. Therefore, the FDA, NRC, and EPA all issued

recommendations utilizing the 100-fold SFs with the additional agencyspecific UFs described above.

While the original selection of SFs appears to have been rather arbitrary,

Dourson and Stara (1983) introduced the concept that UFs (SFs) have empirical data to support their use for both intraspecies and interspecies adjustment.

These workers analyzed the dose-response slopes of 490 rat LD50 studies

reported by Weil (1972) and calculated the intraspecies adjustment factor

required to reduce the dose level 3 standard deviations below the mean. This

approach was used to predict the response of a susceptible subpopulation in a

general population. They reported that an adjustment factor of 10-fold was

adequate to reduce the response of a dose level killing 50% of the rat population to a level that would be lethal to only the most susceptible members (1.3

per 1,000) of the population for 92% of the chemicals studied.

Other studies evaluated for interspecies dose-response relationships by

these workers, primarily between rats and humans, included metals (Evans et

al. 1944, as cited in Dourson and Stara 1983), pesticides (Hayes 1967, as cited

in Dourson and Stara 1983), arsenic and fluorine (Lehman and Fitzhugh 1954).

Dourson and Stara (1983) concluded that although separate factors of 10-fold

for interspecies and intraspecies response adjustments for chronic data appeared reasonable, more experimental data were needed. They believed that

intermediate UFs of less than 10-fold for individual factors or less than 100-

fold for combined factors could be used to estimate the ADI and may be developed on a logarithmic scale (e.g., 31.6 being halfway between 10 and 100 on

a logarithmic scale).

Barnes and Dourson (1988) described EPA's approach and rationale to

assessing noncarcinogenic health risks from chronic chemical exposure. EPA
66 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

approach follows the general format as set forth by the NRC (NRC 1983). The

conceptual difference between “safety” and “uncertainty” is discussed within

the context of the terms SF versus UF and ADI versus RfD. The authors state

that SF suggests the notion of absolute safety and that the ADI is generally and

erroneously interpreted as a strict demarcation between what is “acceptable”

and what is “safe” in terms of chronic exposure. Rather, the ADI represents

an estimate of a xenobiotic exposure or daily dose where the probability of

adverse effects is low but a level where the complete absence of all risk to all

people under all conditions of exposure cannot be assured. Consequently, the

RfD and UF terminology was developed and adopted by EPA. EPA considers

the RfD to be an estimate (with uncertainty spanning perhaps an order of

magnitude of a daily exposure to a human population, including susceptible

subpopulations) that is likely to be without an appreciable risk of deleterious

effects during a lifetime.

Dourson et al. (1992) conducted an analysis of chronic and subchronic

toxicity data on 69 pesticides obtained from EPA's Integrated Risk Information

System (IRIS) to determine the potential impact of missing studies on the

quality of the RfD values derived. Certain of these data proved useful in

determining interspecies variations in toxic response to long-term ingestion of

a wide range of pesticides. The authors' analyses of 1- to 2-year studies indicated that the probability of the rat NOAEL for each of 67 pesticides exceeding the dog NOAEL by greater than 3.16-fold was 28%, and the probability

of the rat NOAEL exceeding the dog NOAEL by greater than 10-fold was

10%. Also, the probability of the dog NOAEL in the same studies exceeding

the rat NOAEL by greater than 3.16-fold was 19%, and the probability of the

dog NOAEL exceeding the rat NOAEL by greater than 10-fold was 4%. 

These data support the value of using UFs derived from data in developing

RfDs and suggest that UFs between species may be significantly less than

10-fold for a wide range of structurally diverse chemicals.

Renwick (1993) considered the expression of toxicity to be the combined

result of toxicokinetics (all processes contributing to the concentration and

duration of exposure of the active chemical toxicant at the target tissue) and

toxicodynamics (mode or mechanism of action of the active toxicant at the

target tissue site). Therefore, he reasoned that since both toxicokinetics and

toxicodynamics contribute quantitatively to the UF, it is necessary to subdivide

each of the 10-fold UFs (interspecies and intraspecies) into these two components to effectively accommodate differences in contributions made by toxicokinetic and toxicodynamic factors. Hence, for any chemical, appropriate data

may be used to derive a specific data-derived factor for that component. The

overall interspecies and intraspecies UFs would subsequently be determined
DERIVATION OF AEGL VALUES 67 

as the product of the known data-derived factor or factors and the "default"

values for the remaining unknown factors. Renwick (1993) evaluated published data for parameters that measure interspecies differences in plasma

kinetics (physiologic changes, differences in rates of absorption, biotransformation, and elimination) in laboratory animals and other parameters for

interspecies differences in toxicodynamics, such as hematologic changes

caused by exposure to organic and inorganic toxins and peroxisome proliferation in in vitro cell cultures. The author used a statistical analysis of variability

in disposition rate of cyclamate and several pharmaceutical agents in healthy

adults as examples for deriving the kinetic contribution to the intraspecies UF.

The estimation of the intraspecies variability in dynamics was also based on

drug responses in a similar human population. On the basis of these evaluations, Renwick proposed a division of the 10-fold UFs for both interspecies

and intraspecies as 4-fold for differences in kinetics and 2.5-fold for differences in dynamics. Although Renwick conceded that the proposed subdivisions represent professional judgments, he stated that, based on consideration

of appropriate data, the method was less arbitrary than using a 10-fold default

to address each aspect.

Dourson et al. (1996) and Dourson (1996) summarized the status of UFs

in noncancer risk assessments and discussed the use of “data-derived” UFs by

various health organizations, EPA, and Health Canada. These authors presented data on interspecies and intraspecies variability of response that supported the use of lower UFs that are protective of human health. Dourson et

al. (1996) also presented research and case studies from EPA and Health Canada risk assessments in which UFs other than a default value of 10-fold were

used in the estimation of a RfD, RfC, TDI, or TC. The authors concluded that

various organizations have begun to recognize that the default values currently

used by risk assessors may in fact be inaccurate and overly conservative. As

a result of the data available at that time, EPA and Health Canada began using

UFs other than default UFs on a more regular basis. Dourson et al. (1996)

provided the basis for concluding that the use of data-derived UFs for the

development of RfDs should become the first choice and that only in situations

in which there are truly inadequate data should the use of a 10-fold default

factor be the first choice.

2.5.3 Considerations and Approaches to the Selection of UFs

for Developing AEGLs

The concepts and the scientific data that support the use of UFs in human
68 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

health risk assessment have progressed considerably during the past 50 years.

The increase in knowledge of both interspecies and intraspecies susceptibility

and variability, the toxicologic mechanisms of action, and the availability and

evaluation of databases support the use of data-derived UFs.

The original 100-fold UFs (or SFs) were intended for use with food additives and were based on assumptions related to, or associated with, the oral

route of exposure. Hence, considerations such as differences in food consumption, food requirements, water balance, and potential synergistic effects

among various substances present in human food are not directly relevant to

the consideration of inhalation exposure. Additionally, the original acceptable

daily intake (ADI) was expressed in milligrams per kilogram of diet versus

milligrams per kilogram of body weight, and application of the original 100-

fold SF was generally accepted across chemicals with little or no evaluation

of scientific data to support or reject the use of this value. Today, there is

greater knowledge concerning bioavailability, and defined methods are available to evaluate susceptibility or variability in responses and selecting or deriving scientifically credible UFs.

Dourson and Stara (1983) introduced the concept that empirical data can

support the use of UFs for both interspecies and intraspecies adjustment. This

observation was followed by the publication of an analysis of the chronic and

subchronic toxicity data obtained from EPA’s Integrated Risk Information

System (IRIS). Certain of those data proved useful in determining the extent

of interspecies variations in response to long-term ingestion of a wide range

of pesticides. More recently, the concept of data-derived UFs has been introduced (Renwick 1993; Dourson et al. 1996). Finally, the concept of dividing,

evaluating, and quantifying separately the toxicokinetic and toxicodynamic

factors from each of the interspecies and intraspecies UFs has been proposed

(Renwick 1993).

One important consideration in the selection or derivation and use of UFs

for the development of AEGLs is the nature of the toxicant and the exposure

period. Much of the data, information, and emphasis to date on noncarcinogenic and nonmutagenic substances has addressed chronic effects from longterm or life-time daily exposures. Certain of the reports discussing the toxicokinetic and toxicodynamic factors as related to variability of response have

drawn on carcinogenic or mutagenic mechanisms as a basis for scientific

support. By contrast, the AEGL values address relatively high concentration,

short-term exposures to threshold effects of acutely toxic chemicals. In attempting to draw on the scientific foundations upon which UFs are being

selected for use in developing chronic guideline levels such as RfDs and RfCs,

it is important to maintain an awareness of certain potential differences when
DERIVATION OF AEGL VALUES 69 

considering acute guideline levels such as AEGLs. Responses to chronic exposures may be greater between species or between individuals as compared with

responses to acute exposures. For example, the impact of individual differences in absorption, excretion, metabolism, rate of repair, or accumulation of

unrepaired damage may be magnified through exposure to lower concentrations over extended time periods. The higher concentrations associated with

acute exposure may tend to overwhelm existing defense mechanisms, possibly

eliminating certain differences in response among species and among individuals within the same species. The higher concentrations associated with single

exposures, together with the short-term nature of the exposure period, may

reduce any differences in absorption, metabolism, and excretion of a substance, as well as differences in repair mechanism rates, and other factors.

Hence, acute exposure to acutely toxic substances in some instances may

reduce the variability in response between species and among individuals of

the same species depending upon the mode of action of the material.

Based on the considerations presented above, the acceptance and use of

default UFs based on chronic exposure data are carried out only after careful

evaluation of chemical specific data for single exposures. However, the concepts, ideas, and approaches to developing UFs that have emanated from the

chronic exposure studies of the past 10 years are valuable in the development

of AEGLs and will be used as appropriate in the selection or derivation of UFs

used in the AEGL program.

2.5.3.1 Interspecies UFs—Use in the Development of AEGL Values—

Discussion

When data are insufficient to determine the relative susceptibility of animals in comparison to humans, a UF of 10 has been used by EPA, ATSDR,

Health Canada, WHO, the International Programme on Chemical Safety

(IPCS), and Rijksinstituut voor Volksgesondheid en Milieu (RIVM) when

developing the equivalent reference doses for chronic exposure to chemicals

(Dourson et al 1996). When extrapolations are made from animals to humans

based on milligrams per kilogram of body weight, the factor of 10-fold is

usually adequate to account for differences in response. Dourson and Stara

(1983) found that a factor of 10 accounted for many of the animal-to-human

differences observed when the dose was adjusted for differences between

human and animal body weights and body-surface areas.

Brown and Fabro (1983) compared the lowest effective dose to cause

teratogenicity in animals (mouse, rat, rabbit, cat, and monkey) and humans for
70 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

eight chemicals (methylmercury, diethylstilbesterol, methotrexate, aminopterin, polychlorinated biphenyls (PCBs) thalidomide, phenytoin, and alcohol).

The LOAEL ratios ranged from 1.8 to 50 with a geometric mean of 7. Humans were generally more susceptible on an administered oral-dose/bodyweight basis but by less than an order of magnitude. This analysis is complicated by the fact that the criteria and confidence in determining the lowest

effective dose are not discussed, and the chemicals may represent potent developmental toxicants in humans since their confirmed teratogenicity in humans

represented the basis for their selection. The potency estimates in humans may

represent only the sensitive part of the distribution of human response to exposure. The animal response dose may be closer to the mean response level, and

therefore presents a higher LOAEL for the species used in this comparision.

However, the retrospective nature allows the choice of the most susceptible

animal species. In most instances the animal database is incomplete. Thus,

this analysis may represent an incomplete spectrum of results in which humans

appear more susceptible than animals to certain developmental toxicants.

Renwick (1993) subdivided the interspecies and intraspecies UFs into two

components to address toxicokinetics and toxicodynamics separately. Although supporting data for this concept stem from chronic animal feeding

studies and in vitro cell cultures, the concept of considering the kinetics and

dynamics separately across species has relevance to UFs for AEGLs. Renwick

proposed specific quantitative values of 4-fold and 2.5-fold for the kinetic and

dynamic components, respectively. Although this approach has merit, the

NAC/AEGL Committee does not make such a precise quantitative differentiation. To date the NAC/AEGL Committee uses only general information on the

kinetic and dynamic components of toxicity to adjust the interspecies UF (e.g.,

from 10 to 3 or 1). This approach is also consistent with the recommendation

by Dourson et al. (1996) to use data-derived UFs when appropriate data are

available. This approach is in keeping with EPA’s general approach in the

development of RfDs. For example, in the case of Aroclor 1016, the default

interspecies UF of 10 was reduced to 3 because of the similarity with which

monkeys and humans respond to PCBs (toxicodynamics), and metabolize

PCBs (toxicokinetics), and the physiologic similarity (toxicokinetics) between

the two species (EPA 1996b).

Comparisons of the current approach to determine UFs for AEGLs with

other short-term exposure limits have not altered the practice of the

NAC/AEGL Committee. In the development of emergency exposure guideline levels (EEGLs) by the NRC (NRC 1986), a factor of 10-fold was used for

interspecies extrapolation.

The NRC Guidelines for Developing Spacecraft Maximum Allowable

Concentrations for Space Station Contaminants (SMACs) states that UFs
DERIVATION OF AEGL VALUES 71 

between 1- and 10-fold are used for each source of uncertainty (NRC 1992a).

The sources include intraspecies (human) response variabilities, interspecies

variabilities, the extrapolation of a LOAEL to a NOAEL, and the extrapolation

from an inadequate or incomplete data base. For 1-h SMACs, the NRC used

an overall (combined intraspecies and interspecies) UF of 10-fold when only

animal data were available or when the route of human exposure differed from

the study. However, the population for which SMACs is intended (astronauts)

does not include infants, children, the elderly, or the infirm and is, therefore,

a more homogeneous and healthier subpopulation.

The NRC (1993a) recommended the use of an interspecies UF within the

range of 1- to 10-fold to account for differences between animals and humans.

The guidance suggests that the UF should be based on the quality of the data

available. In this regard, the NAC/AEGL Committee evaluates data on a chemical-by-chemical basis, considers the weight of evidence, and uses scientific

judgment in the selection of interspecies UFs. As data are available, the

NAC/AEGL Committee uses data-derived interspecies UFs.

Information bearing on the toxicokinetics and toxicodynamics of the

chemical under consideration, as well as structurally related analogues or

chemicals that act by a similar mechanism of action, will be used to derive an

appropriate interspecies uncertainty factor that may range from 10 to 3 or 1.

In the absence of information on a subject or analogous chemical to set dataderived UFs, the use of a default UF of 10 is considered to be protective in

most cases. As always, all information on the chemical, its mechanism of

action, structurally related chemical analogues, and informed professional

judgment will be used when determining appropriate UFs and evaluating the

resultant AEGL values.

2.5.3.2 Interspecies UFs—NAC/AEGL Committee Guidelines

The NRC (1993a) provides guidance on approaches to selecting the most

appropriate species for deriving AEGL values. General guidelines followed

by the NAC/AEGL Committee to select UFs are presented below. In each

section, there is a list of questions that should be addressed to support the

rationale for the UF used. The guidelines are organized into categories for

convenience. However, more than one guideline may be applied to the selection of any one UF.
72 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.3.2.1 Small Interspecies Variability or Most Appropriate 

Species Used

In cases in which the interspecies variability is small (e.g., within a factor

of 3), the most susceptible species is selected, or a species whose biologic

response to the substance in question is closely related to humans is selected,

the interspecies UF is typically 3. It should be noted that in those cases in

which the mode of action can be identified and there is evidence that it is not

expected to vary significantly among species, the UF is generally 3.

The rationale for the selection of a UF should include the following:

1. The species tested.

2. The toxicologic endpoint used for the AEGL derivation.

3. The qualitative and quantitative range of responses of the species

tested.

4. Discussion of why the species and study chosen was the most appropriate.

5. Discussion of the variability among studies with the same species or

among strains.

2.5.3.2.2 Most Susceptible Species Not Used

In instances in which the most susceptible species is not used, a UF of 10

is generally used.

The rationale for the selection of a UF should include the following:

1. The species tested.

2. The toxicologic endpoint used for the AEGL derivation.

3. The qualitative and quantitative range of responses of the species

tested.

4. Discussion of why the most susceptible species was not used and/or

why the less-susceptible species was selected.

2.5.3.2.3 Mechanism or Mode of Action Is Unlikely to Differ 

Among Species

If evidence is available indicating that the mechanism or mode of action,

such as direct-acting irritation or alkylation, is not expected to differ significantly among species, an interspecies UF of 3 is generally used.

The rationale for the selection of a UF should include the following:
DERIVATION OF AEGL VALUES 73 

1. A description of the mechanism of action.

2. A discussion of why the mechanism of action is unlikely or likely to

differ.

3. Is bioavailability, metabolism, detoxification, elimination likely to be

an issue?

2.5.3.2.4 Mechanism or Mode of Action Is Unknown

In cases in which the mechanism or mode of action is unknown, insufficient data on differences between species are available, or there are likely to

be substantial (but inadequately quantified) differences in metabolic and physiologic response between species, an interspecies UF of 10 is applied.

The rationale for the selection of a UF should include the following:

1. Description of the toxicologic effects observed.

2. Description of the range of uncertainty in toxicologic response and

how that relates to this assessment.

3. Discussion of what is known and unknown about the mechanism or

mode of action.

4. Discussion of the extent of data available among species.

2.5.3.2.5 Large Variability in Response Between Species

When there is a high degree of variability among species or strains of

animals or experiments that cannot be explained adequately, an interspecies

UF of 10 is applied.

The rationale for the selection of a UF should include the following:

1. Description of the response.

2. Discussion of the differences or similarities in pharmacokinetic parameters (absorption, metabolism, detoxification, elimination) among

species.

3. Discussion of the range of dose-dependent responses of the species

tested and the qualitative and quantitative aspects of the data.

2.5.3.2.6 Humans More Susceptible Than Animals

When published data show humans are more susceptible than animals, an

interspecies UF of 10 is used unless published results demonstrate otherwise.
74 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

The rationale for the selection of a UF should include the following:

1. Description of the toxicologic endpoints for which humans and animals show differential susceptibility.

2. Discussion of the factors where humans are thought to be more or less

susceptible than animals.

3. State what species were tested.

4. Discussion of the range of response of the species tested. This discussion should address qualitative and quantitative aspects of the data.

5. Discussion of human factors that account for unique susceptibility

compared with test animals.

2.5.3.2.7 Inadequate Data

The UF for interspecies response adjustment is 10 when there are inadequate data or insufficient information about the chemical or its mechanism of

action to justify an alternative UF.

The rationale for the selection of a UF should include the following:

1. Discussion of the inadequacy of the data that are the basis for a UF of

10. For example, the analysis may depend upon data collected in only

one species, high variability of response, or uncertainties in exposure

measurement. The statement may point to data gaps that could be

filled where the need exists.

2.5.3.2.8 A Selected UF Applied to Animal Data Driving the AEGL-2

or -3 to a Value Tolerated by Humans Without Lethal or

Serious Adverse Effects

When the application of an interspecies UF of 10 reduces the AEGL-3

value (the threshold for lethality) or the AEGL-2 value (the threshold for

irreversible or disabling effects) to an exposure concentration that humans are

known to tolerate without adverse effect, the interspecies UF is reduced to 3

or 1.

The rationale for the selection of a UF should include the following:

1. Citations and explanations of the human data and how it relates to the
DERIVATION OF AEGL VALUES 75 

AEGL value derived with a UF selected on the basis of the existing

guidelines.

2.5.3.2.9 A Multiple Exposure Study Used to Set the Level

In cases in which an AEGL value is derived from a multiple exposure

study, because the data set for a single exposure is lacking, the multiple exposure data are considered an inherently conservative estimate. This conclusion

is based on the observation that a biologic organism often demonstrates greater

tolerance to a single exposure compared with multiple exposures at the same

or similar levels to the same chemical. If the adverse effect identified in the

multiple exposure study is cumulative for the AEGL of concern, the

interspecies UF used to adjust the multiple exposure animal data may be reduced. Careful judgment should be used when making this assessment. If a

chemical is cleared very rapidly, or if there is evidence of short-term adaptation, or if there is evidence that the concentration causing the effect does not

vary with duration or number of exposures, then the animal may be able to

sustain repeated insult at a level close to a single acutely toxic exposure. In

those instances, the reduction of the UF based on multiple exposures versus a

single exposure may not be justified.

The rationale for the selection of a UF should include the following:

1. A description of the study.

2. Discussion of the empirical clearance rate and other toxicokinetic

properties of the chemical. For example, does the concentration causing the effect vary significantly with duration or number of

exposures?

2.5.3.2.10 Selection of the NOAEL

The highest NOAEL is generally selected in instances in which acceptable

direct or supporting data exist. In such cases, a UF of 3 or 10 is used, depending on the available data. Although UFs are typically applied, in certain cases,

multiple species have similar NOAELs, the NOAEL selected is substantially

below the NOAELs reported for other species, or there is a high degree of

confidence that the animal model tested is a sensitive surrogate for humans or

is more sensitive than humans. In such cases, a UF of 1 might be used. In all

cases, the NOAEL represents the highest exposure level from animal data in

which the effects used to define a given AEGL tier are not observed.
76 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.3.3 Intraspecies UFs Used in the Development of AEGL Values—

Discussion

Intraspecies UFs are used to address the variability in biologic response

that exists within a human population exposed to a toxic agent. Their use

represents an important step in the AEGL development methodology and is

designed to account for the differences that can occur within the general population.

The NRC guidelines for developing community emergency exposure

levels (CEELs) state that the exposure levels are “designed to protect almost

all people in the general population. . . .” (NRC 1993a ). The NRC guidelines

state that although the levels “are designed to protect 'susceptible' individuals,

some hyper-susceptible individuals might not be protected. . . .” That distinction is based on the premise that CEELs must be set low enough to protect the

general population but must also be set at levels that minimize the public

health and safety risks associated with response to chemicals as a result of rare

or exceptional circumstances. Consequently, the AEGL values may not be

expected to necessarily protect certain individuals with unique or idiosyncratic

susceptibilities. This consideration is clearly communicated in the NAC/AEGL

Committee’s definition of the AEGLs.

When data are insufficient to determine the relative susceptibility of individuals in a human population exposed to a specific chemical, a default UF of

10 has been used by EPA, ATSDR, Health Canada, IPCS, and RIVM when

developing the equivalent reference doses for chronic exposure to chemicals

(Dourson et al. 1996). This value of 10 is generally applied to the NOAEL.

A number of studies have tried to address the issue of the reasonableness or

validity of this UF. Under ideal circumstances, an analysis would provide

information on the ratios of the experimentally observed NOAELs for different

human groups within a population for a wide range of defined exposures to

chemicals. Groups would be identified on the basis of biochemical or physiologic differences that might cause members of the group to respond to chemical exposure in a fundamentally different manner—either quantitatively or

qualitatively. Sample sizes would be large and include a wide variety of genetic backgrounds. Such examples would include differences among newborns, infants, children, adults, the elderly, the infirm, and those compromised

by illness, including those with asthma. The NOAELs also would represent

a distinct relationship between dose level and response. These data would

encompass all variables due to the toxicokinetics and toxicodynamics factors.

Such data are not available, even in carefully controlled, double-blind clinical

trials for new therapeutic drugs. However, surrogates have been developed
DERIVATION OF AEGL VALUES 77 

that provide information on the reasonableness of the choice of the intraspecies

UF of 10 or less. This approach is referred to as the use of data-derived UFs.

Dourson and Stara (1983) analyzed the slopes of LD50 gavage studies in

490 adult rats reported by Weil (1972). They calculated the intraspecies adjustment factor required to reduce the dose 3 standard deviations below the median LD50 response using a probit, log-dose analysis. This gives a z value of

0.4987 from the mean or a calculated response of 1.3/1,000 (Spiegel 1996).

This value was used to predict the response of a susceptible subgroup in the

population. An adjustment factor of 10 was adequate to reduce the response

from a dose killing 50% of the animal population to a level that would kill

only the most susceptible members of the inbred rat population in 92% of the

chemicals studied. These data support the contention that a 10-fold UF is

adequate in many instances to account for intraspecies differences in response

to acute exposures. However, in some instances this UF may not protect the

more susceptible members of the population. The extrapolation reported here

represents a measure of 3 standard deviations from the median response data

points. Statistically, an extrapolation of 3 standard deviations from the mean

includes more than 99% of the population in question, or approximately 999

individuals out of a population of 1,000. The extrapolation of 3 standard deviations as performed by Dourson and Stara (1983) includes a similar proportion

of the population in question, 998.7 of 1,000. It is interesting to note that the

Fowles et al. (1999) analyses of inhalation toxicity experiments revealed that

for many chemicals the ratio between the LC50 and the experimentally observed nonlethal level was on average a factor of approximately 2, the 90th

percentile was 2.9, and the 95th percentile was 3.5. There was a range of

ratios from 1.1 to 6.5. Therefore, the use of a UF of 3 with a NOAEL for

lethality can achieve the same reduction in acute lethality as that reported by

Dourson and Stara (1983). The 490 LD50 studies with rats were undoubtedly

based on a wide range of chemical substances exhibiting many different

toxicologic mechanisms. Hence, the variability due to chemical-specific

properties was included in this evaluation and was accounted for by an adjustment factor of 10 in 92% of the chemicals tested. This type of statistical analysis makes the untested hypothesis that the slope of the dose response was the

same in the experimental dose range and at the untested tails of the experiment. It also reflects the response in a homogeneous (inbred) adult animal

population and does not measure the difference in values between potentially

susceptible subgroups, such as adult vs newborn.

A number of authors have presented data and analyzed adult/newborn

LD50 ratios to assess the differential susceptibility of young and adult animals.

Done (1964, as cited in NRC 1993b) compiled LD50 ratios between immature
78 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

and mature animals. For 34 of 58 chemicals, Done found that the immature

animals were more susceptible than the adults, and for 24 of 58 chemicals, the

adults were more susceptible than the immature animals (NRC 1993b). A

similar compilation of newborn/neonate and adult LD50 ratios for rat and

mouse was done by Goldenthal (1971) on data submitted to FDA in drug

applications. This compilation included a broad range of chemicals, such as

analgesics, bronchodilators, central-nervous-system depressants and stimulants, antidepressants, and tranquilizers. NRC (1993b) analyzed these data and

found that about 225 of the compounds were more toxic to neonates and

45were more toxic to adults. Almost all of the age-related differences from the

Done (1964, as cited in NRC 1993b) and Goldenthal (1971) data collections

were within a factor of 10 of each other, and most of the ratios were within a

factor of 3 (NRC 1993b). Sheenan and Gaylor (1990) analyzed adult/newborn

LD50 ratios for 238 chemicals. The median ratio of the LD50 values between

age groups was 2.6. Approximately 86% of the ratios were less than 10, indicating that this factor is adequate to account for differences in response to

chemical exposure between adult and young in most cases but may be insufficient for 14% of the cases. In these studies, the comparison was made from

the median response.

Another indirect approach to quantify biologic uncertainty is to measure

the observed variability in human populations. Calabrese (1985) examined a

number of parameters related to toxicokinetics (metabolism, binding of chemicals to protein and DNA, and activity levels of enzymes). In studies that included between 10 and 349 subjects, Calabrese concluded that generally 75-

95% of the population fell within a range of 10-fold. However, the author’s

conclusion was based on the supposition that the 10-fold factor was to account

for the total range of human variability as opposed to the range from an experimental no-observed-effect level to the most susceptible person. In a similar

study, Hattis et al. (1987) evaluated toxicokinetic parameters in 101 data sets

(five or more healthy adults) on 49 chemicals (primarily drugs). They found

that 96% of the variation was within a factor of 10. However, this analysis

also measured the total range of human variability. These analyses measured

the range of responses for toxicokinetic parameters and give some indication

of the variability in an adult population only and not in a potentially susceptible subpopulation. They do not measure how far the tail for response goes

beyond the lowest dose in the population measured, nor the response of different populations. Another consideration is the fact that these data represent

measures of toxicokinetic variables that may not directly reflect the threshold

of toxicologic response to chemical exposure.
DERIVATION OF AEGL VALUES 79 

Ideally, one would like to be able to compare NOAELs observed in an

experiment with the tail of the NOAEL distribution to assess the actual frequency of response in the total human population when the intraspecies UF of

10 is applied and obtain a measure of the susceptible person. Determining the

experimental NOAEL is fraught with problems of sample size and dose selection. The response of the susceptible subpopulation at a dose 10-fold lower

than the experimental NOAEL will never be known. Hattis et al. (1999) performed statistical modeling analyses designed to determine the efficacy of

applying the intraspecies UF of 10 to a NOAEL. The authors statistically

analyzed clinical studies on humans that measured parameters related to

toxicokinetics and toxicodynamics. The studies had at least five subjects each

and included approximately 2,700 data points for the toxicokinetic endpoints.

They demonstrated that the population distribution of the data were lognormal

in the data region and assumed that they were lognormally distributed out to

the extreme tails. From the data, and assuming a lognormal distribution, they

calculated the dose required to produce an incidence in 5% of the population.

This is essentially an experimental NOAEL that is divided by the intraspecies

UF when a risk assessment is performed. The dose at the 5% incidence level

was divided by 10 and the response at that dose calculated, assuming a lognormal distribution of data, to the extreme tails. This approach was used to assess

the response rate when a 10-fold UF is applied to a NOAEL. They found that

“acting by itself, a 10-fold reduction in dose from a 5% effect level could be

associated with effect incidences ranging from slightly less than one in ten

thousand for a median chemical/response to a few per thousand for chemicals

and responses that have more human interindividual variability than 19 out of

20 typical chemicals/responses.” The analysis did not include susceptible subpopulations, so the variability seen could be greater. This type of analysis

assumes a lognormal distribution of the data to the extreme tails. It does not

allow for a threshold that is generally assumed to be true for noncancer effects.

Thus, the calculated response at doses 10-fold less than the 5% response level

may be overly conservative. There are no data, human or animal, that far out

in the tail of the distribution curve. The analysis by Hattis et al. (1999) indicates that a human intraspecies UF of 10 would be protective of susceptible

subpopulations and may be overly conservative in many instances.

Another approach to measuring variability among different groups of a

human population is to compare maximum tolerated doses (MTDs) or effect

levels between groups. Reports comparing the MTDs of chemotherapeutic

agents in child and adult cancer patients indicate that most of the substances

studied were tolerated as well and, in many instances, tolerated better by chil-
80 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

dren than by adults when the dose was expressed as milligrams per kilogram

of body weight or milligrams per square meter (Glaubiger et. al. 1982;

Marsoni, et. al. 1985). In those instances in which children demonstrate a

greater response at equivalent dose to these substances, the differences were

less than a factor of 2-fold. Although MTDs are not entirely a precise measure

of a toxicologic threshold, they represent a credible parameter by which relative toxicities between groups can be measured in humans. It is important to

acknowledge that although the substances studied represent a diverse group of

chemical classes, these substances exhibit similar mechanisms of cytotoxicity.

Therefore, the results observed cannot be applied to a large number of other

chemicals with different mechanisms of action. In addition, only MTDs were

reported, not the variability within each group in response to the drugs. Thus,

this type of study gives a measure of response among groups within a population but not the variability within each group.

Other studies regarding differences in susceptibilities among specific

groups in humans to various anaesthetic gases have been reported. These

studies indicate children, particularly infants, are more resistant than adults to

the effects of various volatile anesthetics (Gregory, et. al. 1969; Stevens, et al.

1975; Lerman et. al. 1983; LeDez and Lerman 1987; Katoh and Ikeda 1992;

Chan et al. 1996). The susceptibility of individuals of different ages has been

extensively studied in the anesthesia literature in which the concentrations of

various anesthetic gases in the lung, producing “anesthesia” (i.e., lack of

movement), have been measured. The results are usually reported as the minimum alveolar concentration (MAC) that produces lack of movement in 50%

of persons exposed to that concentration. Occasionally, the ED95 (the alveolar

concentration that prevents movement in 95% of those exposed) is also reported. MACs for several anesthetic gases have been measured as a function

of age. The results consistently show a pattern with maximal susceptibility

(lowest MAC values) in newborns, particularly prematures, pregnant women,

and the elderly. The least susceptibility (highest MAC values) occurs in older

infants, toddlers, and children as compared with adults. The total range of

susceptibility was 2- to 3-fold. Many organic solvents for which AEGLs are

developed can also produce anaesthesia in humans at high doses. As previously stated, this type of study gives a measure of response between groups

within a population but not the variability within each group.

Intraspecies UFs are used to address the variability in biologic response

that exists within a human population exposed to a toxic agent. Their use is

designed to account for the range of responses to exposure by individuals

within the general population. As the studies above demonstrate, a UF of 10
DERIVATION OF AEGL VALUES 81 

is adequate to account for variability in the majority of cases and a factor of 2-

3 is often adequate.

It has been proposed that data on the differences in kinetics and dynamics

be used to modify the UFs from defaults of 10 (Renwick 1993; Dourson et al.

1996). Renwick (1993) proposed dividing interspecies and intraspecies UFs

into two components. Toxicity is considered to be the combined function of

toxicokinetics (all processes contributing to the concentration and duration of

exposure of the active chemical toxicant at the target tissue) and toxicodynamics (mode or mechanism of action of the active toxicant at the target tissue

site). If data are available on the differences between or within species on one

or both of these two processes, then it should be possible to reduce the total UF

by developing a data-derived UF. This approach has in fact been taken by

EPA in the examples below. EPA (1996b) reduced the UF of 10 to 3, because

data from specific susceptible subpopulations were unavailable.

In the case of methylmercury, toxicodynamic data were used to reduce the

intraspecies UF to 3 (EPA 1995b). The RfD was based on a benchmark dose

computed as the lower 95% confidence limit on the 10% increase over the

background for human childhood neurologic abnormalities (this level has been

used to represent the NOAEL) in the susceptible subpopulation (the developing fetus). Therefore, the default intraspecies UF of 10 was reduced to 3.

Since the susceptible subpopulation had been identified, the toxicodynamic

part of the UF had been addressed. However, variability due to toxicokinetics

was maintained with the use of the 3-fold UF.

For styrene, the default intraspecies UF of 10 was reduced to 3 in the

calculation of the RfC value, because the lower 95% limit of the exposure

extrapolation for a NOAEL in a human cross-sectional study was used and the

biologic exposure index had been shown to account for variation in pharmacokinetic and physiologic measures, such as the alveolar ventilation rate (EPA

1993).

In the absence of information to justify data-derived UFs, a UF of 10 is

considered to account for intraspecies variability in most cases. When information is available about the response of a susceptible subpopulation (e.g.,

mechanism of action in different species and/or subgroups within an exposed

population, toxicokinetic data, or toxicodynamic data), those data are factored

into the development of a data-derived UF, which may vary between 10 and

1. All information on the chemical, its mechanism of action, structurally related chemical analogues, a discussion of the weight of evidence, and informed

professional judgment are used when determining UFs.
82 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.3.3.1 Range of Susceptibility

The definition and intended application of AEGL values make distinctions

between susceptible and “hypersusceptible” individuals. It is important to

characterize these two terms and the potential subpopulations they may represent for purposes of UF selection. It is also important to distinguish between

these two populations for purposes of risk communication to emergency planners, emergency responders, and the public.

Individual susceptibility within a population will vary according to individual determinants and the specific properties of a given chemical. The origins of susceptibility are multifactorial and distributed across populations.

According to the U.S. Presidential/Congressional Commission of Risk Assessment and Risk Management, “Genetic, nutritional, metabolic, and other

differences make some segments of a population more susceptible than

others . . . susceptibility is influenced by many factors” (PCCRARM 1997).

The factors are based on intrinsic and acquired differences among individuals

and may include age, gender, genetic factors, ethnicity and race, and quality

of life and life-style considerations. The latter considerations may be further

classified as pre-existing illnesses, prior exposures, nutritional status, personal

behavior (e.g., occupation, smoking, alcohol use, and obesity), and socioeconomic factors. The NRC also characterizes such determinants: “[S]ome of the

individual determinants of susceptibility are distributed bimodally . . . other

determinants seem to be distributed more or less continuously and unimodally”

(NRC 1994).

Hypersusceptibility describes extreme examples of responses. It may represent biologic reactions that are unique, idiosyncratic, and stem from determinants that are generally discontinuous with, and lay outside of, the range of

distributions expected for the general population.

The determination of susceptibility entails the presence of observable

changes in biochemical or physiologic processes reflecting dose-response

relationships unique to a chemical (e.g., sulfur dioxide) or class of chemicals

(e.g., acid aerosols). Susceptibility and hypersusceptibility are not meaningful

concepts outside of the context of specific exposures. "Dose-response relationships are chemical-specific and depend on modes of action; people are not

hypersusceptible to all kinds of exposures" (PCCRARM 1997).

Susceptibility and hypersusceptibility may reflect transient rather than

permanent states. For example, infants are susceptible to some chemicals (e.g.,

ingested nitrates and nitrites as a result of relatively high gastric pH), but lose

that susceptibility as they mature. Susceptible populations may also experi-
DERIVATION OF AEGL VALUES 83 

ence transient periods of hypersusceptibility. For example, asthmatics represent 5-10% of the general population and can be more susceptible than

nonasthmatics to challenge by respiratory irritants. Moreover, at any given

time some asthmatics may be suffering acute asthmatic attacks, which might

lead to a hypersusceptible condition, just prior to an irritant exposure. Because

of the transient condition, these individuals might not be accounted for in the

published AEGL values. Similarly, otherwise normal individuals may suffer

transient periods of hypersusceptibility during periods of illness. For example,

following very severe, acute respiratory infections, many nonasthmatic individuals will experience several weeks or more of bronchiolar hyperreactivity

and bronchospasm following nonspecific exposure to respiratory irritants.

This condition can be considered an example of transient hypersusceptibility.

In general, since there is little or no information regarding the responses of

transiently hypersusceptible individuals to chemical exposures, the corresponding AEGL values might not be protective for this group.

During the past 15 years, a wide range of symptoms and complaints in

patients thought to be related to extreme sensitivity to low levels of diverse

and often nonquantifiable chemical exposures have been reported. This syndrome has been referred to as “multiple chemical sensitivity” or MCS (Cullen

1987). MCS has been characterized as the heightened, extraordinary, or unusual response of individuals to known or unknown exposures whose symptoms do not completely resolve post-exposure or whose sensitivities seem to

spread to other chemicals (Ashford 1999). The syndrome is thought by Ashford to be a two-step process with an initial acute exposure to high concentrations of a substance and the subsequent triggering of symptoms at extraordinarily low levels of exposure to the same substance or different substances.

He believes that repeated or continuous lower level exposures may also lead

to the same type of sensitization. Ashford and Miller (1998) also postulate that

this sensitivity may be the consequence of a variety of disease processes resulting from “toxicant-induced loss of tolerance”—described as “a new theory of

disease providing a phenomenologic description of those disease processes.”

In response to the increasing public demand for governmental attention to

a problem frequently identified as MCS, the Environmental Health Policy

Committee (EHPC) of the U.S. Public Health Service (PHS) formed the Interagency Workgroup on MCS in 1995 to address this issue (Mitchell 1995). The

workgroup’s charge was to review the scientific literature on MCS, consider

the recommendations from various expert panels on MCS, review current and

past federal actions, and make recommendations to policy-makers and researchers at government agencies concerned with evaluating public-health
84 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

issues that might relate to MCS-like syndromes. The workgroup comprised

scientists from the U.S. federal agencies, including, ATSDR, DOD, DOE,

Department of Veterans Affairs, National Center for Environmental Health,

Centers for Disease Control and Prevention, National Institute of Environmental Health Sciences, National Institutes of Health, and EPA. The original draft

report was peer reviewed by 12 independent experts in occupational and/or

environmental medicine, toxicology, immunology, psychology, psychiatry,

and physiology. A Predecisional Draft Report was issued for public comment

on August 24, 1998 (Interagency Workgroup on Multiple Chemical Sensitivity

1998). Although a final report has not yet been issued, the draft report concluded that MCS remains a poorly defined problem. The experts disagree on

possible causes (e.g., physical or mental), and the sufferers complain of a wide

range of symptoms (not associated with any “end-organ” damage) that may

result from a disruption of homeostasis by environmental stressors.

In addition to the EHPC Interagency Workgroup on MCS, the NRC (NRC

1992b,c), professional organizations (ACOEM (see McLellan et al. 1999);

AAAI 1986; AAAAI 1999), and others (Kreutzer et al. 1999; Kipen and

Fiedler 1999; Graveling et al. 1999) have attempted to address this issue.

Despite these attempts, the diagnosis, treatment, and etiologic assessment of

MCS has remained a troublesome medical and social concern for individuals,

physicians, government, and private organizations (McLellan et al. 1999). No

consensus has yet been reached for a case definition (Mitchell 1995; McLellan

et al. 1999); Graveling et al. 1999), diagnostic methods (Mitchell 1995;

AAAAI 1999; McLellan et al. 1999), or treatment (AAAAI 1999). Further,

despite extensive literature on the existence of MCS, “there is no unequivocal

epidemiologic evidence; quantitative exposure data are lacking; and qualitative

exposure data are patchy” (Graveling et al. 1999). Although most researchers

contend that symptoms characteristic of chemical sensitivities exist, they agree

that symptoms may be exaggerated and may be “differentially precipitated by

psychosocial events or stress, or by different physical or chemical exposures”

(Ashford 1999). All researchers and clinicians familiar with the problem agree

more work must be done to understand the unexplained symptoms that are

attributed to MCS (Kipen and Fiedler 1999). 

The American College of Occupational and Environmental Medicine

(ACOEM), the American Academy of Allergy, Asthmatics, and Immunology

(AAAAI) and the International Programme on Chemical Safety (IPCS) have

all recommended that the term “idiopathic environmental intolerance” be used

to replace the term MCS (McLellan et al. 1999; IPCS 1996; AAAAI 1999).

These authors believe that the term MCS incorrectly implies that the condition

affects the immune system and that chemical exposure is its sine qua non

(McLellan et al. 1999). No immunologic dysfunction has been identified in
DERIVATION OF AEGL VALUES 85 

these patients (Graveling et al. 1999; AAAAI 1999). Further, they concur with

other prominent medical organizations in maintaining that evidence does not

exist to define MCS as a distinct clinical entity (McLellan et al. 1999).

While some clinicians hold that MCS occurs as a result of environmental

exposures, mechanism(s) by which that may take place have not been proven

scientifically. No single widely accepted test of physiologic function can be

shown to correlate with observed symptoms (Interagency Workgroup on Multiple Chemical Sensitivity 1998; Brown-DeGagne and McGlone 1999; AAAAI

1999; McLellan et al. 1999). Immunologic, allergic, neuropsychologic, and

traditional psychiatric disorders have all been postulated to cause MCS, but to

date, they have not been supported by well-designed studies (Interagency

Workgroup on Multiple Chemical Sensitivity 1998; McLellan et al. 1999;

Brown-DeGagne and McGlone 1999).

As a result of the considerations presented here, it is not believed that

MCS represents a viable scientific basis for developing AEGL values, including further adjustments for susceptible subpopulations, at the present time.

However, the NAC/AEGL Committee recognizes the need for scientific research on this proposed syndrome that may help explain and describe its features, enable scientifically valid approaches to hazard or risk assessment, and

define appropriate clinical interventions. Also, the committee considers all

new data or information that is scientifically credible and relevant to the development of AEGL values.

2.5.3.3.2 Selection of Intraspecies UFs

 To meet the AEGL definitions that protect susceptible subpopulations but

not necessarily hypersusceptible subpopulations, the NAC/AEGL Committee

evaluates two separate considerations regarding susceptibility. First, evidence

is reviewed to attempt to distinguish “susceptible” from “hypersusceptible”

subpopulations for each chemical of concern. Second, estimation of the range

of response variability is carried out in the general population that includes

susceptible (but not necessarily hypersusceptible) subpopulations and selection

of appropriate intraspecies UFs for development of the AEGL values.

2.5.3.3.3 Distinguishing Susceptible and Hypersusceptible

Subpopulations

A clear distinction between susceptible and hypersusceptible subpopulations in all cases for all chemicals is not achievable with the clinical and

toxicologic information available to date. However, the NAC/AEGL Committee has identified specific categories and subpopulations that may be consid-
86 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

ered susceptible and part of the general population that the AEGL values are

intended to protect. These categories include children and infants, the elderly,

asthmatics, pregnant women and the fetus, and individuals with pre-existing

illnesses, diseases or metabolic disorders who would not ordinarily be considered in a severe or critical medical condition. Examples of susceptible subpopulations based on pre-existing illnesses include those with compromised pulmonary function (e.g., pneumoconiosis, emphysema, respiratory infections,

smoking, immunologic sensitization due to prior exposures, and cystic fibrosis), hepatic function (e.g., alcoholism, hepatitis, and prior chemical exposures), cardiac function (e.g., dysrhythmias and coronary heart disease), and

impaired renal or immunologic function (e.g., AIDS and systemic lupus

erythematosus) 

Hypersusceptible subpopulations are considered to comprise those individuals whose reactions to chemical exposure are unique and idiosyncratic; lie

outside the range of distributions expected for the general population, including susceptible subpopulations; and constitute a relatively small component of

the general population. For example, the AEGLs are intended to be protective

of individuals with mild-to-moderate asthma but are not necessarily protective

of those with severe asthma. Additionally, there are some asthmatics who, at

any given time, could be suffering coincidentally acute asthmatic episodes at

the time of a chemical emergency. Such subpopulations may be considered to

comprise transient hypersusceptible individuals and would not necessarily be

protected by the AEGLs. Examples of hypersusceptible subpopulations might

include those with severely debilitating pulmonary, hepatic, or renal disorders

or diseases, the elderly with serious debilities of primary physiologic systems,

and those individuals with unique hypersensitivies (i.e., severe immune-type

responses) to specific chemicals (e.g., 4,4N-methylene bis(2-chloroaniline);

MOCA) or chemical classes (e.g., isocyanates). It is acknowledged that the

AEGL values might not be protective under such circumstances.

Certain otherwise healthy individuals in the general population also may

suffer transient periods of hypersusceptibility as a result of severe (reversible)

short-term illnesses. For example, during recovery from a severe episode of

acute upper respiratory infection, many nonasthmatic individuals can experience several weeks or more of bronchiolar hyperreactivity and bronchospasm

following nonspecific exposure to respiratory irritants. This reversible condition is considered an example of transient hypersusceptibility, and it is acknowledged that the AEGL values may not be protective of individuals in such

circumstances. 

The nature of the dose-response relationships for immune-type responses

among sensitive and hypersensitive individuals is highly complex and not

well-understood. Additionally, in almost all instances, there is no clear line of
DERIVATION OF AEGL VALUES 87 

demarcation that distinguishes susceptible from hypersusceptible individuals

with respect to chemical responses that are not immune mediated, and there is

no generic or medical guidance that can be followed for a wide range of chemical exposures. However, since most biologic responses are chemical-specific

and are dependent on the mode of action of the substance in question, the issue

of identifying and protecting groups of susceptible subpopulations is addressed

by the NAC/AEGL Committee on a chemical-by-chemical basis. The committee uses all available data on the properties of the chemical and their relationship to both normal and compromised biochemical, physiologic, and anatomical systems in humans to identify and protect susceptible subpopulations. In

the absence of data on the chemical in question, the use of structurally related

chemicals and scientific judgment may be used to select UFs that provide

protection for the public health.

2.5.3.3.4 Estimating the Range of Variability in a Human Population

 The NAC/AEGL Committee estimates the range in variability of response

to specific chemical exposures primarily on the basis of quantitative human

data. Acceptable experimental data are more likely to be available for

AEGL-1 and AEGL-2 endpoints than for AEGL-3 endpoints. For example,

numerous studies have considered induction of bronchospasm after controlled

exposures to sulfur dioxide (SO2) in asthmatic and nonasthmatic individuals

(see references below). There is marked individual variability in the severity

of reaction to inhalation of low concentrations of SO2. Asthmatics, individuals

with hyper-reactive airways, smokers, and those with chronic respiratory or

cardiac disease respond at relatively lower concentrations (Aleksieva 1983;

Simon 1986). Susceptibility may also be increased in people over 60 years of

age, but reports have not been consistent (Rondinelli et al. 1987; Koenig et al.

1993). By contrast, comparable human data for AEGL-3 tier concentrations

are limited to anecdotal case reports.

Deliberations on phosphine AEGL development identified the possibility

that children are more susceptible to phosphine exposure. This condition was

suggested by two case reports describing the deaths of children, but not adults,

after “comparable” phosphine exposures. However, both the children and the

adults in question were present in somewhat restricted environments, suggesting comparable exposure levels. Based on these case reports, the NAC/AEGL

Committee concluded that children may be more susceptible to phosphine

exposure and selected UFs that would provide additional protection for children.

In cases in which quantitative human data are lacking for specific chemicals, but adequate data can be found for structurally or mechanistically similar
88 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

agents, UFs may be selected by analogy to structurally similar chemicals

and/or mechanism of action. For example, asthmatics are particularly susceptible to SO2. Declines of more than 20% in FEV1 have been documented after

inhalation of 0.4-1 ppm for 2-15 min. The effects of SO2 exposure are enhanced in normal and asthmatic individuals by moderate exertion (ventilation

>40 liters per minute with mouth breathing), hyperventilation, and use of oral

airways (Frank 1980; Koenig et al. 1981, 1982; Roger et al. 1985; Balmes et

al. 1987; Linn et al. 1987; Horstman et al. 1988). Duration of bronchospasm

is generally short, and these patients may develop tolerance with prolonged or

repeated SO2 exposure. These studies suggest that mouth-breathing asthmatics

exposed to SO2 develop bronchospasm at levels of approximately 33% of

comparably exposed nonasthmatics. However, Schlesinger and Jaspers (1997)

reported approximately 10-fold difference in susceptibility to SO2.

Schlesinger (1999) also reported 5-fold difference in susceptibility for nitrogen

oxide (NO2). Therefore, a default UF of 10 is generally used to account for the

differences in the potential broad range of human susceptibility to respiratory

irritants. The NAC/AEGL Committee is aware that the variation in responses

of asthmatics to respiratory irritants may range from mild to severe. A UF of

less than 10 might be used when scientific evidence shows that a smaller UF

will be protective of health.

Children and infants are often considered to be a susceptible subpopulation. There is a general belief that children and infants are more susceptible

to the effects of toxic substances than adults. Much of this belief is predicated

upon the fact that children and particularly infants possess immature or developing biochemical, physiologic, and anatomical systems that are not adequate

to combat the adverse affects of toxic chemicals. Further, it is believed that in

certain instances the toxic effects of chemicals may permanently damage or

alter the growth and function of developing organs and organ system. The

potential for greater susceptibility to chemical substances by children and

infants has been reviewed by the NRC (1993b). The report indicates that there

are limited data on the relative toxicity of pesticides and other xenobiotic

compounds in immature and mature humans. Consequently, the NRC (1993b)

focused on laboratory animal studies, age-related pharmacokinetic and

pharmacodynamic differences, and pharmacologic data from controlled clinical investigations with humans. The NRC (1993b) concluded that the mode

of action is generally similar in mammalian species and across age and developmental stages within species. The NRC also concluded that children may

be more or less susceptible than adults to pesticide toxicity, depending on the

chemical, but that the quantitative differences in toxicity between the age

groups are usually less than a factor of approximately 10.
DERIVATION OF AEGL VALUES 89 

Although many reports have been published on the pharmacokinetic differences of pharmacologic agents and other chemicals in children and adults,

the data cannot be translated into meaningful dose-response relationships to

make valid quantitative comparisons in the absence of specific biologically

relevant endpoints. Bruckner and Weil (1999) summarized the biologic factors that may influence the responses of adolescents to chemical exposure.

Based on the limited data available, the extent to which significant differences

exist in the susceptibility of children and infants and of adults is largely unknown. However, the difference is generally considered to be within a factor

of 10 (NRC 1993b), most of the differences in susceptibility being on the order

of 2- to 3-fold. It is highly probable that any differences are chemical-specific

and also related to specific developmental stages of children and infants.

Within the context of the AEGL program, this issue is further complicated by

the consideration of once-in-a-lifetime inhalation exposures of less than 1-8

h. The discussion at the beginning of this section indicates that there is a

paucity of data on age-related differences and the young can be more or less

susceptible than adults to xenobiotic exposures, depending upon the chemical

or chemical class in question. However, it is believed that UFs applicable to

other susceptible subpopulations are adequate to protect children and infants

when decisions are based on the weight of the evidence on a chemical-specific

basis. It is important that all of the relevant information on the chemical be

considered when making judgments about selection of the appropriate UF for

all factors that contribute to differences in susceptibility.

In summary, the maximum variation in responses of susceptible subpopulations are believed to generally range between 3- and 10-fold of the responses

for healthy individuals. All information on the chemical, including its mechanism of action, the biologic responses, physical and chemical properties, data

on structurally related chemical analogues, and toxic endpoints in question, is

considered and informed professional judgment is used when determining

appropriate UFs. Information about similarities and differences in toxicokinetics and toxicodynamics is used when available to modify the UF used.

Therefore, in the absence of the type of information described above, a default

UF of 10 is used in the development of AEGLs to account for susceptible human subpopulations. If such data or information are available, the NAC/AEGL

Committee may conclude that a UF of 3 or 1 will provide adequate protection.

The final selection of UFs is based on a weight-of-evidence decision that

considers the chemical's mechanism of action, the available human and animal

data, and the susceptible subpopulations that may be at risk.
90 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.3.4 Intraspecies UFs—NAC/AEGL Guidelines

Guidelines followed by the NAC/AEGL Committee to select UFs are

presented below. In each section, there is a list of questions that should be

addressed to support the rationale for the choice of the UF used. The guidelines are organized into categories for convenience. However, more than one

guideline may be applied to the selection of any one UF.

In general, in the absence of data or information to the contrary, the default

value for the intraspecies UF is 10. However, a UF of 3, or even 1, may be

used if credible information or data are available. The UF is determined on a

case-by-case basis and may be dependent on the information or data available

on humans or animals; the specific biologic, mechanistic, and physical and

chemical properties of the chemical; and the health-effect endpoint in question.

The following cases provide general guidance for the most common circumstances encountered by the NAC/AEGL Committee in selecting UFs.

2.5.3.4.1 Toxic Effect Is Less Severe Than Defined for the AEGL Tier

If the toxicologic effects described in the chosen database are judged to be

somewhat less severe than those defined for the AEGL tier in question, an

intraspecies UF less than 10-fold may be used.

The rationale for the selection of this UF should include the following:

1. Description of the toxicologic endpoint of concern selected and how

it relates to the AEGL severity tier in question.

2. Comment on the slope of the dose-response relationship if possible

and explain how this impacts the UF.

2.5.3.4.2 Susceptible Individuals Used

If individuals representative of a susceptible subpopulation are used as

subjects in controlled humans studies, and the AEGL is to be calculated based

on effects observed in those individuals, an intraspecies UF of less than 10-

fold may be used.

The rationale for the selection of this UF should include the following:

1. Description of the condition that made the individual susceptible.
DERIVATION OF AEGL VALUES 91 

2. Description of the adverse effects assessed.

3. Discussion of the range of response of the humans tested.

4. Description of the differences or similarities in the responses of susceptible individuals qualitatively and quantitatively as compared with

nonsusceptible individuals.

2.5.3.4.3 Age, Life Stage, and Physical Condition Differences

When available data indicate that certain groups based on age, life stage,

or physical condition may be uniquely susceptible in contrast to the general

population, an intraspecies UF of 10 is generally used.

The rationale for the selection of this UF should include the following:

1. Description of the toxicologic endpoints that differ between humans

of different age groups.

2. Discussion of the magnitude of a difference. For example, quantitatively, how much does the response differ, or what qualitative information indicates differences among age groups?

2.5.3.4.4 Response of Normal and Susceptible Individuals to Chemical

Exposure is Unlikely to Differ for Mechanistic Reasons

In those cases in which the mode or mechanism of action is such that the

response elicited by exposure to the chemical by different subpopulations is

unlikely to differ, an intraspecies UF of 3-fold is generally used. Typically,

this response involves a direct-acting mechanism of toxicity in which metabolic or physiologic differences are unlikely to play a major role. A steep

dose-response curve may also be an indication of little variation within a population and is factored into the weight-of-evidence considerations for UF determination.

The rationale for the selection of this UF should include the following:

1. Description of the mode of action.

2. Discussion of why the response to chemical exposure is unlikely to

differ between healthy and susceptible individuals and whether metabolic or physiologic differences are likely to be an issue.
92 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.5.3.4.5 Mode or Mechanism of Action Is Unknown

When the mode or mechanism of toxic action is uncertain, or unknown,

or metabolic factors may play an important role, and/or when a broad range of

responses to chemical exposure is observed, there is concern that there may be

large differences in susceptibility between individuals. In those cases, an

intraspecies UF of 10 may be applied.

The rationale for the selection of this UF should include the following:

1. Description of the toxicity reported and the uncertainty associated

with the chemical’s mechanism of action or other factors.

2. Statement on why the effects seen add uncertainty to the assessment.

2.5.3.4.6 UFs That Result in AEGL Values That Conflict with Actual

Human Exposure Data

When AEGL values are initially derived, the candidate range of values is

compared with the known spectrum of supporting data on the chemical. In a

weight-of-the-evidence approach, conflicts between the candidate AEGLs

(generally derived from animal data) and the supporting data (either animal

data or human data) may lead to the conclusion that the UFs utilized in the

calculations are inappropriate, because they conflict with other specific and

highly relevant human data. In that case, the candidate AEGLs are revised to

reflect the supporting data. In other cases in which the AEGL may conflict

with an existing standard or guideline, the comparative basis of the two values

may be evaluated to see if the discrepancy is justified or resolvable.

The rationale for the selection of this UF should include the following:

1. A statement on why the use of UFs initially selected conflicts with the

published evidence.

2.6 GUIDELINES AND CRITERIA FOR SELECTION

OF MODIFYING FACTORS

2.6.1 Definition

In addition to the UFs discussed above, an additional modifying factor
DERIVATION OF AEGL VALUES 93 

may be necessary when an incomplete database exists. Hence, the modifying

factors represent an adjustment for uncertainties in the overall database or for

known differences in toxicity among structurally similar chemicals. The modifying factor “reflects professional judgment on the entire data base available

for the specific agent” and is applied on a case-by-case basis (NRC 1993a, p.

88). The modifying factor may range from 1- to 10-fold. The default value is

1.

2.6.2 Use of Modifying Factors to Date in the

Preparation of AEGL Values

Modifying factors have been used in AEGL documents for four chemicals

recently published by the NRC (2000b). Modifying factors of 2 or 3 are under

consideration for chemicals currently undergoing review to account for (1) a

limited data set, (2) instances in which the adverse effects used to set the

AEGL value are more severe than those described in the AEGL definition, and

(3) the differential toxicity of chemical isomers.

2.7 GUIDELINES AND CRITERIA FOR TIME SCALING

AEGLs are derived for 30-min, 1-h, 4-h, and 8-h exposure durations to

meet a wide range of needs for government and private organizations. AEGLs

for 10-min exposure durations will be developed for all future chemicals addressed by the NAC/AEGL Committee, and 10-min AEGLs will be developed

for the first four chemicals published by the NRC (2000). Experimental animal and controlled human exposure-response data and data from human exposure incidents often involve exposure durations differing from those specified

for AEGLs. Therefore, AEGL development usually requires extrapolation

from the reported exposure duration and chemical concentration of a toxic

endpoint to an equivalent concentration for an AEGL-specified exposure

period. This section discusses that concept, the published scientific literature,

the methodologies used for extrapolation, and examples of the application of

these methodogies to specific chemicals for the development of AEGL values.

2.7.1 Overview

The NRC (1993a) guidelines for developing short-term exposure levels

address extrapolation of the effects of genotoxic carcinogens from long-term
94 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

to short-term exposures. Only limited NRC guidance is provided for approaches or methodologies for the extrapolation of reported acutely toxic

effects to shorter or longer durations of exposure.

The relationship between dose and time to response for any given chemical is a function of the physical and chemical properties of the substance and

the unique toxicologic and pharmacologic properties of the individual substance. Historically, the relationship according to Haber (1924), commonly

called Haber’s law (NRC 1993a) or Haber’s rule (i.e., C × t = k, where C =

exposure concentration, t = exposure duration, and k = a constant) has been

used to relate exposure concentration and duration to effect (Rinehart and

Hatch 1964). This concept states that exposure concentration and exposure

duration may be reciprocally adjusted to maintain a cumulative exposure

constant (k) and that this cumulative exposure constant will always reflect a

specific quantitative and qualitative response. This inverse relationship of

concentration and time may be valid when the response to a chemical is equally dependent upon the concentration and the exposure duration. However, an

assessment by ten Berge et al. (1986) of LC50 data for certain chemicals revealed chemical-specific relationships between exposure concentration and

exposure duration that were often exponential. This relationship can be expressed by the equation Cn

 × t = k, where n represents a chemical-specific, and

even a toxic endpoint-specific, exponent. The relationship described by this

equation is basically in the form of a linear regression analysis of the log-log

transformation of a plot of C vs t (see Section 2.7.5.3). ten Berge et al. (1986)

examined the airborne concentration (C) and short-term exposure duration (t)

relationship relative to death for approximately 20 structurally diverse chemicals and found that the empirically derived value of n ranged from 0.8 to 3.5

among this group of chemicals (see Table 2-1). Hence, these workers showed

that the value of the exponent (n) in the equation Cn

 × t = k quantitatively

defines the relationship between exposure concentration and exposure duration

for a given chemical and for a specific health-effect endpoint. Haber's rule is

the special case where n = 1. As the value of n increases, the plot of concentration vs time yields a progressive decrease in the slope of the curve.

In cases in which adequate data are available, the NAC/AEGL Committee

conducts an analysis of chemical-specific toxicity and exposure data to derive

a chemical-specific and health-effect-specific exponent (n) for use in extrapolating available exposure data to AEGL-specified exposure durations. If data

are not available for empirically deriving the exponent n, the NAC/AEGL

Committee identifies the most appropriate value for n by comparing the resultant AEGL values derived using n = 1 and n = 3. The value of n = 1 has been

used historically by others and results in rapid reductions in concentrations
DERIVATION OF AEGL VALUES 95 

TABLE 2-1 Values of n from ten Berge et al. (1986)

Value of n (average)

Systemic Chemicals 2.7 

Hydrogen Sulfide 2.2 

Methyl t-butyl ether 2 

Methylenechlorobromide 1.6 

Ethylenedibromide 1.2 

Tetrachloroethylene 2 

Trichloroethylene 0.8 

Carbon tetrachloride 2.8 

Acrylonitrile 1.1 

Irritants

Ammonia 2 

Hydrogen Chloride 1 

Chlorine pentafluoride 2 

Nitrogen dioxide 3.5 

Chlorine 3.5 

Perfluoroisobutylene 1.2 

Crotonaldehyde 1.2 

Hydrogen Fluoride 2 

Ethylene imine 1.1 

Bromine 2.2 

Dibutylhexamethylenediamine 1

Range of n

No. of Chemicals

per Range

Cumulative No. 

of Chemicals

0.8-1.5 8 8

1.51-2.0 6 14

2.01-2.5 2 16

2.51-3.0 2 18

3.01-3.5 2 20

when extrapolated to longer exposure periods and rapid increases in concentrations when extrapolated to shorter exposure periods. Based on the work of ten
96 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Berge et al. (1986), n = 1 represents the estimate of the lower boundary of the

value of n. The value of n = 3, an estimate of the upper boundary of the value

of n (ten Berge et al. 1986), results in less rapid rates of decrease in estimated

effect concentrations when extrapolated to longer exposure periods and to less

rapid rates of increase in estimated effect concentrations when extrapolated to

shorter exposure periods. This range of values of n from 1 to 3 encompasses

approximately 90% of the chemicals examined by ten Berge et al. (1986). In

selecting a value for n when the derivation of n is not possible, the

NAC/AEGL Committee evaluates the resultant AEGL values determined with

either the upper or the lower boundary value of n (1 or 3) within the context

of other supporting data to determine the reasonableness of the extrapolated

AEGL value. A value of n = 1 is used when extrapolating from shorter to

longer exposure durations and a value of n = 3 is used when extrapolating

from longer to shorter durations. The resultant AEGL value is then compared

with supporting data to determine the scientific reasonableness of the derived

AEGL value and the process favors the use of a value for n that results in an

AEGL value that best fits the supporting data.

In summary, since toxicity data are often not available for any or all of the

AEGL specified time periods, temporal extrapolation is usually necessary to

generate scientifically credible values for the AEGL time points. However, it

is important to point out that the relevant data, together with scientific judgment, are used to determine the extent of temporal extrapolation and its validity in AEGL derivations. This is underscored by the fact that errors in the

estimated exposure concentration–exposure duration relationship (i.e., the

value of n) can progressively increase the magnitude of the uncertainty of the

derived AEGL value as the time from the empirical data point to the extrapolated data point increases.

Therefore, extrapolation of 10-min exposure data to a 4-h or 8-h AEGL

value requires more supporting data and/or assumptions than the extrapolation

of 10-min exposure data to a 30-min or 1-h AEGL. Additionally, extrapolation

of 4-h or 8-h exposure data to a 10-min AEGL value also requires more supporting data than extrapolation of 8-h exposure data to a 1-h or 30-min AEGL.

As a result of the potential uncertainties in dose-response relationships associated with exposure durations of less than 10-min (a transition period in breathing rate, physiologic responses, scrubbing efficiency/saturation, chemicalspecific issues, and other factors) and in the absence of definitive supporting

data, extrapolations using 4-h and 8-h empirical data generally are not extended

to 10-min AEGL values but are assigned the same value as the 30-min AEGL.

Finally, because of the uncertainties for very short exposure durations, no

AEGL values for exposure periods of less 10-min are currently recommended.
DERIVATION OF AEGL VALUES 97 

2.7.2 Summary of Key Publications on Time Scaling

Several investigators have studied the relationship of exposure duration

and exposure concentration as related to the toxic response to airborne chemicals (Flury 1921; Haber 1924; Rinehart and Hatch 1964; ten Berge et al. 1986;

ECETOC 1991; and Pieters and Kramer 1994).

On the basis of observations and studies with gases such as phosgene,

Haber (1924) found that for certain chemicals the product of the exposure

duration multiplied by the exposure concentration was constant for a specific

response or toxic endpoint (i.e., lethality). In experiments with cats, Haber

found that the product of a specific concentration and exposure time would

result in 100% lethal response and that as long as this product value was maintained, regardless of the specific exposure concentration or duration, the response was consistent. This linear relationship became known as Haber’s rule.

Similarly, Flury (1921) found that inhalation of phosgene exhibited a linear

relationship, C × t = E, where E represents the onset of pulmonary edema.

Obviously, the cumulative exposure constant may relate to any number of

responses or physiologic endpoints. However, the information reported by

Haber is limited to a small number of chemicals or chemical classes, and substantial quantitative data derived from controlled studies are lacking.

Historically, Haber's rule has been used for time concentration extrapolations (EPA 1994). This relationship assumes that each unit of damage is irreversible, that no repair takes place during the exposure period and, therefore,

that each unit of exposure is 100% cumulative. However, this is generally not

the case for acutely toxic responses to short-term exposures. The relationship

between concentration and duration of exposure as related to lethality was

examined by ten Berge et al. (1986) for approximately 20 irritant or systemically acting vapors and gases. The authors subjected the entire individual

animal data set to probit analyses with exposure duration and exposure concentration as independent variables. They used the method of Finney (1971)

to investigate the fit of the data into a probit model on the basis of a maximum

likelihood estimate. In re-evaluating the raw data for these chemicals, it was

found that the linear relationship described by Haber’s rule, C × t = k was not

always a valid predictor of lethality. An exponential function (Cn

 × t = k),

where the value of n ranged from 0.8 to 3.5 for different chemicals, was a more

accurate quantitative descriptor. These authors derived empirically based,

chemical-specific regression coefficients for exposure duration and exposure

concentration, as well as chemical-specific values for n. The values for n for

the 20 chemicals studied ranged from 0.8 to 3.5. The analyses indicated that

the concentration-duration relationship for lethality was described more accurately by the exponential function (Cn

 × t = k) and that Haber’s rule was appro-
98 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

priate for only a limited number of chemicals. On the basis of the results of the

analyses, ten Berge et al. (1986) concluded that the concentration-time relationship (i.e., value for n) should be determined empirically from acute inhalation

exposure toxicity data on a chemical-specific basis.

2.7.3 Summary of the Approaches That May Be Taken for Time Scaling

A tiered approach to generating toxicity values for time scaling is taken by

the NAC/AEGL Committee to derive AEGL values from empirical data. This

approach is summarized below. Each of the approaches and the circumstances

under which they are, or could be, used are discussed subsequently in this

section.

1. If appropriate toxicologic data for the exposure concentration–exposure duration relationship of a specific health-effect endpoint are

available for the AEGL-specified exposure periods, use the empirical

data directly.

2. If empirical exposure concentration–exposure duration relationship

data are available, albeit they do not coincide with AEGL-specified

exposure periods, use the available data to derive values of n and

extrapolate the AEGL values using the equation Cn

 × t = k. If supporting data are inconsistent with the extrapolated AEGL value, the

value of n might be modified to reconcile the difference. If definitive

supporting data for 10-min exposures are not available when extrapolating from 8-h empirical data, the 10-min AEGL generally is

assigned the same value as that extrapolated for the 30-min AEGL.

3. If no empirical exposure concentration–exposure duration relationship

data are available to derive a value of n, a value of n = 1 for extrapolating from shorter to longer exposure durations and a value of n = 3

for extrapolating from longer to shorter exposure durations should be

tested initially. The scientific reasonableness of the selection of the

estimated lower and upper boundaries of n (n = 1 and n = 3) is then

evaluated by comparing the resultant AEGL values with all other

supporting data. If appropriate, the final value(s) of n may be modified to reconcile differences between extrapolated AEGL values and

the supporting data. If definitive supporting data for 10-min exposures are not available when extrapolating from 8-h empirical data, the

10-min AEGL generally is assigned the same value as that extrapolated for the 30-min AEGL.
DERIVATION OF AEGL VALUES 99 

4. If there are no supporting data to evaluate selected values of n, a default value of n = 1 for extrapolating from shorter to longer exposure

periods and a default value of n = 3 for extrapolating from longer to

shorter exposure periods should be selected. If definitive supporting

data for 10-min exposures are not available when extrapolating from

8-h empirical data, the 10-min AEGL generally is assigned the same

value as that extrapolated for the 30-min AEGL. In the absence of

other data, the resultant AEGL values are thought to be protective and

scientifically credible.

The remainder of this section of the guidance provides more detailed

information on the approaches stated above.

2.7.4 Use of Empirical Data Available for AEGL-Specified

Exposure Durations

If toxicity data are available for all four AEGL-specified exposure periods,

there is no need to derive values of n, and the empirical data for each exposure

period can be used directly. However, it is rare that toxicity data are sufficiently comprehensive to encompass all the AEGL-specified exposure periods

from 10 min to 8 h. Further, there are instances in which empirical data are not

available to estimate n and predict the exposure concentration–exposure duration relationship using Cn

 × t = k. Therefore, the sequential approaches used

by, or available to, the NAC/AEGL Committee to establish AEGL values for

the specified exposure periods are discussed in the following sections.

2.7.5 Derivation of Values of n When Adequate Empirical Data

Are Available for Durations Other Than the AEGL-Specified

Exposure Durations

A key element in the procedure of time scaling is the use of a value or

values for n in the equation Cn

 × t = k. If empirical data for exposure durations

other than the AEGL-specified exposure periods are available to quantify the

exposure concentration–exposure duration relationships for a health-effect

endpoint, including lethality, the value of n should be derived using the

method of calculation described in this section. It is believed that empirically

derived values of n are scientifically more credible than a default value of n =

1 (Haber’s rule) or attempting to derive an alternate value of n.
100 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.7.5.1 Selection of Appropriate Health-Effect Endpoint for Deriving a

Value for n

The first step in any time scaling methodology is the selection of the

health-effect endpoint of concern. Clearly, the health-effect endpoint selected

should be consistent with the definition of the AEGL tier being determined.

Further, the endpoint should be unambiguous and consistently observed at all

reported exposure durations. For example, death is an unambiguous endpoint

and a quantitatively determined index of toxicity; the LC50, is a response rate

that can be compared reliably among exposures at different time periods. The

use of the LC50 as an index of toxicity is ideal, because it is a statistically

derived concentration that is not subject to the vagaries of dose selection and

exhibits less variability in response than any other experimental endpoint.

Death is included in the AEGL-3 definition and is used for estimating the

value of n.

A comparable endpoint for the AEGL-1 and AEGL-2 tiers would be an

ED50 (the dose that causes a specific response in 50% of the test subjects) for

a precisely defined toxic or health-effect endpoint that is consistent with the

definition of the AEGL tier in question. The actual endpoint is often difficult

to determine in most experiments, because the observed effects are often a

continuum from mild to severe and generally not reported in a format precise

enough to determine a reliable ED50 value. Further, incidence data for nonlethal effects are not always reported. For these reasons, the concentrationresponse relationship and the value of n derived from lethality data have often

been applied to both the AEGL-3 and the AEGL-2 exposure-period extrapolations. However, in instances in which the mechanism of toxicity causing the

health effect of concern at the AEGL-2 tier is thought to be different from that

causing lethality, the value of n derived from LC50 data should not be used.

Under these circumstances, AEGL-2 values can be developed by selecting the

upper and lower boundaries of n (n = 3 and n = 1) for extrapolation from

longer to shorter and shorter to longer exposure periods, respectively. The

resultant AEGL-2 values should be evaluated within the context of other supporting data to evaluate the reasonableness of the values of n selected. In the

absence of supporting data, the AEGL values determined using n = 3 and n =

1 should be utilized as described in No. 3 in Section 2.7.3.

Selection of appropriate endpoints for AEGL-1 values per se represents a

unique and often difficult task. Based on its experience to date, the

NAC/AEGL Committee has found no rigorous data available from which

values of n could be derived for AEGL-1 type of endpoints for any chemical.

The derivation of AEGL-1 values is discussed later in this section.
DERIVATION OF AEGL VALUES 101 

2.7.5.2 Criteria for Adequate Empirical Data for Deriving Values of n

After determining the health-effect endpoint to be used in deriving the

value(s) for n, the next step is to evaluate the quality and the quantity of the

data to be used in the derivation. Obviously, two data points will define the

slope of a curve describing the exposure concentration-duration relationship.

However, the validity and, hence, the values of n will depend on many factors,

including the scientific soundness of the exposure concentration-duration data,

the length of the empirical exposure duration(s) relative to the AEGL-specified

exposure periods, and the known or perceived similarities in effects and mechanism of action of the chemical at the reported exposure concentrations and

durations. Generally, three empirical data points will improve the scientific

validity of the slope and the estimated values for n, and the validity is likely

to increase with an increase in the number of empirical data points used to

derive n, provided that there is a reasonable fit of these data points.

2.7.5.3 Curve Fitting and Statistical Testing of the Generated Curve

Once the health-effect endpoint and data points describing the exposure

concentration-duration relationship have been selected, the values are plotted

and fit to a mathematical equation from which the AEGL values are developed. There may be issues regarding the placement of the exponential function in the equation describing the concentration-duration relationship (e.g.,

Cn

 × t = k vs C × tm = k2 vs Cx × ty = k3). It is clear that the exposure

concentration-duration relationship for a given chemical is directly related to

its pharmacokinetic and pharmacodynamic properties. Hence, the use and

proper placement of an exponent or exponents to describe these properties

quantitatively is highly complex and not completely understood for all materials of concern.

The quantitative description of actual empirical data of the concentrationduration relationship can be expressed by any of a number of linear regression

equations. In the assessment of empirical data reported by ten Berge et al.

(1986), these workers quantified the exposure concentration-duration relationship by varying the concentration to the nth power. Since raising c or t or both

to a power can be used to define quantitatively the same relationship or slope

of the curve and to be consistent with data and information presented in the

peer-reviewed scientific literature, the equation Cn

 × t = k is used for extrapolation. It must be emphasized that the relationship between C and t is an em-
102 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

pirical fit of the log transformed data to a line. No conclusions about specific

biologic mechanisms of action can be drawn from this relationship.

The preferred approach is to use a statistical methodology, which utilizes

all the individual animal data and generates a maximum likelihood estimate

with 95% confidence limits. When individual animal data are available, the

method of Finney (1971) is preferred. This method has been incorporated into

a computer program (provided to the NAC/AEGL Committee by Dr. ten Berge

from The Netherlands).

Unfortunately, the individual animal data are often unavailable and only

LC50 values are listed. In this case, a linear regression analysis of the log-log

transformation of the concentration-duration data is performed as described

below:

When concentration-duration data are plotted on a log-log plot, they generally fall along a straight line. For that reason, a simple linear regression

(Alder and Roessler 1968) is run on the data to generate the mathematical

curve. The basic linear regression equation is in the form

Y = a + bX,

where Y is the predicted value of the dependent variable, X is the value of the

independent variable, a is the Y intercept and b is the slope of the line..

This is the form of the log-transformation of the nonlinear Cn

 × t = k equation to a linear equation (see below):

log C = (log k)/n + (!1/n) × log t,

where C is the predicted value of the concentration to cause an effect at exposure duration t. The (log k)/n is the Y intercept of the plot of log C against log

T, and !1/n is the slope of the plot of log C against log T.

Cn

 × t = k

log(Cn

 × t) = log k

n × log C + log t = log k

n × log C = log k ! log t

log C = (log k)/n ! (log t)/n

log C = (log k)/n ! (1/n) × log t

The regression coefficient or slope, b, returns the slope of the linear regression line through data points X and Y. The slope (rate of change along the
DERIVATION OF AEGL VALUES 103 

regression line) is the distance between the Y values of the two points divided

by the distance between their respective X values. The regression coefficient

is calculated as

b N XY ( X)( Y)

N X ( X) 2 2 = −−

Σ ΣΣ

Σ Σ ,

where N = the number of observations,

or

− −

− 1/ n = N (log t)(log C) ( log t)( log C)N (log t) ( log t) 2 2

Σ ΣΣ

Σ Σ .

The above is solved for n.

The validity of the derived values of n is dependent on the degree of correlation among the various concentration-duration data points used to construct

the curve and the equation. Normally a coefficient of determination (r2

) is

calculated as a measure of how well the generated curve (linear in this case)

fits the data points. If r2

 = 0, then the data do not fit a linear relationship. If

r

2

 = 1, then the data exhibit a strong linear relationship. If the number of data

points are 3 and the real value of r = 0, “the chance of obtaining a fairly high

correlation coefficient for the sample is greater than the chance of obtaining

a small correlation coefficient” (Alder and Roessler 1968). If the number of

data points are 4, “the chance of obtaining a particular correlation coefficient

is equal to that of obtaining any other” (Alder and Roessler 1968). Since the

number of data points typically available are only in the range of 3 or 4 values,

the use of r2

 to measure how well the data fit the generated curve is not meaningful. Therefore, informed professional judgment is exercised by the

NAC/AEGL Committee.

Given the fact that the distribution of r for low numbers of observations

(typically 3 or 4 data points for time scaling) cannot be fit to a normal curve,

meaningful statistical tests of the fit of the regression line (used to derive n) to

the data cannot be performed. Even with those shortcomings, a regression

analysis of the data as previously described gives the best fit of a line to the

data. An inspection of the regression line vs the data also will show the reasonableness of the fit and, hence, the reasonableness of the derived value for

n. This approach is generally the best when empirical data are used to derive

n values for developing AEGL values for specified exposure durations. As

stated earlier, it must be emphasized that when deriving or selecting a value for
104 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

n, the NAC/AEGL Committee evaluates the resultant AEGL values within the

context of other supporting data to determine the reasonableness of the extrapolated values. This is done even when the value of n is derived from empirical

data that describe the exposure concentration-duration relationship. The

NAC/AEGL Committee uses a value for n that results in AEGL values that

best fit the supporting data. Therefore, there is no substitute for informed

professional judgment based on careful review, evaluation, and discussion of

all available data.

2.7.5.4 Examples of NAC/AEGL Committee Derivations of Values of n

from Empirical Data

During the course of AEGL development, the NAC/AEGL Committee has

used empirically based derivations of n in the equation Cn

 × t = k for time

scaling to AEGL-specified exposure periods. Guidelines have been developed

from this experience and are presented in the final part of this section.

2.7.6 Selection of Values of n When Adequate Empirical Data

Are Not Available to Derive Values for n

When adequate data describing exposure concentration-duration relationships for a specific chemical and toxic endpoint of interest are not available,

an alternative approach to estimating this relationship quantitatively must be

followed. The approach used by the NAC/AEGL Committee involves the

application of the equation Cn

 × t = k and the selection of a value or values of

n that results in AEGL values that best fit the supporting data for the chemical

and toxic endpoint in question. It is important to distinguish the difference

between the derivation of values of n as described in the preceding section and

the selection of values of n as described in this section.

An evaluation of the analysis of values of n by ten Berge et al. (1986)

served as the basis to select the limits used by the NAC/AEGL Committee.

The lowest value of n was 0.8 and the highest value of n was 3.5. Approximately 90% of the values of n range between n = 1 and n = 3. Consequently,

these values were selected as the reasonable lower and upper bounds of n.

In the absence of data to derive a value for n, the NAC/AEGL Committee

selects values for n of 1 and 3, depending on an extrapolation from shorter to

longer durations or longer to shorter durations, respectively. The value of n
DERIVATION OF AEGL VALUES 105 

is then used in the equation Cn

 × t = k to extrapolate from empirically reported

exposure concentrations and exposure durations to the AEGL-specified exposure durations. The committee then selects the derived AEGL values in accordance with the supporting data.

2.7.6.1 Selection of Values of n When Extrapolating from Shorter to

Longer Exposure Durations

As discussed previously, a value of n = 1 represents the lower range of the

exposure concentration–exposure duration relationship. If the exponent n =

1 is used in the equation Cn

 × t = k, there is a rapid decrease in extrapolated

values when extrapolations are made from shorter to longer exposure periods

(see Figure 2-2). The extrapolated values are lower and, hence, represent a

conservative estimate of the AEGL value. A value of n = 3 represents a value

in the upper range for the exposure concentration-duration relationship and

results in a less rapid rate of decrease when extrapolating from shorter to longer exposure periods. Therefore, the extrapolated AEGL values for longer

exposure periods are higher and, hence, less conservative in terms of protecting human health (see Figure 2-2).

When empirical data are not available for deriving a value of n, the

NAC/AEGL Committee develops tentative AEGL values from shorter to

longer exposure durations using n = 1 in the equation Cn

 × t = k and evaluates

these values with all other supporting data to determine their scientific reasonableness. Therefore, a weight-of-evidence test is applied to the tentative

AEGLs by comparing these values to the supporting data to determine the

most scientifically credible AEGL values. In instances in which supporting

data indicate that the tentative AEGL developed using a value of n = 1 is

inaccurate, the AEGL may be adjusted to scientifically accommodate the

supporting data. If there are no supporting data indicating that the derived

AEGL should be adjusted, a value of n = 1 is used to account for the uncertainty of the concentration-endpoint relationship at longer exposure durations.
106 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

0 

100 

200 

300 

400 

500 

600 

ppm (C)

0 60 120 180 240 300 360 420 480 

Minutes (t)

n=3

n=2

n=1

Cn x t = k

FIGURE 2-2 Effects of varying n in the equation Cn × t = k. Short- to Long-Duration

Extrapolations: Note that when extrapolating from 60 min to longer exposure durations, the lower the value of n, the lower the extrapolated value. Therefore, when

extrapolating from short- to long-exposure durations, a value of n = 1 yields a more

conservative value than any value of n that is >1. Long- to Short-Duration Extrapolations: Conversely, when extrapolating from 60 min to shorter exposure durations, the

higher the value of n, the lower the extrapolated value. Therefore, when extrapolating

from long to short exposure durations, a value of n = 3 yields a more conservative

value than any value of n that is <3.

2.7.6.2 Selection of Values of n When Extrapolating from Longer to

Shorter Exposure Durations

When extrapolating from longer to shorter exposure durations using the

equation Cn

 × t = k and a value of n = 1, there is a relatively rapid increase in

the extrapolated values (see Figure 2-2). Under these circumstances, the de-
DERIVATION OF AEGL VALUES 107 

rived AEGL value represents a relatively high estimate of the toxic endpoint

concentration at shorter exposure durations and is, therefore, a less conservative value. When extrapolating from longer to shorter exposure durations

using a value of n = 3, there is a less rapid rate of increase in the derived

AEGL value. As a result, the extrapolated AEGL value is more conservative

when selecting a value of n = 3 (see Figure 2-2).

In circumstances in which the NAC/AEGL Committee selects a value for

n to derive AEGL values from empirical data for longer to shorter exposure

periods, tentative AEGLs are derived using a value of n = 3 and then compared

with the derived AEGL values with all other relevant data. Again, this represents a weight-of-evidence approach to selecting a value of n for the most

scientifically credible AEGL values. In instances in which the supporting data

indicate that the tentative AEGL developed using a value of n = 3 is too high

or too low, the AEGL may be adjusted to scientifically account for the supporting data. If no supporting data indicate that the derived AEGL should be adjusted, a value of n = 3 should be used to accommodate for the uncertainty of

the exposure concentration-duration relationship for the shorter exposure durations. If definitive supporting data for 10-min exposures are not available

when extrapolating from 8-h empirical data, the 10-min AEGL generally is

assigned the same value as that extrapolated for the 30-min AEGL.

2.7.7 Special Considerations in the Time Scaling of

AEGL-1 and AEGL-2 Values

The previous descriptions of approaches to time scaling for toxic endpoint

concentrations are most applicable to the derivation of AEGL-3 values, because unequivocal data relating the concentration required to cause an effect

to the exposure duration are LC50 data. Lethality is an unambiguous endpoint

that does not involve gradations of severity or incidence that are often difficult

to quantify precisely (e.g., pulmonary congestion or edema or irritation in the

respiratory tract involving variations in both degree and area affected). With

respect to AEGL-2 values, it is far more difficult to quantify and achieve

consensus on gradations in nonlethal toxic effects with respect to severity and

incidence in a manner that readily results in a simple, quantitative endpoint

exposure concentration-duration relationship. Further, the LC50 is a statistically derived value in the midpoint of the dose-response curve that is less

subject to the vagaries in response at the extremes of the exposure regimen.

For these reasons, the NAC/AEGL Committee primarily has used LC50 data
108 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

in the derivation of exposure-duration scaling relationships. Subsequently,

these quantitative relationships have been used to derive both AEGL-2 and

AEGL-3 values and occasionally AEGL-1 values. This approach is believed

to be scientifically credible if the mechanism of toxicity for AEGL-2 and

AEGL-3 is known or thought to be similar.

It is recognized that the time-scaling relationship observed with a lethality

AEGL-3 endpoint may not accurately describe the irreversible-effects or impairment-of-escape endpoint used for the AEGL-2. However, the NAC/AEGL

Committee compares the AEGL-2 values against the supporting data to assess

the reasonableness of the AEGL-2 determinations. Based on this assessment,

adjustments are made to better fit the supporting data. If there are data that

suggest different toxicologic mechanisms for lethal effects and AEGL-2 health

effects, selected values of n should be used for the development of the AEGL

values. The upper and lower bounds of n = 3 and n = 1 should be used for

extrapolation from longer to shorter and from shorter to longer exposure periods, respectively. The resultant AEGL-2 values should then be evaluated

using all supporting data and adjusted or maintained accordingly.

A difficult application of time scaling is encountered when attempting to

derive AEGL-1 values. The AEGL-1 value defines the airborne concentration

that distinguishes detection from discomfort. As a result, there is greater

difficulty in attempting to quantify this often subjective level with respect to

severity and incidence in a manner sufficient to derive an exposure concentration-duration relationship than to quantify the AEGL-2. This quantification

is further complicated by the nature of the biologic endpoint that one is attempting to quantify. For example, the concentration for odor detection may

actually decrease over time because of olfactory fatigue, as in the case of

hydrogen sulfide. With respect to mild sensory effects, they are generally not

cumulative over a range of exposures of 10 min to 8 h. Hence, the same

AEGL-1 value may be assigned to all AEGL-specified exposure periods. In

certain instances in which experimental data suggest that the sensory effects

may increase because of the cumulative dose over time, the 10-min, 30-min,

and 1-h values may be the same, but may be lower for the 4-h and 8-h AEGL

exposure durations.

In the case of certain sensory irritants, the AEGL values may be constant

across all AEGL time periods, because this endpoint is considered a threshold

effect, and prolonged exposure will not result in an enhanced response. In

fact, individuals may adapt or become inured to sensory irritation provoked by

exposure to these chemicals over these exposure periods such that the warning

properties are reduced.
DERIVATION OF AEGL VALUES 109 

2.7.8 Time Scaling—Guidelines for the

NAC/AEGL Committee Approach

This section presents a compilation of time-scaling guidelines, which are

used when deriving AEGL values for different time periods. As stated earlier,

it must be emphasized that when deriving or selecting a value for n, the

NAC/AEGL Committee evaluates the resultant AEGL values within the context of other supporting data to determine the reasonableness of the extrapolated values. This evaluation is done even when the value of n is derived from

empirical data that describe the exposure concentration-duration relationship.

The NAC/AEGL Committee uses a value for n that results in AEGL values

that best fit the supporting data.

2.7.8.1 Use of Empirical Data to Determine the Exposure 

Concentration–Exposure Duration Relationship

The rationale for the selection of an empirically based time-scaling approach should include the following:

1. The health-effect endpoint of concern.

2. The exposure durations for which data were available.

3. Description of the statistical method used. If no method was used,

then describe how the value of n was derived.

4. Description of the data used, including durations or the concentrationduration values used for extrapolation. Include the formula used.

5. Description of the different values of n from one or more studies and

why a specific derived value of n was used.

6. The value of k calculated from Cn

 × t = k after uncertainty and/or

modifying factors have been applied to C.

7. If the value of n is based on an analysis of the combined data from a

number of different studies, then provide a description of how the

different concentration-duration values were combined and why they

were used.

8. If definitive supporting data for 10-min exposures are not available

when extrapolating from 8-h empirical data, the 10-min AEGL generally is assigned the same value as that extrapolated for the 30-min

AEGL.
110 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.7.8.2 Estimating the Exposure Concentration–Exposure Duration

Relationship Using a Structurally Related Material

The rationale for the selection of this time-scaling approach should include the following:

1. Description of the structure-activity relationships between the two

chemicals.

2. The health-effect endpoint of concern.

3. The exposure durations for which data were available.

4. The statistical method used or a statement of how the value of n was

derived.

5. Description of the data from the surrogate chemical used to derive the

exposure concentration-duration relationship. If a derived value of n

is used, the equation should be included.

6. A description of how the different concentration-duration values were

combined and why they were used if the value of n is based on an

analysis of the combined data from a number of studies.

7. The value of k calculated after uncertainty and modifying factors have

been applied.

2.7.8.3 Estimating the Exposure Concentration–Exposure Duration

Relationship When Data Are Not Available to Derive a Value

for n and Supporting Data Are Available

In the absence of data to derive a value for n, a value for n of 1 is initially

selected when extrapolating from shorter to longer exposure durations and a

value for n of 3 is initially selected when extrapolating from longer to shorter

exposure durations. The values of n are used with the equation Cn

 × t = k to

extrapolate from the empirically reported exposure concentrations and exposure durations to the AEGL-specified exposure durations. AEGL values in

accord with the supporting data are then selected.

The rationale for the selection of the time-scaling approach should include

the following:

1. Presentation of the rationale in the technical support document (TSD)

as follows: The relationship between concentration and duration of

exposure as related to lethality was examined by ten Berge et al.

(1986) for approximately 20 irritant or systemically acting vapors and

gases. The authors subjected the individual animal data sets to probit
DERIVATION OF AEGL VALUES 111 

analysis with exposure duration and exposure concentration as independent variables. An exponential function (Cn

 × t = k), where the

value of n ranged from 0.8 to 3.5 for different chemicals, was found

to be an accurate quantitative descriptor for the chemicals evaluated.

Approximately 90% of the values of n range between n = 1 and n = 3.

Consequently, these values were selected as the reasonable lower and

upper bounds of n. A value of n = 1 is used initially when extrapolating from shorter to longer periods, because the extrapolated values

represent the most conservative approach in the absence of other data.

Conversely, a value of n = 3 is used when extrapolating from longer

to shorter periods, because the extrapolated values are more conservative in the absence of other data. If supporting data are available (description and references for data should be included) and indicate that

the AEGL value initially extrapolated is inaccurate, the AEGL value

has been adjusted to reflect the data.

2. Presentation of the AEGL values or exposure concentrations extrapolated from data using a value of n = 1 or n = 3 and the adjustments

made as a result of supporting data..

3. Because of the uncertainty in 10-min exposure data and the absence

of definitive supporting data, the 10-min AEGL is assigned the same

value as the 30-min AEGL when extrapolating from 4-h or 8-h empirical data.

4. Discussion of the adjustments made and the rationale for making

them.

2.7.8.4 Determining Exposure Concentration–Exposure Duration 

Relationships When Data Are Not Available to Derive a Value

for n and No Supporting Data Are Available

In the absence of data to derive a value of n and the absence of supporting

data to validate a value of n, the value of n = 1 will be selected for extrapolating from shorter to longer exposure durations, and the value n = 3 will be

selected for extrapolating from longer to shorter exposure durations. If definitive supporting data for 10-min exposures are not available when extrapolating

from 8-h empirical data, the 10-min AEGL generally is assigned the same

value as that extrapolated for the 30-min AEGL.
112 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

The rationale for the selection of this time-scaling approach should include the following:

1. Presentation of the rationale in the TSD as follows: The relationship

between concentration and duration of exposure as related to lethality

was examined by ten Berge et al. (1986) for approximately 20 irritant

or systemically acting vapors and gases. The authors subjected the

individual animal data sets to probit analysis with exposure duration

and exposure concentration as independent variables. An exponential

function (Cn

 × t = k), where the value of n ranged from 0.8 to 3.5 for

different chemicals, was found to be an accurate quantitative descriptor for the chemicals evaluated. Approximately 90% of the values of n range between n = 1 and n = 3. Consequently, these values

were selected as the reasonable lower and upper bounds of n to use

when data are not available to derive a value of n. A value of n = 1 is

used when extrapolating from shorter to longer periods, because the

extrapolated values are conservative and therefore, reasonable in the

absence of any data to the contrary. Conversely, a value of n = 3 is

used when extrapolating from longer to shorter periods, because the

extrapolated values are conservative and therefore reasonable in the

absence of any data to the contrary. Because of the uncertainty in 10-

min exposure data and the absence of definitive supporting data, the

10-min AEGL is assigned the same value as the 30-min AEGL when

extrapolating from 4-h or 8-h empirical data.

2.7.8.5 AEGL Exposure Values Are Constant Across Time

The rationale for the selection of the time-scaling approach should include

the following:

1. The data and mode or mechanism of action of the chemical and its

effect on humans that supports the assignment of constant AEGL

values across exposure durations.

2.8 GUIDELINES AND CRITERIA FOR ADDRESSING SHORTTERM EXPOSURE TO KNOWN AND SUSPECT CARCINOGENS

Cancer represents a serious adverse health effect. Historically, the concerns for chemically induced cancers were based on continuous long-term
DERIVATION OF AEGL VALUES 113 

exposure in controlled animal studies or information derived from clinical or

epidemiologic studies of continuous or long-term exposures in humans. To

conduct quantitative risk assessments for cancer in humans, mathematical

(probit-log-dose) models were developed to utilize primarily animal bioassay

data and extrapolate from the higher experimental levels to assess the carcinogenic risk to humans at low levels of chemical exposure. The evolution and

usefulness of mathematical models to accommodate new understanding or new

concepts regarding the mechanisms of carcinogenesis have been summarized

in two publications by the NRC: Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants (NRC 1992a),

and Guidelines for Developing Community Emergency Exposure Levels for

Hazardous Substances (NRC 1993a).

In the United States, some state and federal regulatory agencies conduct

quantitative risk assessments on known or suspect carcinogens for continuous

or long-term human exposure by extrapolating downward in linear fashion

from an upper confidence limit on theoretical excess risk (FDA 1985; EPA

1986). The values derived for a specified “acceptable” theoretical excess risk

to the U.S. human population, based on a lifetime of exposure to a carcinogenic substance, have been used extensively for regulatory purposes.

There are no adopted state or federal regulatory methodologies for deriving short-term exposure standards for workplace or ambient air based on carcinogenic risk, because nearly all carcinogenicity studies in animals and retrospective epidemiologic studies have entailed high-dose, long-term exposures.

As a result, there is uncertainty regarding the extrapolation from continuous

lifetime studies in animals to the case of once-in-a-lifetime human exposures.

This is particularly problematical, because the specific biologic mechanisms

at the molecular, cellular, and tissue levels leading to cancer are often exceedingly diverse, complex, or not known. It is also possible that the mechanisms

of injury of brief, high-dose exposures will often differ from those following

long-term exposures. To date, U.S. federal regulatory agencies have not established regulatory standards based on, or applicable to, less than lifetime exposures to carcinogenic substances.

2.8.1 NRC Guidance

Guidance on the development of short-term exposure levels, published by

the NRC, identified cancer as one of the potential adverse health effects that

might be associated with short-term inhalation exposures to certain chemical

substances (NRC 1993a). That guidance document discusses and recommends

specific risk-assessment methods for known genotoxic carcinogens and for
114 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

carcinogens whose mechanisms are not well understood. As a first approximation, the default approach involves linear low-dose extrapolation from an

upper confidence limit on theoretical excess risk. Further, the NRC guidance

states that the determination of short-term exposure levels will require the

translation of risks estimated from continuous long-term exposures to risks

associated with short-term exposures. Conceptually, the approach recommended for genotoxic carcinogens adopted the method developed by Crump

and Howe (1984) for applying the linearized multistage model to assessing

carcinogenic risks based on exposures of short duration. In the case of

nongenotoxic chemical carcinogens, the NRC guidance acknowledges that the

approach is less clear because of the many different modes of action, the complexities of epigenetic carcinogenic mechanisms, and, in many cases, the

paucity of data on chemical-specific mode of action. It is acknowledged also

that dose thresholds exist for certain nongenotoxic carcinogens. The NRC

guidance suggests that, in lieu of linear, low-dose extrapolation, approaches

involving noncarcinogen risk-assessment techniques or cell kinetic models

from the class of initiation-promotion-progression models be used, provided

a known mechanism of action can justify the specific approach. The guidance

emphasizes the importance of the underlying biologic processes when using

any such models.

2.8.2 Precedents for Developing Short-Term Exposure Limits

Based on Carcinogenicity

The NRC guidance (1993a) for assessing the excess risks of genotoxic

carcinogens is based on an adaptation of the work of Crump and Howe (1984).

The Committee on Toxicology’s (COT’s) adaptation of the method was made

for developing emergency exposure guidance levels (EEGLs) and short-term

public emergency guidance levels (SPEGLs) for the U.S. Department of Defense (NRC 1986). EEGLs represent exposure levels that are acceptable for

the performance of specific tasks by military personnel during emergency

conditions lasting 1 to 24 h. SPEGLs represent acceptable airborne concentrations for a single, unpredicted short-term emergency exposure to the public.

The exposure periods range from 1 h or less to 24 h, and the SPEGLs are

generally set at 0.1 to 0.5 times the corresponding EEGL values.

The criteria and methods document prepared by COT for the development

of EEGLs and SPEGLs indicates that theoretical excess carcinogenic risk

levels in the range of 10-4 to 10-6 were generally considered acceptable risk

levels (NRC 1986). However, the document states, “The role of short-term

exposures in producing cancer is not clear. . . . [A]ny exposure to a carcinogen
DERIVATION OF AEGL VALUES 115 

has the potential to add to the probability of carcinogenic effects . . . [but] the

effects of long or repeated exposures could greatly overshadow brief exposures

(up to 24 h).” Additionally, the NRC report states, “The assumption that the

carcinogenic response is directly proportional to total dose is likely not to hold

for all materials and all tissues that these materials affect.” However, these

concerns not withstanding, the NRC set SPEGL values based on the carcinogenic risk-assessment method previously mentioned for hydrazine, methyl

hydrazine, and 1,1-dimethyl hydrazine (NRC 1985). In each case, the theoretical excess cancer risk level used was 10-4, and the derived values were determined to be lower than corresponding airborne concentrations that were estimated to cause acute toxicity. SPEGL values for exposure periods of less than

24 h of other known or suspect human carcinogens were not based on carcinogenicity. These chemicals included benzene, trichloroethylene, ethylene oxide, and lithium chromate.

The National Aeronautics and Space Administration (NASA) requested

that the NRC develop spacecraft maximum allowable concentrations (SMACs)

for space-station contaminants. The NRC published guidelines for the development of short-term and long-term SMACs (NRC 1992a). Short-term

SMACs refer to concentrations of airborne substances that will not compromise the performance of specific tasks during emergency conditions lasting up

to 24 h. Because of NASA's concern for the health, safety, and functional

abilities of space crews, SMACs for exposure from 1 to 24 h should not cause

serious or permanent effects but may cause reversible effects that do not impair judgment or interfere with proper responses to emergencies. The longterm SMACs are designed to prevent deterioration in space-crew performance

with continuous exposure for up to 180 days.

The guidelines for determining SMACs for carcinogens recommend the

methods proposed by Kodell et. al. (1987) based on the linear multistage

model. The level of theoretical excess risk used in the computation was 10-4.

The guidelines suggest extrapolations of long-term (often lifetime) exposures

to shorter durations, such as 1, 30, or 180 days, and refer to a single-day exposure as “the case of near instantaneous exposure.” Further, the guidance states,

“It must be remembered that extrapolation from a daily lifetime exposure level

and conversion to an instantaneous exposure level using . . . [equations presented] . . . is an extreme case and is valid only under the assumptions underlying the multistage theory of carcinogenesis.” A review of the first three volumes of published SMACs (35 chemicals), including 10 known or suspected

carcinogens, indicated that an assessment of excess risk for less than a 24-h

exposure period was conducted on only 1 of the 10 carcinogenic substances.

Carcinogenic assessments for excess risk were conducted on all 10 chemicals

for 24 h, as well as 7, 30, and 180 days. The reasons provided in the NRC
116 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

report for not undertaking a risk assessment on carcinogenic substances for

exposure periods of less than 24 h included the following: (1) “Data not considered applicable to the exposure time (1 hr)”; (2) “Extrapolation to 1 hour

exposure duration produces unacceptable uncertainty in the values”; and (3)

“The NRC model was not used to calculate acceptable concentrations for

exposures shorter than 24 hours” (NRC 1992a).

As stated previously, to date no U.S. federal or state regulatory agency has

promulgated or established regulatory limits for single short-term (less than 24

h) exposures based on carcinogenic properties.

2.8.3 Scientific Basis for Credible Theoretical Excess Carcinogenic

Risk Assessments for Single Exposures of 8 Hours or Less

The NRC guidance (NRC 1993a) explains that AEGLs can be developed

using carcinogenic risk-assessment methods for exposure durations of 1 to 8

h provided adequate data are available. However, the guidance states that risk

assessments on chemical carcinogenicity in humans should be based on all

relevant data and embody sound biologic and statistical principles. While

some of the substances may be considered known human carcinogens, most

of the information is based on animal testing information. Additionally, since

the mode of action for animal carcinogens are not always the same with respect to biologic properties among animal species or strains and humans, a

weight-of-evidence evaluation must be carried out on a case-by-case basis.

The weight-of-evidence evaluation considers comparative metabolic disposition, dose-dependent pharmacokinetic parameters, routes of exposure, mechanisms of action, and organ or species differences in response in animals and

humans.

Uncertainties regarding lifetime theoretical excess carcinogenic risk assessments increase as shorter durations of a single exposure are considered.

Most of these concerns stem from the reliance of both conclusions of carcinogenicity and quantitative assessments on long-term exposures in humans in

occupational settings or in test animals. Thus, calculations for short-term risks

require substantial extrapolation. At the same time, there are special concerns

and unresolved issues regarding short exposures that will require more relevant

data before they can be resolved. As evidenced from the actual application of

these guidelines, COT was reluctant in most cases to develop quantitative

carcinogenic risk assessments for less than 24-h exposures in the development

of SMACs.

To better understand the empirical database for single exposures, EPA

funded a study for the AEGL Program (Dr. Edward Calabrese of the Univer-
DERIVATION OF AEGL VALUES 117 

sity of Massachusetts was given a contract) to review the published literature

and assess the circumstances during which a single exposure of short duration

may be associated with a confirmed increase in carcinogenic response. This

effort, referred to as the Single Exposure Carcinogen Database, represents a

computerized summary that may assist the NAC/AEGL Committee’s assessment of whether a single exposure to a particular chemical under consideration

for AEGL development might cause tumor development following a one-time

inhalation exposure. The data base is designed to contain numerous parameters important to tumor outcome and/or quality of the studies conducted. The

database will contain approximately 5,500 “studies” or data sets involving

approximately 500 chemicals from nearly 2,000 references.

Although a summary of the Single Exposure Carcinogen Database Project

has been presented to the NAC/AEGL Committee, at the present time it is not

known whether the data available on single exposures of carcinogenic substances will be sufficient to justify their use in the development of AEGL

values. A preliminary review of the database indicates that only a limited

number of short-term carcinogenesis bioassays conducted by the inhalation

route are available. Hence, route-to-route extrapolations would be required in

a manner that would not substantially weaken the conclusions reached for

certain substances using standard EPA or NRC procedures if the toxicant is

likely to cause tumors at a site other than the port of entry. If the substance

causes tumors at the site of application or port of entry in oral or parenteral

protocols, extrapolation to the inhalation route of exposure becomes problematic. For this reason, the NAC/AEGL Committee in most cases will rely on

data from long-term animal studies as the basis for the quantitative cancer risk

assessments for short-term exposures of 8 h or less. It is anticipated that work

on the Single Carcinogen Database may be completed in 2001. 

The Single Carcinogen Database may prove to be useful in obtaining some

important information for AEGL development. The database shows that single

exposure to various chemical classes, using various species and strains of

animals, can result in tumor formation. Furthermore, chemicals can be selected from the database for which there is dose-response information. Data

and information from positive responses of the chemical in the database could

be compared between the single-dose study and the long-term study.

2.8.4 Practical Issues of Using Quantitative, Carcinogenic

Risk Assessments for Developing AEGLs

In addition to fundamental scientific issues regarding carcinogenic risk

assessments in the development of AEGL values, there are important practical
118 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

issues to be considered by emergency planners and responders regarding

AEGL values based on possible carcinogenic risk. The theoretical excess

cancer risk for a lifetime exposure to known or suspect human carcinogens

considered safe and protective of the public health ranges from 10-6 to 10-4 for

EPA and most other U.S. federal regulatory agencies (EPA 1991). The AEGL

values, however, are designed for emergency planning for, response to, and

prevention of accidental releases from chemical accidents. Thus, theoretical

excess cancer risk may be accumulated in 30 min or in a few hours. In addition to the individual risk of 10-6 to 10-4, one should also consider a measure

of population based risk. Experts in the chemical accident field indicate that

the typical U.S. population at risk during most accidental chemical releases is

in the range of 1,000 to 5,000 persons. The actual number of persons exposed

depends on many factors, such as population density, quantity released, release

rate, prevailing wind direction and velocity, terrain, and ambient temperature

to name a few. Therefore, a population-based risk range of 10-6 to 10-4, assuming a credible carcinogenic assessment can be made, approaches zero for a

population of 1,000 to 5,000 or higher. The consideration of population-based

risks using assessment methodologies designed for individual risks has precedent in EPA assessments of new industrial chemicals under TSCA (Toxic

Substance Control Act) Section 5 and pesticide chemicals under FIFRA (Federal Insecticide Fungicide and Rodenticide Act).

Implementation of emergency-response procedures based on theoretical

excess risk values of 10-6 to 10-4 may be problematical. For example, if such

values were used, they would be based on an anticipated increased cancer risk

of 10-6 to 10-4, a policy consistent with EPA's acceptable cancer risk for lifetime exposures to known or suspect human carcinogens. However, the public

health and safety risks associated with evacuation and other response measures

might pose greater risks of injury or perhaps death. Thus, setting AEGL values based on uncertain theoretical cancer risk estimates might lead to response

measures that increase actual or total risk for the exposed population.

2.8.5 Current Approach of the NAC/AEGL Committee to Assessing

Potential Single Exposure Carcinogenic Risks

On the basis of the discussions and considerations presented in the earlier

sections of this chapter on cancer risk assessment, the NAC/AEGL Committee

has developed no AEGL values based on carcinogenicity. In view of the great

uncertainty of the assumptions used in extrapolating from lifetime exposures

to 8 h or less, the paucity of single-exposure inhalation data, the relatively
DERIVATION OF AEGL VALUES 119 

small populations involved, and the potential risks associated with evacuations

and other response measures, the NAC/AEGL Committee does not believe

their use in setting AEGL values is justifiable at the present time.

However, the NAC/AEGL Committee will continue to identify and evaluate carcinogenic data during the development of AEGLs on a chemical-bychemical basis. The scientific parameters used in this analysis are presented

later in this section. In those cases in which, in the judgment of the committee,

it is appropriate, risk assessments for 10-4, 10-5, and 10-6 levels of cancer risk

will be conducted. It is believed that information on known or suspect human

carcinogens should be provided to emergency planners and responders and

made available to the public even when such information is not used to set

AEGL values. Therefore, the NAC/AEGL Committee will continue to provide

data and information on the carcinogenic properties of chemicals in the TSDs

and, in instances in which the appropriate data are available, develop quantitative cancer risk assessments at risk levels of 10-4, 10-5, and 10-6 in accordance

with the NRC guidance (NRC 1993a). The NAC/AEGL Committee will

attempt to limit potential cancer risk to 10-4 or less when there are scientifically

credible data to support the risk estimates when based on a single exposure.

When substantial and convincing scientific data become available that clearly

establish a relationship between a single short-term inhalation exposure to a

chemical and the onset of tumors that are likely to occur in humans, the carcinogenic risk in the development of the appropriate AEGL values will be given

appropriate weight-of-evidence considerations.

2.8.5.1 Evaluation of Carcinogenicity Data

The evaluation of the carcinogenic potential of a chemical exposure in

humans must be based on analyses of all relevant data. Human epidemiologic

and clinical studies, as well as accidental-exposure reports are considered and

used to evaluate the carcinogenic potential of a substance. In the absence of

human data, long-term bioassay data from controlled animal studies are used

to derive theoretical excess carcinogenic risk estimates for exposed humans.

The selection of data for estimating risk is based on the species and strain

considered to resemble the human response most closely to provide the most

accurate estimates.

Data suggestive of a single exposure inducing a carcinogenic response,

including related mechanistic data that support such a possibility, are considered. Weight should be given to those studies most relevant to estimating

effects in humans on a case-by-case basis. Data for assessing the strength of
120 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

conclusions drawn from controlled animal studies should include information

on comparative metabolic pathways, dose-dependent pharmacokinetic parameters, mode of exposure, mechanisms of action, and organ or species differences

in response. In general, the NAC/AEGL Committee will follow a weight-ofevidence approach in the evaluation of carcinogenicity that is consistent with

the availability and biologic variability of the data and its relationship to the

likelihood of effects in humans.

2.8.5.2 Methodology Used for Assessing the Carcinogenic Risk of a

Single Exposure

Guidance published by the NRC (1993a) states that the setting of AEGLs

(CEELs) should involve linear low-dose extrapolation from an upper confidence limit on excess risk for genotoxic carcinogens and for carcinogens with

mechanisms of action that are not well understood. More specifically, the

NRC guidance suggests an approach utilizing the methods proposed by Kodell

et al. (1987) based on multistage models. Although the NRC guidance states

that multistage models could be useful for setting AEGL values, the guidance

acknowledges that sufficient information may not be available to postulate the

total number of stages in the cancer process and the stages that are dose-related. In these instances, the NRC guidance recommends the use of the

time-weighted-average dose where the instantaneous dose D at time t0 is assumed to be the equivalent of the lifetime excess carcinogenic risk as daily

dose D up to time t. This equivalence is expressed by the equation D = d × t.

As shown by Kodell et al. (1987), the actual risk will not exceed the number

of stages in the model (k). In instances in which multistage models can be

used and prudence dictates conservatism, the NRC guidance suggests reducing

the approximation of D by an adjustment factor of 2 to 6, depending on the

number of assumed stages in the multistage model used.

To date, the NAC/AEGL Committee has evaluated excess theoretical risk

at levels of 10-4, 10-5, and 10-6 for a one-time exposure to known or suspect

human carcinogens by determining the total cumulative lifetime dose and

applying Haber’s law for exposure periods ranging from 30 min to 8 h. The

resultant doses are then divided by an adjustment factor to account for the

multistage nature of carcinogens (see Appendix H).

2.8.5.2.1 Determination of an Adjustment Factor for the DoseDependent Stage of Carcinogenesis

There is an extensive body of literature that deals with the concept of
DERIVATION OF AEGL VALUES 121 

malignant tumor development, progression of an initiated cell through of

successive stages, and quantitative carcinogenic risk assessment. Two references, Crump and Howe (1984) and Kodell et al. (1987), are cited in the NRC

(1993a) publication. The concept has been further discussed (Goddard et al

1995; Murdoch et al. 1992; Murdoch and Krewski 1988; Bogen 1989). This

process is referred to as a cell kinetic multistage model. There are several

published variations of the basic tenants in the model. If only one or more

stages are dose-dependent and exposure is concentrated in the dose-dependent

stage, it is possible to underestimate risk when the risk is based on lifetime

exposure. For example, if the first stage is dose-dependent, and there is a

single exposure to an infant, the probability of cancer induction is maximized,

because the entire lifetime of the individual is available for progression

through the remaining stages in the development of the cancer. If the same

dose were given to an elderly person, the probability of inducing cancer approaches zero, because there is insufficient time remaining in the life of that

individual for the initiated cell to progress through the subsequent stages to a

malignant cancer. Kodell et al. (1987) demonstrated that the underestimation

of risk that is based on a lifetime of exposure will not exceed the number of

stages in the multistage model. For this reason, the NRC (1986) recommends

dividing the risk assessment based on the lifetime exposure by a factor between 2 and 6 to account for the number of stages in the multistage model

applicable to the particular chemical of concern.

In addition to the multistage model, there have been a number of publications investigating the two-stage birth-death-mutation model (Morrison 1987;

Chen et al. 1988; Murdoch and Krewski 1988; Moolgavkar and Luebeck

1990; Murdoch et al. 1992; Goddard et al. 1995). This model is similar to the

multistage model. However, the impact of the number of stem cells at the time

of chemical exposure is considered as well as the net growth rate of cells that

have undergone the first stage of initiation. If the first-stage initiating event

creates a cell that has a net growth rate greater than that of the stem cell, then

the risk of that initiating event will be greater than it would be if the initiated

cell grew at the same relative rate as the stem cell. In this case, exposure early

in life results in a greater risk than exposure late in life. Conversely, exposure

to a promoter (effects only the second stage) late in life will be more effective

than early exposure, because relatively more initiated cells are present. If this

stage is the only stage affected by the chemical, this situation is the same as

that in the two stages of the multistage model. However, if the net growth rate

of the initiated cells is 10 times the stem-cell rate, the relative effectiveness of

exposure late in life could be 10-fold (Murdoch and Krewski 1988). Exposure to promoters between the first- and second-stage event can have an impact

by increasing the net growth rate of initiated cells over that of stem cells. For
122 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

maximum effectiveness, exposure to promoters (generally considered to be a

nongenotoxic event) must encompass multiple challenge (Chen et al. 1988;

Murdoch and Krewski 1988). Thus, the cancer risk associated with a single

exposure to a promoter should not be greater than that predicted for multiple

exposures, and no correction to the estimated risk has to be made in this case.

A major impact upon the risk assessment of the two-stage model comes

from carcinogen exposure during the first stage in which the initiation event

creates a cell with a greater net growth rate than the stem-cell rate. Modelers

have considered a number of scenarios in which the net growth rate of initiated

cells varies from -10 to +10. The greatest increase in risk in the two-stage

model occurs when the first stage is dose-dependent and the initiating event

creates a cell with a net growth rate of +10. In that case, the increased risk is

10-fold (Murdoch and Krewski 1988; Murdoch et al. 1992; Goddard et al.

1995).

Data are lacking on the biologic plausibility of the maximum value for the

net growth rate of initiated cells (Murdoch et al 1992). Major data requirements for the two-stage birth-death-mutation model include the number of

stem cells at different times of the life cycle, their rates of division and differentiation, and their response to chemical exposure in terms of cell division and

mutation rate. This information is also needed for the initiated-cell populations (Moolgavkar and Luebeck 1990). Because of these data gaps, the projections made for the two-stage model remain more speculative than those for the

multistage model in which there is general agreement that the number of stages

should not exceed six.

For the above reasons, the linearized multistage model is used as a default

when estimating risks for short-term exposures from lifetime carcinogenesis

bioassays. In all of the above referenced publications on the multistage model,

the maximum number of stages modeled was six.

AEGL values are applicable to humans in all stages of life, so the maximum risk to an infant must be taken into consideration. In this case, the concentration based on a lifetime exposure study is divided by 6 unless there is

evidence that the chemical is a late-stage carcinogen or operates by mechanisms different from those assumed in development of the linearized multistage model. As a first approximation, the NAC/AEGL Committee will use

the divisor of 6 in agreement with the NRC (1993a) guidance on the development of short-term exposure limits, which states that a factor of 6 represents

a conservative adjustment factor for a near-instantaneous exposure.
DERIVATION OF AEGL VALUES 123 

2.8.5.3 Summary of Cancer-Assessment Methodology Used by the

NAC/AEGL Committee

The EPA q1* values listed on the Integrated Risk Information System

(IRIS) or the GLOBAL86-generated slope-factor values (Howe et al. 1986) are

used to compute lifetime theoretical excess carcinogenic risk levels. These

values are based on EPA (1986) guidance. The EPA (1996a) proposed methodology will be considered in the future. These values are used to compute the

concentration for a single exposure for the time periods of interest. As discussed in the beginning of this section, these values are typically divided by

6 to account for early exposure to a carcinogen in which the first stage is dosedependent or for late exposure to a carcinogen in which the last stage is dosedependent. If there is information about the number of stages required for

development of the cancer or the stage that is dose-dependent, the divisor will

be modified accordingly. An example of a carcinogenicity assessment is given

in Appendix H.

The cancer evaluation includes a weight-of-evidence discussion, which

considers the following factors:

• Less evidence of carcinogenicity from a short-term exposure.

— No evidence for human carcinogenicity (may or may not lend

support to cancer induction from a single exposure but an important consideration).

— Lifetime or long-term exposure necessary to elicit cancer.

— Positive response only at very high doses.

— Neoplasia appears reversible (when treatment is discontinued).

— Appears to be a “threshold” carcinogen.

— Weak or absent mutagenic response in multiple in vivo and in

vitro test systems.

• Greater evidence of carcinogenicity from a short-term exposure.

— Confirmed human carcinogen (may or may not lend support to

cancer induction from a single exposure but an important consideration).

— Short time to tumor.

— Evidence for cancer from one to a few exposures.

— Positive response at low doses.

— Complete carcinogen.

— Irreversible (when treatment is discontinued).

— Potent mutagen in multiple in vivo and in vitro test systems.
124 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

2.9 GUIDELINES AND CRITERIA FOR MISCELLANEOUS

PROCEDURES AND METHODS

2.9.1 Mathematical Rounding of AEGL Values

Given the uncertainties involved in generating AEGL values, it could be

argued that only one significant figure should be used. However, because of

a number of considerations discussed below, AEGL numbers are rounded to

two significant figures (e.g., 1.5, 23, or 0.35). The value 7.35 is rounded to 7.4.

Trivial differences in numbers can give large differences in practice if only

one significant figure is used. For example, values of 14.9 and 15.1 would

yield AEGL values of 10 and 20, respectively. This is a 2-fold difference for

a very small difference in computed AEGL values. Values of 18, 14, 11, and

6 ppm for 30 min, 1 h, 4 h, and 8 h would give values of 10, 10, 10, and 20

ppm, respectively, for the time points. As these numbers are often used in

exposure models to make risk-management decisions, the use of two significant figures allows for a more reasonable progression when different exposure

scenarios are considered.

Two significant figures may seem overly precise when values less than 1

ppm are presented, because those levels may be difficult to quantify to that

level of precision. However, the AEGL-2 values will often be used to compare with ambient air-dispersion modeling projections for planning purposes.

In this case, the use of two vs one significant figure can have substantial practical impact. Other rounding schemes may be used on a case-by-case basis

with justification.

2.9.2 Multiplication of UFs

The NAC/AEGL Committee often multiplies two UFs of 3. Since the

value 3 represents the geometric mean of 10 and 1, the actual number is 3.16.

Therefore, the product of two different UFs is not 3 × 3 but 3.16 × 3.16, which

equals 10. For simplicity’s sake, 3.16 × 10 is represented by 30. 

2.9.3 Conversion Between Parts per Million and

Milligrams per Cubic Meter

Expressing the airborne concentration of a chemical in parts per million

represents a volume-by-volume approach, and milligrams per cubic meter
DERIVATION OF AEGL VALUES 125 

represents a mass-by-volume approach to quantifying the concentration. Because a change of temperature with little or no change in pressure or a change

in pressure with little or no change in temperature will result in changes in the

volume of the air with no change in the mass of the chemical dispersed in the

air, the airborne concentration of the chemical expressed as milligrams per

cubic meter can vary at different elevations above sea level and at different

temperatures at the same elevation. Airborne concentrations expressed as parts

per million represent a volume-by-volume comparison and therefore do not

change, regardless of changes in elevation (pressure) or temperature. 

AEGLs are expressed in parts per million. However, many inhalation

studies on toxicity report the chemical concentrations in milligrams per cubic

meter. In deriving AEGL values, it is assumed that the concentrations reported

were measured at normal temperature and pressure (i.e., 25o

 C or 298o K and

760 mm Hg). The NAC/AEGL Committee uses this assumption in all cases

in which concentrations in milligrams per cubic meter are converted from parts

per million, or data in parts per million are converted to milligrams per cubic

meter.

The effect of elevation above sea level is approximately 15% when comparing mass-by-volume (milligrams per cubic meter) in New York City and

Denver, Colorado. Although elevation may not be a major consideration, the

effect of converting parts per million to milligrams per cubic meter at various

pressures (elevations) and temperatures can be made by using the following

equation:

mg/m3

 at Pa and Ta = (ppm) × ((MW)/(24.45 × (760 mm Hg) × Ta/(Pa ×

(298o

K)))),

where

Pa = the absolute pressure (in mm Hg) at actual conditions.

Ta = the absolute temperature (in o

K) at actual conditions.

MW = molecular weight.
124

3. Format and Content of

Technical Support Documents

The technical support document (TSD) is the compilation of all relevant data

and information from all key studies and references and the most important

supporting studies and references for both human exposures and laboratory

animal exposures. Additionally, this support document addresses all the methodologies used in the derivation of the AEGL values and presents the rationale

and justification for the use of certain data in the derivation and for the elimination of certain studies or data. The TSD addresses why specific methodologies and adjustment factors were or were not used, the scientific evidence

supporting the rationale and justification, and the appropriate references to the

published scientific literature or sources of unpublished information.

Major components of the TSD are (1) a summary section that includes a

concise summary of toxicity information on the chemical, rationales used for

time scaling and selection of uncertainty factors, and a table of AEGL values

for the three tiers as well as key references; (2) a detailed discussion of the

items listed in 1; and (3) a derivation summary table that includes a list and

discussion of the key data elements and the rationale used to derive the AEGL

values.

EDITORIAL CONVENTIONS

• Concentrations will be expressed in the units used in the original

publication. If the data in the publication or other data sources are
FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS 125 

expressed in parts per million (ppm), enter only ppm values. If the

data are expressed in milligrams per cubic meter (mg/m3

) or other

units, then state the concentrations as expressed in the data source and

add the ppm values in parentheses.

• References to footnotes should be superscript and lower case.

3.1 FORMAT AND CONTENT OF

TECHNICAL SUPPORT DOCUMENTS

Preface

The AEGL tiers are defined in the Preface of each TSD. See Section 2.1

for definitions of AEGLs 1, 2, and 3.

Table of Contents

Major headings in the text, tables, and figures should be marked

with the word processor indexing tool so that the Table of Contents can

be generated by the computer. A sample Table of Contents is presented

in Appendix D.

Summary

The Summary should include the following:

• The name and CAS number of the chemical being reviewed.

• A brief description of the substance, its physical properties, and uses.

• A brief statement or overview of the toxicology, including the extent

of the data and information retrieved and reviewed, highlights of the

most important research and strengths and weaknesses of the database.

Discuss data on human exposures and data on laboratory animals.

• A brief summary (one paragraph for each AEGL tier) of the key study

(with references), the data used, and the derivation of the AEGL

values. Each summary will include the following:

— Information on the endpoints of concern and exposure levels used

as the basis for deriving the AEGL values.
126 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

— Exposure level (If the data in the publication are expressed in

ppm, enter only ppm values. If the data are expressed in mg/m3

or other units, state the concentrations as expressed in the publication and add the ppm values in parentheses.).

— Exposure period.

— Why the time-concentration point was selected (include effects

observed or not observed, relate to the AEGL level, etc.).

— The species and number of animals used.

— Consistency with human data as appropriate.

— The reference to the key study.

— Uncertainty factors and modifying factors used or not used and

why a specific value was chosen.

— The time-scaling method used and why it was selected (include

the rationale for the value of n in the time-scaling equation).

• A brief statement regarding carcinogenicity, if appropriate.

• A brief statement on the adequacy of the data (see Section 2.3.3 of this

SOP manual).

• A summary table of draft/proposed AEGL values with

— Values presented in ppm with mg/m3 values in parentheses.

— A rationale and reference for AEGL-1, -2, and -3.

— Reasons for no AEGL value.

• References.

A sample Summary is presented in Appendix E.

Outline of the Main Body of the Technical Support Document

1. Introduction

• General information regarding occurrence, production and use, and

physical-chemical data (table for physical-chemical data)

2. Human Toxicity Data

2.1 Acute Lethality (include anecdotal case reports if pertinent)

2.2 Nonlethal Toxicity

2.2.1 Acute Studies (include anecdotal case reports if pertinent)

2.2.2 Epidemiologic Studies

2.3 Developmental and Reproductive Toxicity
FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS 127 

2.4 Genotoxicity

2.5 Carcinogenicity (include EPA and IARC classifications)

2.6 Summary (weight-of-evidence approach)

• Tabulation of data as appropriate within sections and/or in summary

3. Animal Toxicity Data

3.1 Acute Lethality (include species and strain, number of animals, exposure concentrations and durations, mortality rates and ratios, time to

death) (To maintain a standardized format, the order of animals shown

below should be used.)

3.1.1 Nonhuman Primates

3.1.2 Dogs

3.1.3 Rats

3.1.4 Mice

3.1.5 Guinea Pigs

3.1.6 Rabbits

3.1.7 Other Species

• Sections to include relevant studies (potential key studies and supporting data) or provide overall picture of toxicity data as appropriate

• Third-level headers to vary, depending upon available data; exclusion

of header to mean no relevant data available

3.2 Nonlethal Toxicity (include species and strain, number of animals,

exposure concentrations and durations, critical effects, time-course

data) (The order of animals shown should be used. If no data are available for a species, the number should be used for the next species

discussed.)

3.2.1 Nonhuman Primates

3.2.2 Dogs

3.2.3 Rats

3.2.4 Mice

3.2.5 Guinea Pigs

3.2.6 Rabbits

3.2.7 Other Species

• Sections to include relevant studies (potential key studies and supporting data) or provide overall picture of toxicity data as appropriate
128 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

• Third-level headers to vary, depending upon available data; exclusion

of header to mean no relevant data available

3.3 Developmental and Reproductive Toxicity

3.4 Genotoxicity

3.5 Carcinogenicity

3.6 Summary (weight-of-evidence approach)

• Tabulation of data as appropriate within sections and/or in summary

4. Special Considerations

4.1 Metabolism and Disposition (general background; interspecies and

individual variabilities, especially as they pertain to AEGL derivation)

4.2 Mechanism of Toxicity (general background; interspecies and individual variabilities, especially as they pertain to AEGL derivation)

4.3 Structure-Activity Relationships (data relevant to filling data gaps on

the chemical)

4.4 Other Relevant Information

4.4.1 Species Variability 

4.4.2 Concurrent Exposure Issues (e.g., potentiation)

• Third-level headers to vary, depending upon available data; exclusion

of header to mean no relevant data available

5. Data Analysis for Proposed AEGL-1

5.1 Summary of Human Data Relevant to AEGL-1 (general summary

description of selected key and supporting study or studies if available)

5.2 Summary of Animal Data Relevant to AEGL-1 (general summary

description of selected key and supporting study or studies if available)

5.3 Derivation of AEGL-1 (key study, critical effect, dose-exposure concentration, uncertainty factor application and justification, temporal

extrapolation, assumptions, confidence, consistency with human data

if appropriate)
FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS 129 

6. Data Analysis for Proposed AEGL-2

6.1 Summary of Human Data Relevant to AEGL-2 (general summary

description of selected key and supporting study or studies if available)

6.2 Summary of Animal Data Relevant to AEGL-2 (general summary

description of selected key and supporting study or studies if available)

6.3 Derivation of AEGL-2 (key study, critical effect, dose-exposure concentration, uncertainty factor application and justification, temporal

extrapolation, assumptions, confidence, consistency with human data

if appropriate)

7. Data Analysis for Proposed AEGL-3

7.1 Summary of Human Data Relevant to AEGL-3 (general summary

description of selected key and supporting study or studies if available)

7.2 Summary of Animal Data Relevant to AEGL-3 (general summary

description of selected key and supporting study or studies if available)

7.3 Derivation of AEGL-3 (key study, critical effect, dose-exposure concentration, uncertainty factor application and justification, temporal

extrapolation, assumptions, confidence, consistency with human data

if appropriate)

8. Summary of Proposed AEGLs

8.1 AEGL Values and Toxicity Endpoints

8.2 Comparison with Other Standards and Criteria (summarized in text

and presented in a table; see SOP Appendix J for an example)

8.3 Data Adequacy and Research Needs (for content, see Section 2.3.3 of

this manual)

9. References

• List of references cited in document.
130 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

10. Appendixes

APPENDIX A (Derivation of AEGL Values) (see SOP Appendix F for

an example)

APPENDIX B (Time-Scaling Calculations) (see SOP Appendix G for an

example)

APPENDIX C (Carcinogenicity Assessment) (see SOP Appendix H for

an example)

APPENDIX D (Derivation Summary) (see SOP Appendix I for specific

format and an example) 

Format for Derivation Summary:

DERIVATION SUMMARY (CHEMICAL NAME)

(CAS No.)

AEGL-1 (OR -2 OR -3) Values

10 min 30 min 1 h 4 h 8 h

ppm ppm ppm ppm ppm

Reference:

Test Species/Strain/Number:

Exposure Route/Concentrations/Durations:

Effects:

Endpoint/Concentration/Rationale:

Uncertainty Factors/Rationale:

Modifying Factor:

Animal to Human Dosimetric Adjustment:

Time Scaling:

Data Adequacy:a

a

 Elements that should be included in the Data Adequacy entry are discussed in

Section 2.3.3 of this SOP manual. If an AEGL-1 value is not recommended, there

should be a short discussion of the rationale for that choice. The rationale should

include, as appropriate, a discussion that numeric values for AEGL-1 are not recommended because (1) relevant data are lacking, (2) the margin of safety between the

derived AEGL-1 and AEGL-2 values is inadequate, or (3) the derived AEGL-1 is

greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below

the AEGL-2 is without adverse effects.
FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS 131 

 3.2 GRAPHIC DESCRIPTION OF DATA

Graphic descriptions of relevant data can be helpful in identifying, understanding, and comparing similarities and differences, degree of variation, and

trends among the values cited. Well-prepared graphs provide the reader with

an overview of dose-response relationships in terms of both airborne concentrations and exposure periods in various studies and various species. The

graphs should supplement the data tables but cannot replace tabular summaries. The graphs can be placed in the body of the document or in an appendix.

Below are examples of presentations of graphic data.

Comparisons between different times and the toxicity values are difficult

because the values vary according to the time. A particularly useful way to

present the data (Table 3-1 and Figure 3-1) is based on the concept of placing

the toxic response into severity categories (Hertzberg and Miller, 1985;

Hertzberg and Wymer, 1991; Guth et al., 1991). In Table 3-1, the severity

categories fit into definitions of the AEGL health effects. The category severity definitions for the column headings are 0 = no effect; 1 = discomfort; 2 =

disabling; 3 = lethal; NL = did not die at a lethal concentration (at an experimental concentration in which some of the animals died and some did not, the

NL label refers to the animals that did not die); AEGL or C = AEGL or

censored (severity category could not be established). The effects that place

an experimental result into a particular category vary according to the spectrum of data available on a specific chemical and the effects from exposure to

that chemical. When the exposure concentration is placed into the appropriate

column, the graph in Figure 3-1 is generated. The doses often span a number

of orders of magnitude, especially when human data exist. Therefore, the concentration is placed on a log scale. Note that the AEGL values are designated

as a triangle without an indication to their level. The AEGL-3 is higher than

the AEGL-2, which is higher than the AEGL-1.

This type of plot is useful for a number of reasons and can be used to

address the following questions:

• Are the AEGL values protective?

— Are the AEGL-3 values below the concentration causing death in

experimental animals? If the answer is no, then the question

should be raised about the appropriateness of the AEGL-3 value.

Is the AEGL-3 value appropriate and the data point anomalous, or

should the AEGL-3 value be lowered?

— Similar questions should be asked about the AEGL-1 and AEGL2 values.
TABLE 3-1 Grouping Data into Categories for Plotting

Reference Species Sex

# Exposures ppm Min ppm ppm ppm ppm ppm ppm Cate- gory Gp Size Incid- ence Comments

Toluene 0 1 2 NL 3 AEGL Category

0 = no effect1 = discomfort 2 = disabling3 = lethal ND = did not die at le concentrationAEGL or C = AEGL 

 censore

NAC/AEGL-1 115 30 115 AEGLNAC/AEGL-1 82 60 82 AEGLNAC/AEGL-1 41 240 41 AEGLNAC/AEGL-1 29 480 29 AEGLNAC/AEGL-2 267 30 267 AEGLNAC/AEGL-2 189 60 189 AEGLNAC/AEGL-2 94 240 94 AEGLNAC/AEGL-2 67 480 67 AEGLNAC/AEGL-3 897 30 897 AEGLNAC/AEGL-3 634 60 634 AEGLNAC/AEGL-3 317 240 317 AEGLNAC/AEGL-3 224 480 224 AEGLBaelum et al.1985

hu 1 100 390 100 1 sensory irritation,

sleepiness, intoxicatiodecreased manualdexterity and colordiscrimination

Wilson 1943 hu many 200 480 200 1 headache, lassitude,

anorexia

Wilson 1943 hu many 200 480 200 2 headache, nausea,

incoordination, increareaction time
Wilson 1943 hu many 500 480 500 2 headache, nausea,

incoordination, increareaction time

Wilson 1943 hu many 500 480 500 1 headache, nausea,

incoordination, decreareaction time and palption, extreme weaknes

Ukai et al. 1993 hu many 100 480 100 1 weight loss, dizziness

headache, tightness inchest, dimmed vision

Lee et al. 1988 hu many 100 480 100 1 weight loss, dizziness

headache

Gamberale & Hultengren1972

hu 1 300 20 300 1 reaction time affected

Gamberale &Hultengren1972

hu 1 700 20 700 1 decrease in perceptua

speed

von Oettingenet al. 1942

hu 1 200 480 200 2 muscular weakness, c

fusion, impaired coordnation, dilated pupils

von Oettingenet al. 1942

hu 1 200 480 200 2 severe incoordination

confusion, dilated pupnausea, extreme fatigu

von Oettingenet al. 1942

hu 1 600 480 600 2 severe incoordination

confusion, dilated pupnausea, extreme fatigu

von Oettingenet al. 1942

hu 1 800 180 800 2 loss of self-control,

muscular weakness,extreme fatigue, nausebone marrow suppres
TABLE 3-1 (Continued)Reference Species Sex

# Exposures ppm Min ppm ppm ppm ppm ppm ppm Cate- gory Gp Size Incid- ence Comments

Toluene 0 1 2 NL 3 AEGL Category

Baelum et al.1990

hu 1 100 420 100 1 sensory irritation, alte

temp. perception,headache, dizziness

Echeverria etal. 1991

hu 1 150 420 150 1 decreased performanc

on spatial andneurobehavioral tasksheadache, eye irritatio

Andersen et al.1983

hu 1 40 360 40 1 no effect/sensory

irritation, increase in odor level

Andersen et al.1983

hu 1 100 360 100 1 no effect/sensory

irritation, increase in odor level

Rahill et al.1996

hu 1 100 360 100 0 increased latency on a

neurobehavioral task a biologically relevanneurobehavioral defic

Dick et al. 1984 hu 1 100 240 100 0 decreased accuracy on

visual-vigilance test (nbiologically relevantneurobehavioral defic

Cherry et al.1983

hu 1 80 240 80 0 no impairment on

neurobehavioral tasks

Carpenter et al.1976

hu 1 220 15 220 1 sensory threshold for 

irritation
Pryor et al.1978

rat 1 26,700 60 26,700 NL LC50

Pryor et al.1978

rat 1 26,700 60 26,700 3 LC50

Cameron et al.1938

rat 1 24,400 90 24,400 NL 60% mortality

Cameron et al.1938

rat 1 24,400 90 24,400 3 60% mortality

Kojima andKobayashi1973

rat 1 15,000 150 15,000 NL 80% mortality

Kojima andKobayashi1973

rat 1 15,000 150 15,000 3 80% mortality

Cameron et al.1938

rat 1 12,200 390 12,200 3 100% mortality

Carpenter et al.1976

rat 1 8,800 240 8,800 NL LC50

Carpenter et al.1976

rat 1 8,800 240 8,800 3 LC50

Smyth et al.1969

rat 1 4,000 240 4,000 NL 16% mortality 

Smyth et al.1969

rat 1 4,000 240 4,000 3 16% mortality 

Bonnet et al.1979

mouse 1 6,940 360 6,940 NL LC50

Bonnet et al.1979

mouse 1 6,940 360 6,940 3 LC50

Svirbely et al.1943

mouse 1 5,320 420 5,320 NL LC50
TABLE 3-1 (Continued)Reference Species Sex

# Exposures ppm Min ppm ppm ppm ppm ppm ppm Cate- gory Gp Size Incid- ence Comments

Toluene 0 1 2 NL 3 AEGL Category

Svirbely et al.1943

mouse 1 5,320 420 5,320 3 LC50

Moser andBalster 1985

mouse 1 38,465 10 38,465 NL LC50

Moser andBalster 1985

mouse 1 38,465 10 38,465 3 LC50

Moser andBalster 1985

mouse 1 21,872 30 21,872 NL LC50

Moser andBalster 1985

mouse 1 21,872 30 21,872 3 LC50

Moser andBalster 1985

mouse 1 19,018 60 19018 NL LC50

Moser andBalster 1985

mouse 1 19,018 60 19,018 3 LC50
10.0 

100.0 

1000.0 

10000.0 

100000.0 

ppm

0 60 120 180 240 300 360 420 480 

Minutes

no or minimal effectdiscomfortdisablingdid not die @ lethal colethalAEGL or censored

Chemical Toxicity - TSD All Data

Toluene

textbox

FIGURE 3-1 Plot of categories of data. 
138 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

• Are there data points that appear to be statistical outliers? Why are

they outliers? Should they be considered in the development of

AEGL values or discarded because of faulty experimental technique?

• Does the spread of data points for a particular severity category indicate major differences between species or are the results from different

species congruent?

• Is the time-scaling algorithm reasonable and consistent with the data?

For example, using the derived or chosen value of n in the equation Cn

× t = k, does the plot of the AEGL-3 values parallel the slope of the

lethality data? Similar questions can be asked about the AEGL-1 and

AEGL-2 plots.

• Is there evidence that a different time-scaling factor should be used for

the AEGL-2?

• What are the most appropriate data points to use for the time scaling?
139

4. Current Administrative Processes

and Procedures for the Development

of AEGL Values

The primary purpose of the AEGL program and the NAC/AEGL Committee

is to develop AEGLs for short-term exposures to airborne concentrations of

acutely toxic, high-priority chemicals. AEGLs are needed for a wide range of

planning, response, and prevention applications. These applications may include many U.S. initiatives, such as the Environmental Protection Agency

(EPA) Superfund Amendments and Reauthorization Act (SARA) Title III

Section 302-304 emergency planning program, the Clean Air Act Amendments (CAAA) Section 112(r) accident prevention program, and the remediation of Superfund sites program; the Department of Energy (DOE) environmental restoration, waste management, waste transport, and fixed facility

programs; the Department of Transportation (DOT) emergency waste response

program; the Department of Defense (DOD) environmental restoration, waste

management, and fixed facility programs; the Agency for Toxic Substances

and Disease Registry (ATSDR) health consultation and risk assessment programs; the National Institute for Occupational Safety and Health (NIOSH) and

Occupational Safety and Health Administration (OSHA) regulations and

guidelines for workplace exposure; the state CAA Section 112(b) programs

and other state programs; the U.S. Chemical Manufacturer’s Association (now

known as American Chemistry Council) Chemtrec program; and other chemical emergency programs in the U.S. private sector. From an international

perspective, it is anticipated that the AEGLs will find a wide range of applica-
140 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

tions in chemical emergency planning, response, and prevention programs in

both the public and private sectors of member countries of the Organization for

Economic Cooperation and Development (OECD). It is hoped that the AEGLs

also will be used by other countries in the international community.

A principal objective of the NAC/AEGL Committee is to develop the most

scientifically credible, acute (short-term) exposure guideline levels possible

within the constraints of data availability, resources, and time. This objective

includes highly effective and efficient efforts in data gathering, data evaluation, and data summarization, fostering the participation of a large cross-section of the relevant scientific community, both nationally and internationally,

and the adoption of procedures and methodologies that facilitate consensusbuilding for AEGL values within the NAC/AEGL Committee.

Another principal objective of the NAC/AEGL Committee is to develop

AEGL values for approximately 400 to 500 acutely hazardous substances

within the next 10 years. Therefore, the near-term objective is to increase the

production of AEGL documents to approximately 50 chemicals per year without exceeding budgetary limitations or compromising the scientific credibility

of the values developed.

To reach these objectives, the NAC/AEGL Committee must adopt and

adhere to specific processes and procedures both scientifically and administratively. This objective is accomplished through the development and maintenance of a comprehensive standing operating procedures (SOP) manual that

addresses the scientific and administrative procedures required to achieve the

objectives of the NAC/AEGL Committee. This section is devoted to those

administrative processes and procedures deemed necessary to achieve the

AEGL program objectives.

4.1 COMMITTEE MEMBERSHIP AND

ORGANIZATIONAL STRUCTURE

The NAC/AEGL Committee is composed of representatives of U.S. federal, state and local agencies, and organizations in the private sector that derive

programmatic or operational benefits from of the AEGL values. Federal representatives are from EPA, DOE, ATSDR, NIOSH, OSHA, DOT, DOD, the

Centers for Disease Control and Prevention (CDC), the Food and Drug

Administration (FDA), and the Federal Emergency Management Agency

(FEMA). States providing committee representatives include New York, New

Jersey, Texas, California, Minnesota, Illinois, Connecticut, and Vermont. Private companies with representatives include Honeywell, Inc., ExxonMobil,

and Arch Chemical, Inc. Other organizations with representatives include the
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 141 

American Industrial Hygiene Association (AIHA), the American College of

Occupational and Environmental Medicine (ACOEM), the American Association of Poison Control Centers (AAPCC), and the American Federation of

Labor–Congress of Industrial Organizations (AFL-CIO). In addition, the

committee membership includes individuals from academia, a representative

of environmental justice groups, and representatives of other organizations in

the private sector. A current list of the NAC/AEGL Committee members and

their affiliations is shown on page 5. At present, the committee has 31 members.

Recently, the Organization for Economic Cooperation and Development

(OECD) and various OECD member countries have expressed an interest in

the AEGL program. Several OECD member countries such as Germany and

the Netherlands have been participating in committee activities and actively

pursuing formal membership on the NAC/AEGL Committee. It is envisioned

that the committee and the AEGL program in general will progressively expand its scope and participation to include the international community.

The director of the AEGL program has the overall responsibility for the

entire AEGL program and the NAC/AEGL Committee and its activities. A

designated federal officer (DFO) is responsible for all administrative matters

related to the committee to ensure that it functions properly and efficiently.

These individuals are not voting members of the committee. The NAC/AEGL

Committee chair is appointed by EPA and is selected from among the committee members. In concert with the program director and the DFO, the chair

coordinates the activities of the committee and also directs all formal meetings

of the committee. From time to time, the members of the committee serve as

chemical managers and chemical reviewers in a collaborative effort with assigned scientist authors (noncommittee members) to develop AEGLs for a

specific chemical. These groups of individuals are referred to as AEGL Development Teams, and their function is discussed in Section 4.8 of this manual.

4.2 THE AEGL DEVELOPMENT AND PEER-REVIEW PROCESS

The process that has been established for the development of the AEGL

values is the most comprehensive ever used for the determination of short-term

exposure limits for acutely toxic chemicals. A summary of the overall process

is presented in diagram form in Figure 4-1. The process consists of four basic

stages in the development and status of the AEGLs, and they are identified

according to the review level and concurrent status of the AEGL values. They

include (1) “draft” AEGLs, (2) “proposed” AEGLs, (3) “interim” AEGLs, and

(4) “final” AEGLs. The entire development process can be described by
142 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Major

Comments/

Issues?

NAS-NRC AEGL

Subcommittee

Concurrence

NAC/AEGL

Committee

Consensus on

Proposed

AEGLs

Non-published,

Non-peer Reviewed

Industry Data

Published

Literature

Search

Other

Data / Information

Sources

AEGL Development

Team - ORNL

Scientist, Chemical

Manager, Chemical

Reviewers

Technical

Support

Documents

(TSDs)

Distribute Draft or

Proposed TSDs /

AEGLs to

Committee

Members

NAC/AEGL

Committee Meeting to Discuss

Draft or Proposed AEGLs

FR Publication

Interim AEGLs

NAS-NRC AEGL

Subcommittee

NAS-NRC

Publication of

Final AEGLs

YES

NO

YES

Special

Toxicity

Studies

NO

NO

YES

NAC/AEGL

Committee

NAC/AEGL

Committee

Consensus on

Revisions to

Proposed

AEGLs

Major Changes

Minor Changes

FIGURE 4-1 The AEGL development process.
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 143 

individually describing the four basic stages in the development of AEGL

values.

Stage 1: Draft AEGLs

This first stage begins with a comprehensive search of the published scientific literature. Attempts are made to mobilize all relevant unpublished data

through industry trade associations and from individual companies in the

private sector. A more detailed description of the published and unpublished

sources of data and information utilized is provided in Section 2.3 of this

manual, which addresses search strategies. The data are evaluated following

the guidelines published in the National Research Council (NRC) guidance

document (NRC 1993a) and this SOP manual, and selected data are used as the

basis for the derivation of the AEGL values and the supporting scientific rationale. Data evaluation, data selection, and the development of a TSD are all

performed as a collaborative effort among the staff scientists at the organization that drafts TSDs, the chemical manager, and two chemical reviewers.

This group is the AEGL Development Team. NAC/AEGL Committee members are specifically assigned this responsibility for each chemical under review. Hence, a separate team composed of different committee members is

formed for each chemical under review. The product of this effort is a TSD

that contains draft AEGLs. The draft TSD is subsequently circulated to all

other NAC/AEGL Committee members for review and comment prior to a

formal meeting of the committee. Revisions to the initial TSD and the draft

AEGLs are made up to the time of the NAC/AEGL Committee meeting scheduled for formal presentation and discussion of the AEGL values and the documents. At the committee meeting, the committee deliberates and, if a quorum

is present, attempts to reach a consensus or a two-thirds majority vote to elevate the AEGLs to "proposed" status. A quorum of the NAC/AEGL Committee is defined as 51% or more of the total NAC/AEGL Committee membership. If agreement cannot be reached, the committee conveys its issues and

concerns to the AEGL Development Team, and further work is conducted by

this group. After completion of additional work, the chemical is resubmitted

for consideration at a future meeting. If a consensus or two-thirds majority

vote of the committee cannot be achieved because of inadequate data, no

AEGL values will be developed until adequate data become available.

Stage 2: Proposed AEGLs

Once the NAC/AEGL Committee has reached a consensus or a two-thirds
144 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

majority vote on the AEGL values and supporting rationale, they are referred

to as proposed AEGLs and are published in the Federal Register for a 30-day

review and comment period. Following publication of the proposed AEGLs

in the Federal Register, the committee reviews the public comments, addresses

and resolves relevant issues, and seeks a consensus or a two-thirds majority

vote on the original or modified AEGL values and the accompanying scientific

rationale.

Stage 3: Interim AEGLs

Following resolution of relevant issues raised through public review and

comment and subsequent approval of the committee, the AEGL values are

classified as interim. The interim AEGL status represents the best efforts of

the NAC/AEGL Committee to establish exposure limits, and the values are

available for use as deemed appropriate on an interim basis by federal and state

regulatory agencies and the private sector. The interim AEGLs, the supporting

scientific rationale, and the TSD are subsequently presented to the NRC Subcommittee on Acute Exposure Guideline Levels (NRC/AEGL Subcommittee)

for its review and concurrence. If concurrence cannot be achieved, the

NRC/AEGL Subcommittee will submit its issues and concerns to the

NAC/AEGL Committee for further work and resolution. 

Stage 4: Final AEGLs

When concurrence by the NRC/AEGL Subcommittee is achieved, the

AEGL values are considered final and published by the NRC. Final AEGLs

may be used on a permanent basis by all federal, state, and local agencies and

private-sector organizations. It is possible that from time to time new data will

become available that challenges the scientific credibility of final AEGLs. If

that occurs, the chemical will be resubmitted to the NRC/AEGL Subcommittee

and recycled through the review process.

4.3 OPERATION OF THE NAC/AEGL COMMITTEE

The NAC/AEGL Committee meets formally four times each year for 21⁄2

days. The meetings are scheduled for each quarter of the calendar year and are

generally held in the months of March, June, September, and December.

Based on overall cost considerations, the meetings are generally held in Wash-
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 145 

ington, D.C. However, from time to time, committee meetings may be held

at other locations for justifiable reasons.

At least 15 days prior to the committee meetings, a notice of the meeting

is published in the Federal Register together with a list of chemicals and other

matters to be addressed by the committee and provides dates, times, and location of the meetings. The agenda is finalized and distributed to committee

members approximately 1 week prior to the meeting. The agenda also is

available to other interested parties at that time, upon request, through the

designated federal officer (DFO).

All NAC/AEGL Committee meetings are open to the public and interested

parties may schedule individual presentations of relevant data and information

by contacting the DFO to establish a date and time. Relevant data and information from interested parties also may be provided to the committee through

the DFO during the period of development of the draft AEGLs so that it can

be considered during the early stage of development. Data and information

may be submitted during the proposed and interim stages of AEGL development as well.

The NAC/AEGL Committee meetings are conducted by the chair who is

appointed by EPA in accordance with the Federal Advisory Committee Act

(FACA). At the time of the meeting, both the chair and all other committee

members will have received the initial draft and one or more revisions of the

TSD and draft, proposed, or interim AEGL values for each chemical on the

agenda. Reviews, comments, and revisions are continuous up to the time of

the meeting, and committee members are expected to be familiar with the

draft, proposed, or interim AEGLs, supporting rationale, and other data and

information in each TSD and to participate in the resolution of residual issues

at the meeting. Procedures for the AEGL Development Teams and the other

committee members regarding work on AEGLs in proposed or interim status

are similar to those for draft AEGLs.

All decisions of the NAC/AEGL Committee related to the development of

draft, proposed, interim, and final AEGLs and their supporting rationale are

made by consensus or a two-thirds majority vote of members at a committee

meeting.

The highlights of each meeting are recorded by the scientists who draft the

TSDs, and written minutes are prepared, ratified, and maintained in the committee’s permanent records. Deliberations of each meeting also are tape-recorded

and stored in the committee’s permanent records by the DFO for future reference as necessary.

All proposed AEGL values and supporting scientific rationale are published in the Federal Register. Review and comment by interested parties and

the general public are requested and encouraged. The committee’s response
146 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

to official comments on Federal Register Notices on proposed AEGL values

consists of the discussions and deliberations that take place during the committee meetings for elevating the AEGLs from proposed to interim status. This

information is reflected on the tapes and in the minutes of the meetings and

will be maintained for future reference. Changes in the proposed AEGL values and the supporting rationale that are considered appropriate by the

NAC/AEGL Committee based on Federal Register comments will be made

prior to elevating the AEGLs to interim status.

As mentioned in Chapter 1, a Standing Operating Procedures Workgroup

(SOP Workgroup), established in March 1997, documents, summarizes, and

evaluates the various procedures, methodologies, and guidelines used by the

committee in the gathering and evaluation of scientific data and information

and in the development of the AEGL values. The SOP Workgroup performs

a critical function by continually providing the committee with detailed information on the committee’s interpretation of the NRC guidelines and on its

approaches used in the derivation of each AEGL value for each chemical

addressed. This documentation enables the committee to assess continually

the basis for its decision-making, ensure consistency with the NRC guidelines,

and maintain the scientific credibility of the AEGL values and accompanying

scientific rationale. This ongoing effort is continually documented in the SOP

manual.

4.4 ROLE OF THE DIRECTOR OF THE AEGL PROGRAM

The director has the overall responsibility for the AEGL program, including the NAC/AEGL Committee and its interface with other programs and

organizations in the public- and private-sectors nationally and internationally.

More specifically, he or she is responsible for the overall management of the

AEGL program as it relates to the following:

• NAC/AEGL Committee and AEGL program objectives of scientific

credibility, quality, productivity, and cost effectiveness.

• Resource needs of the AEGL program.

• Fostering of a collaborative spirit among committee members, staff

scientists of the organization that drafts TSDs, and interested parties

from all participating organizations in the public and private sectors.

• Matters related to the U.S. National Academy of Sciences–National

Research Council.

• Expansion of the scope of the AEGL program, including international

participation.
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 147 

4.5 ROLE OF THE DESIGNATED FEDERAL OFFICER

The designated federal officer (DFO) serves as the administrative officer

of the committee to ensure that all operations, processes, and general procedures function properly and efficiently. The DFO serves as an executive

secretariat to the NAC/AEGL Committee and is responsible for the following:

• Effective communication and coordination with NAC/AEGL Committee members, the committee chair, the organization that drafts TSDs,

and interested parties in the public and private sectors.

• Day-to-day administrative management of the NAC/AEGL Committee with respect to the agenda for future meetings, distribution of

TSDs and other correspondence with committee members, maintenance of meeting minutes, tapes of meetings and other important committee records, funding and other financial matters, and committee

membership matters.

• Administrative management of quarterly meetings, including responsibility for all Federal Register Notices related to NAC/AEGL Committee activities, minutes, decision-making records, meeting venues,

facilities, and equipment, as well as the assurance that the meetings

are held in compliance with the Federal Advisory Committee Act

(FACA).

• Compliance with FACA on all matters that extend beyond the quarterly meetings, such as the submission of appropriate reports to the

U.S. Office of Management and Budget (OMB) and the Library of

Congress.

4.6 ROLE OF THE NAC/AEGL COMMITTEE CHAIR

The NAC/AEGL Committee chair is appointed by EPA as specified in

FACA and selected from the NAC/AEGL Committee membership. The

chair's responsibilities include conducting and directing specific activities to

ensure the effective and efficient conduct of business by the committee:

• Provide support in the planning and preparation of upcoming meetings

by collaborating with the AEGL program director, the DFO, and the

organization that drafts TSDs, including the review of the meeting

agenda.

• Manage the NAC/AEGL Committee meetings in an effective and

efficient manner to ensure completion of the agenda for each meeting.
148 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

• Attempt to reach a consensus of the NAC/AEGL Committee by ensuring adequate time for presentation of differing opinions and focusing

on the major issues to break deadlocks or stalemates.

• Participate in scientific matters on AEGLs related to the U.S. National Academy of Sciences–National Research Council.

• Participate with the AEGL program director and the DFO in evaluating and improving NAC/AEGL Committee activities and expanding

the scope of the AEGL program.

4.7 CLASSIFICATION OF THE STATUS OF AEGL VALUES

Draft AEGL values are AEGL values that have been proposed by the

AEGL Development Team (see Section 4.8) before the full NAC/AEGL Committee discussion and approval.

Proposed AEGL values are AEGL values that have been formally approved and elevated to “proposed” status by a consensus or a two-thirds majority vote of the NAC/AEGL Committee.

Interim AEGL values are AEGL values that have been formally

approved by the NAC/AEGL Committee and elevated to “interim” status after

publication in the Federal Register, response to comments, and appropriate

adjustments made by the committee. Interim AEGL values are forwarded to

the Committee on Toxicology of the NRC for review and comment by the

Subcommittee on Acute Exposure Guideline Levels (NRC/AEGL Subcommittee).

Final AEGL values are AEGL values that have been reviewed, finalized,

and published by the NRC.

4.8 FUNCTION OF AEGL DEVELOPMENT TEAMS

Each AEGL Development Team consists of a staff scientist from the organization that drafts TSDs, a chemical manager, and two chemical reviewers

who are members of the NAC/AEGL Committee. The primary function of the

NAC/AEGL Development Team is to provide the NAC/AEGL Committee

with draft AEGL values and a TSD containing relevant data and information

on the chemical and the derivation of the draft AEGLs. The staff scientist

provides the initial effort by identifying and preliminarily evaluating available

data from varied resources including on-line literature databases, other databases, journal reviews, secondary source reviews, unpublished data, federal

and state documents and other sources, including accounts of accidents in the
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 149 

workplace or in the community (see Section 2.3). Interaction takes place

among the chemical manager, the chemical reviewers, and the staff scientist

during the development of the TSD and the draft AEGL values. The resulting

document is then distributed and reviewed by committee members prior to a

formal meeting, and attempts are made to resolve issues of concern expressed

by committee members prior to distribution of the TSD to the NAC/AEGL

Committee and formal presentation and discussion at a committee meeting.

4.8.1 Role of a Chemical Manager

The chemical manager has the overall responsibility for the development

of the draft, proposed, and interim AEGL values and their presentation to the

rest of the NAC/AEGL Committee and to the NRC/AEGL Subcommittee for

evaluation of final AEGLs. The chemical managers serve on a rotating basis

as the committee's principal representative on the AEGL Development Team

for a specific chemical. The chemical manager in turn selects two committee

members to serve as chemical reviewers.

The chemical manager collaborates with the staff scientist and the chemical reviewers on the development of the AEGLs, the supporting rationale, and

the TSDs. In instances in which the chemical manager has accepted the responsibilities, taken ownership for the AEGL values, resolved scientific issues,

and led the discussions with committee members, the NAC/AEGL Committee

has moved rapidly toward the development of a consensus. Where the chemical manager's role has been less decisive, the committee's deliberations have

been more protracted, less focused, and highly inefficient. Implicit in the

description of the chemical manager's role is the expectation that he or she will

work with the staff scientist, the chemical reviewers, and the rest of the committee members to develop exposure guidance levels that are appropriate and

scientifically credible. It is expected that the chemical manager will achieve

a consensus within the AEGL Development Team on the issues related to the

development of the AEGL values prior to the meeting of the full NAC/AEGL

Committee. Further, as time permits, the chemical manager will attempt to

resolve issues raised by individual committee members prior to the scheduled

committee meeting.

The following is a summary outline of specific activities and responsibilities of the chemical manager within the NAC/AEGL Committee:

• Participate as the leader of the ad hoc AEGL Development Team.

• Select and utilize two chemical reviewers as technical support.

• Provide direct support to the staff scientist assigned to the chemical in
150 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

the development of the TSDs, the draft AEGL values, and the supporting rationale.

• Serve as liaison between NAC/AEGL Committee members and the

staff scientist during the development of draft AEGL values and the

TSD.

• Resolve scientific issues prior to the NAC/AEGL Committee meetings, such as the following:

— Completeness of data gathering (published and unpublished).

— Selection of key and supporting data (following guidelines).

— Interpretation of data.

— Credibility of AEGL values (use of appropriate methodology).

— Validity of scientific rationale for AEGLs.

— Other (as necessary for development of scientifically credible

AEGL values).

• Seek consensus of NAC/AEGL Committee members by resolving

issues with individual committee members prior to the committee

meeting.

• Frame important scientific issues related to the chemical and the

AEGLs for presentation at the NAC/AEGL Committee meeting (i.e.,

significant issues that cannot be resolved before the meeting).

• Participate in the presentation of AEGL values, supporting the rationale and important issues at the NAC/AEGL Committee meeting in

collaboration with the staff scientist.

• Oversee appropriate follow-up activities:

— Revisions as appropriate (AEGL values, TSD, rationales).

— Toxicity testing.

— Federal Register Notice comments (conversion of “proposed” to

“interim” values).

— Preparation of AEGL proposal to the NRC.

4.8.2 Role of a Chemical Reviewer

• Participate as a member of the ad hoc AEGL Development Team.

• Conduct a detailed review of the assigned document and key references.

• Assist the chemical manager and staff scientist in evaluating the data,

the candidate AEGLs, and the scientific rationale for their support.

• Participate actively in discussions of the document during NAC/

AEGL Committee meetings.
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 151 

• Stand in for the chemical manager if he or she is unable to perform his

or her duties.

4.8.3 Role of a Staff Scientist at the Organization That Drafts TSDs

The staff scientist has the primary responsibility for data gathering, data

evaluation, identification of potential key data and supporting data, identification of potential methodologies, calculations, and extrapolations, and the preparation of the TSD. The following tasks are included:

• Participate as a member of the ad hoc AEGL Development Team.

• Participate with the others on the AEGL Development Team in the

development of draft AEGL values and their presentation at the

NAC/AEGL Committee meetings.

• Prepare TSDs in a timely manner and make appropriate revisions

based on discussions and decisions of the AEGL Development Team

and later based on the discussions and decisions of the NAC/AEGL

Committee.

• Develop and maintain a data file on the chemical substance.

• Present a summary of the data and information on the substance in

collaboration with the chemical manager at the NAC/AEGL Committee meetings.

• Provide continuing support to an assigned chemical through the draft,

proposed, interim, and final stages of AEGL development, including

preparation for, and response to, Federal Register Notice review and

comment.

4.9 ROLE OF NAC/AEGL COMMITTEE MEMBERS

• Review all TSDs in advance of meetings, and work out issues with the

chemical manager at the earliest possible date. The importance of

resolving issues before NAC/AEGL Committee meetings is greatly

emphasized to increase the efficiency and productivity of the meetings.

• Circulate TSDs to other qualified scientists within their respective

organizations or other organizations as appropriate to broaden the

evaluation by the scientific community.

• Serve as experts in specific areas or on specific scientific issues (e.g.,

sensitive human subpopulations) as a member of an ad hoc task force
152 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

under the SOP Workgroup chair.

• Volunteer as a chemical manager at least once a year, and select

chemicals on the basis of special knowledge, expertise, or past experience, whereby a significant contribution can be made to the development of credible AEGL values.

• Assist in the application of AEGLs in appropriate programs within the

organization represented by the NAC/AEGL Committee member.

• Make suggestions for modification or expansion of the Chemical

Priority List by providing lists of chemicals and supporting rationale

for their priority to the designated federal officer (DFO).

• Attend all scheduled NAC/AEGL Committee meetings, and participate in the discussions and decision-making of all AEGL values.

AEGL values are approved or disapproved by a two-thirds majority

vote of the committee quorum (51% or more of the committee members present).

4.10 ROLE OF THE ORGANIZATION THAT DRAFTS TSDs

The role of the organization that drafts the TSDs is to provide the principal

technical support in gathering and evaluating the relevant scientific data and

information from all sources in the preparation and revision of the TSDs,

following the guidance provided in this SOP manual. As a member of the

AEGL Development Team,

• Collaborates with the chemical manager and chemical reviewers in the

preparation and distribution of draft AEGLs, the supporting rationale,

and the TSDs for the NAC/AEGL Committee members.

• Provides continuing technical and administrative support to assigned

chemicals through the Draft, Proposed, Interim, and Final stages of

AEGL development, with revisions based on the consensus or majority of the NAC/AEGL Committee and the NRC/AEGL Subcommittee.

• Provides the staff scientists and the administrative personnel with the

facilities and equipment necessary for data gathering, maintenance of

databases, dissemination of relevant information to committee members, presentations or co-presentations (with chemical managers) at

the NAC/AEGL Committee meetings, development and revisions of

TSDs, preparation of submissions to the Federal Register, summarization of Federal Register comments and identification of important

scientific issues, presentations to the committee on Federal Register
CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES 153 

comments, and preparation of technical information to be entered on

the Internet.

• Distributes the TSDs to companies and other interested parties as

directed by the DFO after review and comment by the NAC/AEGL

Committee. Distribution to interested parties will be only by request

through the DFO. The initial distributed version will be without the

AEGL values and the rationale used to derive them and will occur

between 1 and 14 days before the committee meeting.
154

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Appendixes

165

Appendix A

Priority Lists of Chemicals

A master list of approximately 1,000 acutely toxic chemicals was initially

compiled through the integration of individual priority lists of chemicals

submitted by each U.S. federal agency placing a representative on the

NAC/AEGL Committee. The master list was subsequently reviewed by individuals from certain state agencies and representatives from organizations in

the private sector and modified as a result of comments and suggestions received. The various priority chemical lists were compiled separately by each

federal agency based on their individual assessments of the hazards, potential

exposure risk, and relevance of a chemical to their programmatic needs.

On May 21, 1997, a list of 85 chemicals was published in the Federal

Register. This list identified those chemicals to be of highest priority across

all U.S. federal agencies and represented the selection of chemicals for AEGL

development by the NAC/AEGL Committee for the first 2-3 years of the

program. The committee has now addressed most of these chemicals, and they

are currently in the “proposed,” “interim,” or “final” stages of development.

Certain chemicals did not contain an adequate database for AEGL development and, consequently, are on hold pending decisions regarding further toxicity testing. This initial “highest” priority list of 85 chemicals is shown in

Table A-1.

A second “working list” of approximately 100 priority chemicals is being

selected from the original master list or from new high-priority candidate
166 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

1

The initial list of 85 priority chemicals shown in Table A-1 has been created by

identifying the highest priority hazardous chemicals from the Master List. This initial

list is a starting point for the development of AEGL values by the National Advisory

Committee for Acute Exposure Guideline Levels for Hazardous Chemicals

(NAC/AEGL). However, the list of chemicals is subject to modification, pending

changes in priorities recommended by the various stakeholders that make up the

NAC/AEGL. While it is anticipated that most of these chemicals will remain as high

priority for AEGL development, changes to the list could occur. The NAC/AEGL

Committee hopes to select 30 to 40 chemicals per year to address in the AEGL

development process. Consequently, the initial list will expand as the NAC/AEGL

Committee continues to address chemicals of interest to its member organizations.

chemicals submitted by U.S. agencies and organizations and by member countries of the Organization for Economic Cooperation and Development (OECD)

that are planning to participate in the AEGL Program. Although “working

lists” will be published in the Federal Register and elsewhere from time to

time to indicate the NAC/AEGL Committee’s agenda, the priority of chemicals addressed, and, hence, the “working list,” is subject to modification if

priorities of the NAC/AEGL Committee or individual stakeholder organizations, including international members, change during that period.

INITIAL LIST OF 85 PRIORITY CHEMICALS

FOR AEGL DEVELOPMENT

Organization Lists Used to Compile the Master List and

The Initial List of 85 Priority Chemicals1

ATSDR Medical 

Managment U.S. Agency for Toxic Substances and Disease

Registry

M = Chemicals with an ATSDR Medical

Management Guideline

T = Chemicals with an ATSDR Toxicology

Profile

DOD U.S. Department of Defense

A = Army Toxicity Summary Chemical

C = Chemical Weapons Convention Schedule

3.A Toxic Chemical
APPENDIX A 167 

Cs = Chemical Stockpile Emergency

Preparedness Program (CSEPP) Chemical

I = Air Force Installation Restoration Program

Chemical

N = Navy Chemical

S = Strategic Environmental Research and

Development Program (SERDP) Chemical

DOE SCAPA U.S. Department of Energy Subcommittee for

Consequence Assessment and Protective Action

Chemical

DOT ERP U.S. Department of Transportation Emergency

Response Guidebook

P = Priority DOT ERG Chemical

O = Other ERG Chemical

EPA CAA 112b U.S. Environmental Protection Agency Clean Air Act

112b Chemical

EPA CAA 112r U.S. Environmental Protection Agency Clean Air Act

112b Chemical (+ = SARA s.302 also)

EPA Superfund U.S. Environmental Protection Agency Superfund

Chemical

OSHA PSM U.S. Occupational Safety and Health Administration

Process Safety Management Chemical

OSHA STEL U.S. Occupational Safety and Health Administration

Short-term Exposure Limit Chemical

NIOSH IDLH NIOSH Immediately Dangerous to Life or Health

Chemical

Seveso Annex III International Seveso Convention List
TABLE A-1 Priority List of Chemicals

CAS No. Chemical ATSDR DOD

DOESCAPA

DOTERG

EPACAA112b

EPACAA112r

EPASuperfund

OSHAPSM

OSHASTEL

NIOSHIDLH

SeveAnnIII

56-23-5 Carbon tetrachloride T AIS X X X57-14-7 1,1-Dimethyl hydrazine P X X+ X X60-34-4 Methyl hydrazine P X X+ X X X62-53-3 Aniline M P X + X X67-66-3 Chloroform T AIS X X+ X X68-12-2 Dimethylformamide X X71-43-2 Benzene X AIS X X X71-55-6 1,1,1-Trichloroethane T X X X X74-90-8 Hydrogen cyanide M C P X X+ X X X74-93-1 Methyl mercaptan T P X+ X X75-09-2 Methylene chloride MT AIS X X X75-21-8 Ethylene oxide MT P X X+ X X X75-44-5 Phosgene M C P X X+ X X X75-55-8 Propyleneimine X X+ X X75-56-9 Propylene oxide X X+ X X75-74-1 Tetramethyllead X X+ X X X75-77-4 Trimethychlorosilane X+75-78-5 Dimethyldichlorosilane X X+ X75-79-6 Methyltrichlorosilane X+ X78-82-0 Isobutyronitrile X+79-01-6 Trichloroethylene MT AIS X X X
79-21-0 Peracetic acid X+ X X79-22-1 Methy chloroformate X+91-08-7 Toluene 2,6-diisocyanate M X+106-89-8 Epichlorohydrin X X+ X107-02-8 Acrolein T P X X+ X X X X X107-11-9 Allyl amine P X+ X X107-12-0 Propionitrile X+107-15-3 Ethylenediamine X+ X107-18-6 Allyl alcohol P X+ X X X107-30-2 Chloromethyl methyl ether O X X+ X X108-23-6 Isopropyl chloroformate P X+108-88-3 Toluene MT AINS X X108-91-8 Cyclohexylamine X+109-61-5 Propyl chloroformate O X+110-00-9 Furan X+ X X110-89-4 Piperidine X+123-73-9 Crotonaldehyde, (E) X+ X126-98-7 Methacrylonitrile O X+ X127-18-4 Tetrachloroethylene T AIS X X X151-56-4 Ethyleneimine P X X+ X X X302-01-2 Hydrazine T I X X X+ X353-42-4 Boron triflouride compound

with methyl ether (1:1)

X+ X

506-77-7 Cyanogen chloride X+ X509-14-8 Tetranitromethane X+ X
TABLE A-1 (Continued)CAS No. Chemical ATSDR DOD

DOESCAPA

DOTERG

EPACAA112b

EPACAA112r

EPASuperfund

OSHAPSM

OSHASTEL

NIOSHIDLH

SeveAnnIII

540-59-0 1,2-Dichloroethylene T X X540-73-8 1,2-Dimethylhydrazine P X X+ X X584-84-9 Toluene 2,4-diisocyanate M X X+ X X X594-42-3 Perchloromethyl-mercaptan X+ X X X624-83-9 Methyl isocyanate P X X+ X X X811-97-2 HFC 134A (1,1,1,2-

Tetrafluoroethane)

N

814-68-6 Acrylyl chloride X+ X1330-20-7 Xylenes (mixed) X AIN X X1717-00-6 HCFC 141b (1,1-Dichloro-1-

fluoroethane)

N

4170-30-3 Crotonaldehyde cis & trans

mixture

P X+ X

6423-43-4 Propylene glycol dinitrate (Otto

Fuel II)

T Navy

7446-09-5 Sulfur dioxide P X+ X X X X7446-11-9 Sulfur trioxide P X+ X X7647-01-0 Hydrogen chloride P X X+ X X X X X7647-01-0 Hydrochloric acid P X X+ X X X X7664-39-3 Hydrogen fluoride M P X X+ X X X X7664-41-7 Ammonia MT X+ X X X X7664-93-9 Sulfuric acid P + X X
7697-37-2 Nitric acid X P X+ X X X7719-12-2 Phosphorus trichloride P X+ X X X7726-95-6 Bromine P X+ X X X X7782-41-4 Fluorine P X+ X X7782-50-5 Chlorine M P X X+ X X X X X7783-06-4 Hydrogen sulfide M X X+ X7783-60-0 Sulfur tetrafluoride P X+7783-81-5 Uranium hexafluoride X7784-34-1 Arsenous trichloride P X+7784-42-1 Arsine M X P X X+ X X X X7790-91-2 Chlorine trifluoride X O X X7803-51-2 Phosphine M X P X X+ X X X X8014-95-7 Oleum P X+ X10025-87-3 Phosphorus oxychloride O X+ X10049-04-4 Chlorine dioxide X X X X10102-43-9 Nitric oxide P X+ X X10102-44-0 Nitrogen dioxide X X X X10294-34-5 Boron trichloride P X+ X13463-39-3 Nickel carbonyl P X X+ X X X13463-40-6 Iron, pentacarbonyl- P X+ X X19287-45-7 Diborane X P X+ X X25323-89-1 Trichloroethane T AS X X X70892-10-3 Jet fuels (JP-5 and JP-8) N163702-07-6 Methyl nonafluorobutyl ether

(HFE 7100 component)

N

163702-08-7 Methyl nonafluorobutyl ether

(HFE 7100 component)

N

Appendix B

Diagram of the

AEGL Development Process
174 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Major

Comments/

Issues?

NAS-NRC AEGL

Subcommittee

Concurrence

NAC/AEGL

Committee

Consensus on

Proposed

AEGLs

Non-published,

Non-peer Reviewed

Industry Data

Published

Literature

Search

Other

Data / Information

Sources

AEGL Development

Team - ORNL

Scientist, Chemical

Manager, Chemical

Reviewers

Technical

Support

Documents

(TSDs)

Distribute Draft or

Proposed TSDs /

AEGLs to

Committee

Members

NAC/AEGL

Committee Meeting to Discuss

Draft or Proposed AEGLs

FR Publication

Interim AEGLs

NAS-NRC AEGL

Subcommittee

NAS-NRC

Publication of

Final AEGLs

YES

NO

YES

Special

Toxicity

Studies

NO

NO

YES

NAC/AEGL

Committee

NAC/AEGL

Committee

Consensus on

Revisions to

Proposed

AEGLs

Major Changes

Minor Changes
175

Appendix C

Glossary of Acronyms,

Abbreviations, and Symbols

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienist

ACOEM American College of Occupational and Environmental

Medicine

ADI acceptable daily intake.

AEGL acute exposure guidelines levels

AFL-CIO American Federation of Labor–Congress of Industrial

Organizations

AIHA American Industrial Hygienist Association

ATSDR Agency for Toxic Substances and Disease Registry (U.S.)

BMC benchmark concentration

BMC05 benchmark concentration, 5% response

BMC10 benchmark concentration, 10% response

CAAA Clean Air Act Amendments (U.S. EPA)

CAER Community Awareness and Emergency Response

CMA Chemical Manufacturers Association, now known as the

American Chemistry Council

CAS Chemical Abstract Service (U.S.)

CDC Centers for Disease Control and Prevention (U.S. DHHS)

CEEL community emergency exposure levels (U.S. NRC)
176 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

CEL continuous exposure limits (U.S. NRC)

COT Committee on Toxicology (U.S. NRC)

C × t concentration × time

CURE Chemical Unit Record Estimate database

DFO designated federal officer

DOD Department of Defense (U.S.)

DOE Department of Energy (U.S.)

DOT Department of Transportation (U.S.)

DTIC Defense Technical Information Center (U.S.)

ECETOC European Chemical Industry Ecology and Toxicology Centre

EEGL emergency exposure guidance levels (U.S. NRC)

EEL emergency exposure limits (U.S. NRC)

einsatztoleranzwert [action tolerance levels] (Federation for the Advancement of

German Fire Prevention)

EPA Environmental Protection Agency (U.S.)

ERP emergency response planning (AIHA)

ERPG emergency response and planning guidelines (AIHA) 

FACA Federal Advisory Committee Act (U.S.)

FDA Food and Drug Administration (U.S.)

FEDRIP Federal Research in Progress (U.S.)

FEMA Federal Emergency Management Agency (U.S.)

FEV1 forced expiratory volume

GLP Good Laboratory Practices

GSA General Services Administration (U.S.)

HEAST Health Effects Assessment Tables

HSDB Hazardous Substances Data Base

HUD Department of Housing and Urban Development (U.S.)

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health (U.S. NIOSH)

IPCS International Programme for Chemical Safety

IRIS Integrated Risk Information System (U.S. EPA)

LC01 lethal concentration, 1 % lethality

LC50 lethal concentration, 50 % lethality

LCL lower confidence limit

LOAEL lowest-observed-adverse-effect level

MAC minimum alveolar concentration

MAC maximum acceptable concentration (The Netherlands)

MAK maximale arbeitsplatzkonzentration [maximum workplace

concentration] 8-h time-weighted average (German Research

Association)
APPENDIX C 177 

MAK. S spitzenbegrenzung (kategorie ii, 2) [MAK peak limit

(category II, 2)] 30 min × 2 per day (Germany)

MCS multiple chemical sensitivity

MF modifying factor

MLE maximum likelihood estimate

MLE01 maximum likelihood estimate, 1% response

MTD maximum tolerated dose

N/A not applicable

NAAQS National Ambient Air Quality Standards (U.S.)

NAC National Advisory Committee

NAC/AEGL National Advisory Committee for Acute Exposure Guideline

Levels for Hazardous Substances (NAC/AEGL Committee)

NAS National Academy of Sciences (U.S.)

NASA National Aeronautical and Space Administration (U.S.)

NCI National Cancer Institute (U.S.)

NIOSH National Institute for Occupational Safety and Health (U.S.)

NOAEL no-observed-adverse-effect level

NRC National Research Council (U.S.)

NRC/AEGL National Research Council Subcommittee on Acute Exposure

Guideline Levels (NRC/AEGL Subcommittee) (U.S.)

NSF National Science Foundation (U.S.)

NTIS National Technical Information Service (U.S.)

NTP National Toxicology Program (U.S.)

OECD Organization for Economic Cooperation and Development

ORNL Oak Ridge National Laboratories (U.S.)

OSHA Occupational Safety and Health Administration (U.S.)

OSWER Office of Solid Waste and Emergency Response (U.S.)

PEL-TWA permissible exposure limit–time-weighted average (U.S.

OSHA)

PEL-STEL permissible exposure limit–short-term exposure limit (U.S.

OSHA)

QA quality assurance

QC quality control

QSARs quantitative structure activity relationships

REL-STEL recommended exposure limit–short-term exposure limit (U.S.

NIOSH)

REL-TWA recommended exposure limits–time-weighted average (U.S.

NIOSH)

RfC reference concentration (U.S. EPA)

RfD reference dose (U.S. EPA)

RTECS Registry of Toxic Effects of Chemical Substances
178 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

SARA Superfund Amendments and Reauthorization Act (CERCLA)

SMAC spacecraft maximum allowable concentrations

SOP standing operating procedures

SPEGL short-term public emergency guidance levels (U.S. NRC)

STPL short-term public limit (U.S. NRC)

TARA Toxicology and Risk Assessment Document List 

(U.S. ORNL)

TLV-STEL Threshold Limit Value–short-term exposure limit (ACGIH)

TLV-TWA Threshold Limit Value–time-weighted average (ACGIH)

TSD technical support document

UF uncertainty factor

WEEL workplace environmental exposure level (AIHA)

> greater than

≥ greater than or equal to

< less than

≤ less than or equal to

% percent

dL deciliter

g gram

h hour

μm micrometer

μg microgram

mg milligram

min minute

mL milliliter

mm millimeter

ppb parts per billion

ppm parts per million

ppt parts per trillion
179

Appendix D

Example of a Table of Contents of

A Technical Support Document

TABLE OF CONTENTS

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

 LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

 1. INTRODUCTION ........................................ 9

2. HUMAN TOXICITY DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.1. Acute Lethality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.2. Nonlethal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.2.1. Acute Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.2.2. Epidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . 11

2.3. Developmental/Reproductive Toxicity . . . . . . . . . . . . . . . . . . 11

2.4. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2.5. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2.6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
180 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

3. ANIMAL TOXICITY DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3.1. Acute Lethality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.1.1. Nonhuman Primates . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.1.2. Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.1.3. Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.1.4. Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.1.5. Hamsters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.2. Nonlethal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.2.1. Nonhuman Primates . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.2.2. Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.2.3. Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

3.2.4. Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

3.3. Developmental/Reproductive Toxicity . . . . . . . . . . . . . . . . . . 15

3.4. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

3.5. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

3.6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4. SPECIAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.1. Metabolism and Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.2. Mechanism of Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.3. Structure-Activity Relationships . . . . . . . . . . . . . . . . . . . . . . . 21

4.4. Other Relevant Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

4.4.1. Species Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

4.4.2. Unique Physicochemical Properties . . . . . . . . . . . . . . 22

4.4.3. Concurrent Exposure Issues . . . . . . . . . . . . . . . . . . . . 22

5. DATA ANALYSIS FOR AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . 22

5.1. Summary of Human Data Relevant to AEGL-1 . . . . . . . . . . . 22

5.2. Summary of Animal Data Relevant to AEGL-1 . . . . . . . . . . . 22

5.3. Derivation of AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

6. DATA ANALYSIS FOR AEGL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . 23

6.1. Summary of Human Data Relevant to AEGL-2 . . . . . . . . . . . 23

6.2. Summary of Animal Data Relevant to AEGL-2 . . . . . . . . . . . 23

6.3. Derivation of AEGL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

7. DATA ANALYSIS FOR AEGL-3 . . . . . . . . . . . . . . . . . . . . . . . . . . 24

7.1. Summary of Human Data Relevant to AEGL-3 . . . . . . . . . . . 24

7.2. Summary of Animal Data Relevant to AEGL-3 . . . . . . . . . . . 24

7.3. Derivation of AEGL-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
APPENDIX D 181 

8. SUMMARY OF AEGLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

8.1. AEGL Values and Toxicity Endpoints . . . . . . . . . . . . . . . . . . 25

8.2. Comparison with Other Standards and Criteria . . . . . . . . . . . . 26

8.3. Data Adequacy and Research Needs . . . . . . . . . . . . . . . . . . . . 27

9. REFERENCES CITED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Appendix A (Derivation of AEGL Values) . . . . . . . . . . . . . . . . . . . . . . . 32

Appendix B (Time Scaling Calculations for Dimethylhydrazine AEGLs) 36

Appendix C (Carcinogenicity Assessment for Dimethylhydrazine) . . . . 39

Appendix D (Derivation Summary for Dimethylhydrazine AEGLs) . . . 41
182

Appendix E

Example of a Summary of

A Technical Support Document

SUMMARY

Dimethylhydrazine occurs as symmetrical (1,2-dimethylhydrazine) and

unsymmetrical (1,1-dimethylhydrazine) isomers. Unless otherwise specified,

dimethylhydrazine refers to unsymmetrical dimethylhydrazine in this document. Both compounds are clear, colorless liquids. 1,1-Dimethylhydrazine

is a component of rocket fuels and is also used as an adsorbent for acid gas,

as a plant-growth control agent, and in chemical synthesis. Although it has

been evaluated as a high-energy rocket fuel, commercial use of 1,2-dimethylhydrazine is limited to small quantities, and it is usually considered to be a

research chemical. Because data are limited for 1,2-dimethylhydrazine, the

acute exposure guideline level (AEGL) values for both isomers are based upon

1,1-dimethylhydrazine. Limited data suggest that 1,1-dimethylhydrazine may

be somewhat more toxic than 1,2-dimethylhydrazine.

Data on acute exposures of humans to both isomers of dimethylhydrazine

are limited to case reports of accidental exposures. Signs and symptoms of

exposure include respiratory irritation, pulmonary edema, nausea, vomiting,

and neurologic effects. However, definitive exposure data (concentration and

duration) were unavailable for these accidents. The limited data in humans

suggest that the nonlethal toxic response to acute inhalation of dimethylhydra-
APPENDIX E 183 

zine is qualitatively similar to that observed in animals. No information was

available regarding lethal responses in humans. In the absence of quantitative

data in humans, the use of animal data is considered a credible approach for

developing AEGL values. 

Toxicity data of varying degrees of completeness are available for several

laboratory species, including, rhesus monkeys, dogs, rats, mice, and hamsters

(Weeks et al. 1963). Most of the animal studies were conducted using 1,1-

dimethylhydrazine, although limited data suggest that 1,2-dimethylhydrazine

exerts similar toxic effects. Minor nonlethal effects such as respiratory tract

irritation appear to occur at cumulative exposures of less than 100 parts per

million multiplied by hours (ppm"h). At cumulative exposures of 100 ppm"h

or slightly greater than this level, more notable effects have been reported,

including, muscle fasciculation, behavioral changes, tremors, and convulsions.

Lethality has been demonstrated when cumulative exposures exceed these

levels only slightly. The available data suggest that there is a very narrow

margin between exposures resulting in no significant toxicity and those

causing substantial lethality (the lethal concentration for 50% of the animals

(LC50)  900-2,000 ppm"h).

Developmental toxicity of dimethylhydrazines has been demonstrated in

rats following parenteral administration of maternally toxic doses.

Both isomers of dimethylhydrazine have been shown to be carcinogenic

in rodents following chronic oral exposure and 6-mon inhalation exposure to

1,1-dimethylhydrazine. Increased tumor incidence was observed in mice,

although these findings are compromised by the contaminant exposure to dimethylnitrosamine. An increased incidence of lung tumors and hepatocellular

carcinomas was also seen in rats but not in similarly exposed hamsters. The

U.S. Environmental Protection Agency (U.S. EPA) inhalation slope factors are

currently unavailable for dimethylhydrazine.

AEGL-1 values for dimethylhydrazine are not recommended because of

inadequate data to develop health-based criteria and because the concentrationresponse relationship for dimethylhydrazine indicated that a very narrow margin exists between exposures producing no toxic response and those resulting

in significant toxicity. 

Behavioral changes and muscle fasciculations in dogs exposed for 15 min

to 1,1-dimethylhydrazine at 360 ppm (Weeks et al. 1963) served as the basis

for deriving AEGL-2 values. Available lethality data in dogs and rats indicated a near linear temporal relationship (n = 0.84 and 0.80 for dogs and rats,

respectively). For temporal scaling (C1

 × t = k) to derive values for AEGLspecific exposure durations, a linear concentration-response relationship, n =

1, was used. (C = exposure concentration, t = exposure duration, and k = a
184 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

constant.) This value was adjusted by an uncertainty factor of 30. An uncertainty factor of 3 for interspecies variability was applied, because the toxic

response to dimethylhydrazine was similar across the species tested. This was

especially true for lethality among rats, mice, dogs, and hamsters with LC50

values for time periods ranging from 5 min to 4 h. A comparison of LC50

values for the same exposure durations in these species did not vary more than

3-fold. An uncertainty factor of 10 was used for intraspecies variability. This

factor was based primarily on the variability observed in dogs in which responses varied from one of extreme severity (vomiting, tremors, convulsions,

and death) to no observable effects. Additionally, Weeks et al. (1963) indicated that dogs previously stressed by auditory stimuli may have potentiated

their response to dimethylhydrazine. Based on these data, it was assumed that

humans may be equally variable in their response to dimethylhydrazine as a

result of similar stresses.

The AEGL-3 values were derived from the 1-h LC50 (981 ppm) for 1,1-

dimethylhydrazine in dogs (Weeks et al. 1963). Because of the steep slope of

the dose-response curve of 1,1-dimethylhydrazine, the 1-h LC50 of 981 ppm

was adjusted to estimate the lethality threshold of 327 ppm. An uncertainty

factor of 3 for interspecies variability was applied for several reasons. The 4-h

LC50 values for mouse, rat, and hamster differ by a factor of approximately 2

and were consistent with the dog data when extrapolated from 1 h using n =

1. The more susceptible species, the dog, was used to derive the AEGL-3

values. An uncertainty factor of 10 for intraspecies variability was used

because a broad spectrum of effects were seen including behavioral effects,

hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and susceptibility among individuals may vary.

 Following identical exposures, the responses of the dogs varied from one of

extreme severity (vomiting, tremors, convulsions, and death) to no observable

effects. Temporal scaling as previously described was applied to obtain

exposure values for AEGL-specific exposure periods.

Verified inhalation and oral slope factors were unavailable from U.S. EPA

for dimethylhydrazine. A cancer assessment based upon the carcinogenic

potential (withdrawn cancer slope factors) of dimethylhydrazine revealed that

AEGL values for a theoretical excess lifetime 10-4 carcinogenic risk exceeded

the AEGL- 2 values that were based on noncancer endpoints. Because the risk

for dimethylhydrazine exposure was estimated from nonverified sources and

because AEGLs are applicable to rare events or single once-in-a-lifetime exposures to a limited geographic area and small population, the AEGL values

based on noncarcinogenic endpoints were considered to be more appropriate.
Summary of AEGL Values for 1,1- and 1,2-DimethylhydrazinesClassification 30 min 1 h 4 h 8 h Endpoint (Reference)AEGL-1(Nondisabling)

NR NR NR NR Not recommended due to insufficient data;

concentration-response relationships suggeslittle margin between exposures causingminor effects and those resulting in serioustoxicitya

AEGL-2(Disabling)

6 ppm(14.7 mg/m3

)

3 ppm(7.4 mg/m3

)

0.75 ppm(2 mg/m3

)

0.38 ppm(1 mg/m3

)

Behavioral changes and musclefasciculations in dogs exposed at 360 ppmfor 15 min (Weeks et al. 1963)

AEGL-3(Lethal)

22 ppm(54 mg/m3

)

11 ppm(27 mg/m3

)

2.7 ppm(6.6 mg/m3

)

1.4 ppm(3.4 mg/m3

)

Lethality threshold of 327 ppm for 1 hestimated from 1-h LC50 in dogs (Weeks et

al. 1963)

Numeric values for AEGL-1 are not recommended because (1) available data are lacking, (2) data indicate that toxic effects occur at or below the odor threshold, (3) the margin of safety that exists between the derived AEGL-1 and the AEGL-2 is inadequ

or (4) the derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGis without adverse effects.Abbreviations: NR, not recommended; ppm, parts per million; mg/m3, milligrams per cubic meter.

Reference: Weeks, M.H., Maxey, G.C., Sicks, Greene, E.A. 1963. Vapor toxicity of UDMH in rats and dogs from short exposu

American Industrial Hygiene Association Journal 24:137-143.
186

Appendix F

Example of the Derivation of

AEGL Values Appendix in

A Technical Support Document

DERIVATION OF AEGL-1 VALUES

Key study: None. An AEGL-1 was not recommended because of inadequate data for developing health-based criteria and because

exposure-response relationships suggest little margin between

exposures resulting in no observable adverse effects and those

producing significant toxicity. The absence of an AEGL-1

does not imply that exposure below the AEGL-2 is without

adverse effects.

DERIVATION OF AEGL-2 VALUES

Key study: Weeks et al. 1963

Toxicity 

endpoint: Dogs exposed to 1,1-dimethylhydrazine at 360 ppm for 15

min exhibited behavioral changes and muscle fasciculations
APPENDIX F 187 

Uncertainty 

factors: An uncertainty factor of 3 for interspecies variability was

applied because the toxic response to dimethylhydrazine was

similar across the species tested. This was especially true for

lethality responses (LC50 values for varying time periods

ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure

durations in these species did not vary more than 3-fold.

An uncertainty factor of 10 was retained for intraspecies

variability (protection of sensitive populations). A broad

spectrum of effects were seen that included behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and

vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary.

Following identical exposures, the responses of the dogs

varied from extreme severity (vomiting, tremors, convulsions,

and death) to no observable effects. A factor of 10 was also

applied because experiments by Weeks et al. (1963) indicated

that dogs that had been previously stressed (auditory stimuli)

were more susceptible to the adverse effects of

dimethylhydrazine.

Calculations: 360 ppm/30 = 12 ppm

C1

 × t = k

12 ppm × 15 min = 180 ppm"min

Time scaling: C1

 × t = k (ten Berge et al. 1986)

(12 ppm)1

 × 15 min = 180 ppm"min

LC50 data were available for 5-, 15-, 30-, 60-, and 240-min

exposures in rats and 5, 15, and 60 min in dogs. Exposureresponse data indicated a near linear concentration-response

relationship (n = 0.84 for rats; n = 0.80 for dogs). For timescaling, a linear relationship was assumed and a value of n =

1 was selected.

30-min AEGL-2: C1

 × 30 min = 180 ppm"min

C = 6 ppm

1-h AEGL-2: C1

 × 60 min = 180 ppm"min

C = 3 ppm

4-h AEGL-2: C1

 × 240 min = 180 ppm"min
188 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

C = 0.75 ppm

8-h AEGL-2: C1

 × 480 min = 180 ppm"min

C = 0.38 ppm

DERIVATION OF AEGL-3

Key study: Weeks et al. 1963

Toxicity 

endpoint: 1-h LC50 of 981 ppm in dogs reduced by a factor of three to

327 ppm as an estimate of a lethality threshold. Weeks et al.

(1963) provided data showing that 15-min exposure of dogs

at 36-400 ppm produced only minor, reversible effects (behavioral changes and mild muscle fasciculations)

Uncertainty 

factors: An uncertainty factor of 3 for interspecies variability was

applied because the toxic response to dimethylhydrazine was

similar across the species tested. This was especially true for

lethality responses (LC50 values for varying time periods

ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure

durations in these species did not vary more than 3-fold.

An uncertainty factor of 10 was applied for intraspecies variability (protection of sensitive populations). A broad spectrum of effects were seen that included behavioral effects,

hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary.

Following identical exposures, the responses of the dogs

varied from extreme severity (vomiting, tremors, convulsions,

and death) to no observable effects. A factor of 10 was also

applied because experiments by Weeks et al. (1963) indicated

that dogs that had been previously stressed (auditory stimuli)

were more susceptible to the adverse effects of dimethylhydrazine.

Calculations: 327 ppm/30 = 10.9 ppm

C1

 × t = k

11.9 ppm × 60 min = 654 ppm"min
APPENDIX F 189 

Time scaling: C1

 × t = k (ten Berge et al.1986)

11.9 ppm1

 × 60 min = 654 ppm"min

LC50 data were available for 5, 15, 30, 60, and 240-min

exposures in rats and 5, 15, and 60 min in dogs. Exposureresponse data indicated a near linear concentration-response

relationship (n = 0.84 for rats, n = 0.80 for dogs). For timescaling, a linear relationship was assumed and a value of n =

1 was selected.

30-min AEGL-2: C1

 × 30 min = 654 ppm"min

C = 22 ppm

1-h AEGL-2: C1 × 60 min = 654 ppm"min

C = 11 ppm

4-h AEGL-2: C1

 × 240 min = 654 ppm"min

C = 2.7 ppm

8-h AEGL-2: C1

 × 480 min = 654 ppm"min

C = 1.4 ppm
190

Appendix G

Example of Time-Scaling

Calculations Appendix in 

A Technical Support Document

TIME-SCALING CALCULATIONS FOR

 DIMETHYLHYDRAZINE AEGLs

The relationship between dose and exposure time to produce a toxic effect for

any given chemical is a function of the physical and chemical properties of the

substance and the unique toxicologic and pharmacologic properties of the

individual substance. Historically, the relationship according to Haber (1924),

commonly called Haber's law (NRC 1993) or Haber's rule (i.e., C × t = k,

where C = exposure concentration, t = exposure duration, and k = a constant)

has been used to relate exposure concentration and duration to a toxic effect

(Rinehart and Hatch 1964). This concept states that exposure concentration

and exposure duration may be reciprocally adjusted to maintain a cumulative

exposure constant (k) and that this cumulative exposure constant will always

reflect a specific quantitative and qualitative response. This inverse relationship of concentration and time may be valid when the toxic response to a

chemical is equally dependent upon the concentration and the exposure

duration. However, an assessment by ten Berge et al. (1986) of LC50 data for
APPENDIX G 191 

certain chemicals revealed chemical-specific relationships between exposure

concentration and exposure duration that were often exponential. This relationship can be expressed by the equation Cn

 × t = k, where n represents a

chemical-specific and even a toxic endpoint-specific exponent. The relationship described by this equation is basically the form of a linear regression

analysis of the log-log transformation of a plot of C vs t. ten Berge et al.

(1986) examined the airborne concentration (C) and short-term exposure

duration (t) relationship relative to death for approximately 20 chemicals and

found that the empirically derived value of n ranged from 0.8 to 3.5 among this

group of chemicals. Hence, these workers showed that the value of the exponent (n) in the equation Cn

 × t = k quantitatively defines the relationship

between exposure concentration and exposure duration for a given chemical

and for a specific health effect endpoint. Haber's rule is the special case where

n = 1. As the value of n increases, the plot of concentration vs time yields a

progressive decrease in the slope of the curve.

Two data sets of LC50 values for different time periods of exposure were

analyzed using a linear regression analysis of the log-log transformation of a

plot of C vs t to derive values of n for dimethylhydrazine.

Dimethylhydrazine Dog Data from Weeks et al. 1963

The LC50 values for 5-, 15-, and 60-min exposures were 22,300, 3,580, and

981 ppm, respectively.

Time Concentration

Log

Time

Log

Concentration

5 22,300 0.6990 4.3483 

15 3,580 1.1761 3.5539 

60 981 1.7782 2.9917 

n = 0.8

Calculated LC50 values:

Min Concentration

30 2036.15 

60 860.12 

240 153.48 
192 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

480 64.83 

Dimethylhydrazine Rat Data from Weeks et al. 1963

The LC50 values for 5-, 15-, 30-, 60-, and 240-min exposures were 24,500,

8,230, 4,010, 1,410, and 252 ppm, respectively.

Time Concentration

Log

Time

Log

Concentration

5 24,500 0.6990 4.3892 

15 8,230 1.1761 3.9154 

60 4,010 1.4771 3.6031 

240 252 2.3802 2.4014 

n = 0.84
APPENDIX G 193 

Calculated LC50 values:

Min Concentration

30 3,323.28

60 1,449.93

240 276.00

480 120.42
194

Appendix H

Example of a Carcinogenicity

Assessment Appendix in 

A Technical Support Document

CARCINOGENICITY ASSESSMENT OF DIMETHYLHYDRAZINE

Slope factors for 1,1-dimethylhydrazine and 1,2-dimethylhydrazine were

available but have been withdrawn from the U.S. EPA Integrated Risk Information System (IRIS) (U.S. EPA 1986). For a preliminary carcinogenicity

assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine

(cited in ATSDR 1994) will be used. The assessment follows previously described methodologies (NRC 1985; Henderson 1992).

The withdrawn slope factor for 1,1-dimethylhydrazine was 3.5 (mg/

kg"d)!1

, which, based upon a human inhalation rate of 20 m3/d and a body

weight of 70 kg, is equivalent to 1 (mg/m3

)

!1

.

To convert to a level of monomethylhydrazine that would cause a theoretical excess cancer risk of 10-4:

Risk of 1 × 10-4 = (1 × 10-4/1) × 1 mg/m3 = 1 × 10-4 mg/m3

(virtually safe dose)

To convert a 70-y exposure to a 24-h exposure:
APPENDIX H 195 

24-h exposure = d × 25,600

= (1 × 10-4 mg/m3

) × 25,600 d

= 2.56 mg/m3

To account for uncertainty regarding the variability in the stage of the

cancer process at which monomethylhydrazine or its metabolites may act, a

multistage factor of 6 is applied (Crump and Howe 1984):

(2.56 mg/m3

)/6 = 0.43 mg/m3 (0.18 ppm)

Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-h exposure would be 0.9 mg/m3

 (0.5 ppm).

If the exposure is limited to a fraction (f) of a 24-h period, the fractional

exposure becomes 1/f × 24 h (NRC 1985).

24-h exposure = 0.43 mg/m3

 (0.18 ppm)

8-h = 1.3 mg/m3

 (0.5 ppm)

4-h = 2.6 mg/m3

 (1.1 ppm)

1-h = 10.3 mg/m3

 (4.2 ppm)

0.5 h = 20.6 mg/m3

 (8.5 ppm)

Because the AEGL-2 values based upon acute toxicity were equivalent to

or lower than the 10-4 risk values derived based on potential carcinogenicity,

the acute toxicity data were used for the AEGLs for dimethylhydrazine. For

10-5 and 10-6 risk levels, the 10-4 values are reduced by 10-fold or 100-fold,

respectively.
196

Appendix I

Example of the AEGL Derivation

Summary Appendix in 

A Technical Support Document

DERIVATION SUMMARY FOR

ACUTE EXPOSURE GUIDELINE LEVELS

FOR DIMETHYLHYDRAZINE

(CAS No. 57-14-7; 1,1-Dimethylhydrazine)

(CAS No. 540-73-8; 1,2-Dimethylhydrazine)

AEGL-1 Values

30 min 1 h 4 h 8 h

Not

recommended

Not

recommended

Not

recommended

Not

recommended

Reference: Not applicable

Test Species/Strain/Number: Not applicable

Exposure Route/Concentrations/Durations: Not applicable 

Effects: Not applicable

Endpoint/Concentration/Rationale: Not applicable (Continued)
APPENDIX I 197 

Uncertainty Factors/Rationale: Not applicable 

Modifying Factor: Not applicable 

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Not applicable

Data Adequacy: Numeric values for AEGL-1 are not recommended because (1)

data are not available, (2) data indicate that toxic effects may occur at or below

the odor threshold, (3) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (4) the derived AEGL-1 is greater than the

AEGL-2. Absence of an AEGL-1 does not imply that exposure below the

AEGL-2 is safe.

NOTE: If an AEGL-1 value is not recommended, there should be a short discussion

of the rationale for that choice. The rationale should include as appropriate a discussion that numeric values for AEGL-1 are not recommended because (1) relevant data

are lacking, (2) the margin of safety between the derived AEGL-1 and AEGL-2 values

is inadequate, or (3) the derived AEGL-1 is greater than the AEGL-2. Absence of an

AEGL-1 does not imply that exposure below the AEGL-2 is safe.

AEGL-2 Values

30 min 1 h 4 h 8 h

 6.0 ppm 3.0 ppm 0.75 ppm 0.38 ppm

Reference: Weeks, M.H., G.C. Maxey, M.E. Sicks, and E.A. Greene. 1963.

Vapor toxicity on UDMH in rats and dogs from short exposures. Am. Ind. Hyg.

Assoc. J. 24:137-143

Test Species/Strain/Sex/Number: mongrel dogs, 2-4/group, sex not specified 

Exposure Route/Concentrations/Durations: Inhalation; 1,200-4,230 ppm for 5

min; 360, 400, or 1,530 ppm for 15 min; 80-250 ppm for 60 min

Effects:

Exposure (15 min) Effect

360 ppm muscle fasciculations in 1 of 4 dogs (determinant for

AEGL-2)

400 ppm behavioral changes in 2 of 4 dogs

1,530 ppm tremors, convulsions, vomiting in 2 of 2 dogs

Endpoint/Concentration/Rationale: 15-min exposure at 360 ppm considered a

threshold for potentially irreversible effects or effects that would impair escape. 

At this exposure, muscle fasciculations were observed in 1 of 4 exposed dogs,

and at 400 ppm, behavioral changes were observed. (Continued)
198 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Uncertainty Factors/Rationale: Total uncertainty factor: 30

Interspecies: 3 - The toxic response to dimethylhydrazine (LC50 values)

was similar across species. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog

data when extrapolated from 1 h using n = 1. The more susceptible species, the dog, was used to derive the AEGL-2 values.

Intraspecies: 10 - A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary. This variability was especially

demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. 

Therefore, a factor of 10 was applied. A factor of 10 was also applied because experiments by Weeks et al. (1963) indicated that dogs had been previously stressed (auditory stimuli), which may have affected their response

to dimethylhydrazine. Based upon these data, it was assumed that humans

may be equally variable in their response to dimethylhydrazine.

Modifying Factor: None

Animal to Human Dosimetric Adjustment: None applied, insufficient data

Time Scaling: Cn

 × t = k, where n = 1 and k = 180 ppm"min; LC50 data were

available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and

60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n = 0.84 for rats; n = 0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n = 1 was selected.

Data Adequacy: Information regarding the human experience for acute inhalation exposure to dimethylhydrazine are limited to qualitatively case reports indicating nasal and respiratory tract irritation, breathing difficulties, and nausea. 

Data in animals have shown concentration-dependent effects ranging from respiratory tract irritation, pulmonary edema and neurologic effects to lethality. 

Because the nonlethal effects in humans and animals are qualitatively similar,

the animal data were considered relevant and appropriate for development of

AEGL values. The AEGL values for dimethylhydrazine reflect the steep

exposure-response relationship suggested by available data. 
APPENDIX I 199 

AEGL-3 Values

30 min 1 h 4 h 8 h

22 ppm 11 ppm 2.7 ppm 1.4 ppm

Reference: Weeks, M.H., G.C. Maxey, M.E. Sicks, and E.A. Greene. 1963.

Vapor toxicity of UDMH in rats and dogs from short exposures. Am. Ind. Hyg.

Assoc. J. 24:137-143

Test Species/Strain/Sex/Number: mongrel dogs, 3-4/group; sex not 

specified

Exposure Route/Concentrations/Durations: Inhalation; exposure to 

various concentrations (80-22,300 ppm) for 5, 15, or 60 min

Effects:

1-h LC50 981 ppm (reduction by 1/3 was basis for AEGL-3 

derivation)

15-min LC50 3,580 ppm

5-min LC50 22,300 ppm

Endpoint/Concentration/Rationale: 1-h LC50 (981 ppm) reduced by 1/3 was

considered an estimate of the lethality threshold (327 ppm). Based on the available exposure-response data for this chemical (Jacobson et al. 1955), a 3-fold

reduction in LC50 values results in exposures that would not be associated with

lethality.

Uncertainty Factors/Rationale: Total uncertainty factor: 30

Interspecies: 3 - The toxic response to dimethylhydrazine (LC50 values)

was similar across species. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog

data when extrapolated from 1 h using n = 1. The more susceptible species, the dog, was used to derive the AEGL-3 values.

Intraspecies: 10 - A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and susceptibility among individuals regarding these effects may vary. This variability was especially

demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. 

Therefore, a factor of 10 was used. A factor of 10-fold was also used because experiments by Weeks et al. (1963) indicated that dogs previously

stressed by auditory stimuli may have a potentiated response to dimethylhydrazine. Based upon these data, it was assumed that humans may be

equally variable in their response to dimethylhydrazine subsequent to similar stresses.

Modifying Factor: None

Animal to Human Dosimetric Adjustment: None applied, insufficient data 
200 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

Time Scaling: Cn × t = k, where n = 1 and k = 654 ppm$min; LC50 data were

available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and

60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n = 0.84 for rats; n = 0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n = 1 was selected by

the National Advisory Committee.

Data Adequacy: Information regarding the lethality of dimethylhydrazine in

humans were not available. Lethality data for several animal species allowed

for a defensible development of the AEGL-3 values but uncertainties remain

regarding individual variability in the toxic response to dimethylhydrazines.
201

Appendix J

List of Extant Standards and

Guidelines in 

A Technical Support Document

Section 8.2 of the technical support document (TSD) compares the AEGL

values for a chemical with other standards and guidelines previously published

for exposure durations ranging from 10 min to 8 h. A summary discussion of

important comparisons should be presented in the text and the values for

recognized standards and guidelines, if available, should be presented in the

table. The statement, “All currently available standards and guidelines are

shown in Table . . .” should be included in the text to affirm completeness of

the table. Only those standards or guidelines with published values for a given

chemical should be included in the table. In cases where the exposure duration

of a published standard or guideline differs from those designated for AEGLs

(e.g., 15-min PEL-STEL), the value should be placed in parentheses in the

column of the closest AEGL exposure duration category and footnoted to

indicate its true exposure duration. A list of recognized standards and guidelines and the order in which they should appear in the following table.
202 STANDING OPERATING PROCEDURES FOR DEVELOPING AEGLS

LIST AND ORDER OF PRESENTATION OF

EXTANT STANDARDS AND GUIDELINES IN THE TSD TABLE

AEGL-1 acute exposure guideline level-1

AEGL-2 acute exposure guideline level-2

AEGL-3 acute exposure guideline level-3

ERPG-1 (AIHA) emergency response planning guideline-level 1

ERPG-2 (AIHA) emergency response planning guideline-level 2

ERPG-3 (AIHA) emergency response planning guideline-level 3

SPEGL (NRC) short-term emergency guidance level

EEL (NRC) emergency exposure limit

STPL (NRC) short-term public limit

CEL (NRC) continuous exposure limit

EEGL (NRC) emergency exposure guidance level

SMAC (NRC) spacecraft maximum allowable concentration for

space-station contaminants

PEL-STEL (OSHA) permissible exposure limit–short-term exposure

limit

PEL-TWA (OSHA) permissible exposure limit–time weighted average

IDLH (NIOSH) immediately dangerous to life and health

REL-STEL (NIOSH) recommended exposure limit

TLV-STEL (ACGIH) Threshold Limit Value–short-term exposure limit

TLV-TWA (ACGIH) Threshold Limit Value–time-weighted average

MAC (Netherlands) maximum acceptable concentration

MAK (Germany) [maximale arbeitsplatzkonzentration] maximum

workplace concentration, 8-h time weighted

average, German Research Association

MAK S. (Germany) spitzenbegrenzung (kategorie ii, 2) [peak limit II,

2] 30 min × 2 per day

einsatztoleranzwert action tolerance levels

 (Germany)