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7
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9 Standing Operating Procedures
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14 ofthe
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20 National Advisory Committee
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22 on
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24 Acute Exposure Guideline Levels
2s for Hazardous Substances
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37 Version 08-02
38 June 30, 2000
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2 PREFACE
3
4 The National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
5 Substances (NAC/AEGL Committee) was established to develop scientifically credible short-term
6 exposure limits for approximately 400 to 500 acutely toxic substances. These short-term exposure limits,
7 referred to as Acute Exposure Guideline Levels, or AEGLs, are essential for emergency planning,
8 response, and prevention of accidental releases of chemical substances. Further, it is important that the
9 values developed be scientifically credible so that effective planning, response, and prevention can be
10 accomplished.
11
12 To insure scientific credibility, five major elements have been integrated into the AEGL
13 development process. These include adherence to the 1993a National Resource Council with changes or
14 additions as set forth in the Standing Operating Procedures Manual (SOP Manual), U. S. National
15 Academy of Sciences (NRC-NAS) guidelines for developing short-term exposure limits, a
16 comprehensive search and review of relevant data and information from both published and unpublished
17 sources, the extensive evaluation of the data and the development of AEGLs by a committee of scientific
18 and technical experts from both the public and private sectors, a multi-tiered peer review process
19 culminating with final review and concurrence by the U. S. National Academy of Sciences (NAS), and,
20 the use of scientifically acceptable processes and methodologies to insure consistent and scientifically
21 credible AEGL values.
22
23 With the recent participation of certain member-countries of the Organization for Economic and
24 Cooperation Development (OECD), it is anticipated that the AEGL program will be expanded to include
25 the international community. This should result in increased scientific and technical support, a broader
26 scope of the review process, and an even greater assurance of scientifically credible AEGL values.
27
28 This Standing Operating Procedures Manual (SOP Manual) represents the documentation by the
29 NAC/AEGL Committee's SOP Workgroup of those procedures, methodologies, criteria and other
30 guidelines employed by the NAC/AEGL Committee in the development of the AEGL values. The
31 information contained herein is based on the guidance provided by the NAS in its 1993 publication
32 Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (NRC,
33 1993a) This manual contains additions and further details and clarification of specific procedures,
34 methodologies, criteria, and guidelines interpreted from the NAS guidelines that have been determined
35 by the NAC/AEGL Committee to be a necessary supplement to the 1993a NAS guidelines Procedures
36 and methodologies included in this manual have been reviewed by the NAC/AEGL Committee,
37 numerous OECD member countries, and have received a review and concurrence by the U S. National
38 Academy of Sciences. New or modified procedures and methodologies that are developed and adopted
39 by the NAC/AEGL Committee are classified as "Proposed." Such procedures and methodologies will,
40 from time to time, be submitted to the NAS for review and concurrence. Upon concurrence by the NAS,
41 they will be considered final and will serve as a supplement to the 1993 NRC-NAS guidelines and to the
42 2000 SOP guidance manual
43
44 It is believed that adherence to a rigorous AEGL development process in general, and the use of
45 scientifically sound procedures and methodologies in particular, will provide the most scientifically
46 credible exposure levels that are reasonably possible to achieve. This document is considered a "living
47 document" and the various procedures and methodologies, including those classified as "Final", are
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1 subject to change as deemed necessary by the NAC/AEGL Committee and the U. S. National Academy
2 of Sciences (NAS Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology,
3 National Research Council). As new data become available and new scientific procedures and
4 methodologies become accepted by a majority of the relevant scientific community, the NAC/AEGL
5 Committee and the National Academy of Sciences, they will be integrated into the AEGL development
6 process and the SOP Manual. With this approach, both the scientific credibility of the AEGL values and
7 the reduction in nsk to the general population will be insured
11
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1 TABLE OF CONTENTS
2
3 PREFACE i
4
5 1. OVERVIEW OF CURRENT AEGL PROGRAM AND NAC/AEGL COMMITTEE 1
6 HISTORY 1
7 PURPOSE AND OBJECTIVES OF THE AEGL PROGRAM AND THE NAC/AEGL
8 COMMITTEE 3
9 COMMITTEE MEMBERSHIP AND ORGANIZATIONAL STRUCTURE 4
10 SELECTION OF CHEMICALS FOR AEGL DEVELOPMENT 5
11 SCIENTIFIC CREDIBILITY OF AEGLS 6
12 THE AEGL DEVELOPMENT AND PEER REVIEW PROCESS 7
13 OPERATION OF THE COMMITTEE 9
14 VALUE OF A COLLABORATIVE EFFORT IN THE AEGL PROGRAM 10
15 APPLICATIONS OF THE AEGL VALUES 12
16
17 2. DERIVATION OF AEGL VALUES 15
18 2.1 DEFINITIONS OF AEGL-1, AEGL-2 AND AEGL-3 15
19 PREFACE 15
20 2.2 EMPIRICAL TOXICOLOGIC ENDPOINTS, AND METHODS FOR
21 DETERMINING EXPOSURE CONCENTRATIONS USED TO DERIVE
22 AEGL-1,2, AND 3 LEVELS 17
23 2.2.1 SELECTION OF THE HIGHEST EXPOSURE LEVEL WHERE THE
24 EFFECTS USED TO DEFINE AN AEGL LEVEL WERE NOT
25 OBSERVED 17
26 2.2.2 SELECTION OF HEALTH EFFECTS ENDPOINTS FOR AEGL-1,
27 AEGL-2, AND AEGL-3 20
28 2.2.2.1 AEGL-1 Endpomts 21
29 2.2.2.1.1 No Value Established - AEGL-1 Exceeds AEGL-2 . 22
30 2.2.2.1.2 No Value Established - Insufficient Data 22
31 2.2.2.1.3 Highest Experimental Exposure Without an AEGL-1
32 Effect 22
33 2.2.2.1.4 Effect Level for a Response 22
34 2.2.2.2 AEGL-2 Endpoints 23
35 2.2.2.2.1 Highest Experimental Exposure Without an AEGL-2
36 Effect 23
37 2.2.2.2.2 Effect Level for a Toxic Response Which was Not
38 Incapacitating or Not Irreversible 23
39 2 2.2.2.3 A Fraction of the AEGL-3 Level 24
40 2.2.2.3 AEGL-3 Endpomts 24
41 2.2.2.3.1 Highest Exposure Level Which Does Not Cause Lethality
42 - Experimentally Observed Threshold (AEGL-3 NOEL)
43 24
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1 2.2.2.3.2 Highest Exposure Level Which Does Not Cause Lethality
2 - Estimated Lethality Threshold -1/3 of the LC50 24
3 2.2.2.3.3 Highest Exposure Level Which Does Not Cause Lethality
4 - Benchmark Exposure Calculation of the 5 % and 1%
5 Response 25
6 2.2.2.3.4 Effect Level for a Response 25
7 2.3 GUIDELINES/CRITERIA FOR THE SEARCH STRATEGY, EVALUATION,
8 SELECTION AND DOCUMENTATION OF KEY DATA AND SUPPORTING
9 DATA USED FOR THE DERIVATION OF AEGL VALUES 27
10 2.3.1 Search Strategy 27
11 2.3.2 Evaluation, Selection and Documentation of Key and Supporting Data ..31
12 Elements for the Evaluation of Key and Supporting Data and Studies .. 36
13 2.3.3 Elements for Discussion on Data Adequacy and Research Needs 38
14 2.4 DOSIMETRY CORRECTIONS FROM ANIMAL TO HUMAN EXPOSURES .. 39
15 2.4.1 Discussion of Potential Dosimetry Correction Methodologies for Gases
16 39
17 2.4.1.1 The Respiratory System as a Target Organ 39
18 2.4.1.2 Systemic Toxicity 41
19 2.4.2 Current Approach of the NAC/AEGL Committee to Dosimetry Corrections
20 42
21 2.5 GUIDELINES/CRITERIA FOR SELECTION OF UNCERTAINTY FACTORS TO
22 ADDRESS THE VARIABILITY BETWEEN ANIMALS AND HUMANS AND
23 WITHIN THE HUMAN POPULATION 44
24 2.5.1 Introduction 44
25 2.5.2 Background 45
26 2.5.3 Considerations and Approaches to the Selection of Uncertainty Factors for
27 Developing AEGLs 48
28 2.5.3.1 Interspecies Uncertainty Factors - Use in the Development of
29 AEGL Values - Discussion 50
30 2.5.3.2 Interspecies Uncertainty Factors - NAC/AEGL Committee
31 Guidelines 51
32 2.5.3.2.1 Most Appropriate Species Used 52
33 2.5.3.2.2 Most Sensitive Species Not Used 52
34 2.5.3.2.3 Mechanism of Action is Unlikely to Differ Among
35 Species 52
36 2.5.3.2.4 Mechanism of Action is Unknown 53
37 2.5.3.2.5 Variability in Response Between Species 53
38 2.5.3.2.6 Humans More Sensitive than Animals 53
39 2.5.3.2.7 Use of an Uncertainty Factor of 10 54
40 2.5.3.2.8 A Selected Uncertainty Factor Applied to Animal Data
41 Would Drive the AEGL-2 or -3 Level to a Value Which
42 Humans can Tolerate without Lethal or Senous Adverse
43 Effects 54
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1 2.5.3.2.9 A multiple exposure study was used to set the level... 54
2 2.5.3.3 Intraspecies Uncertainty Factors - Use m the Development of
3 AEGL Values - Discussion 56
4 2.5.3.3.1 Range of Susceptibility 61
5 2.5.3.3.2 Selection of Intraspecies Uncertainty Factors 64
6 2.5.3.3.3 Distinguishing Susceptible and Hypersusceptible
7 Individuals 64
8 2.5.3.3.4 Estimating the Range of Variability in a Human
9 Population 65
10 2.5.3.4 Intraspecies Uncertainty Factors - NAC/AEGL Guidelines 68
11 2.5.3.4.1 Toxic Effect is Less Severe than Defined for the AEGL
12 Tier 68
13 2.5.3.4.2 Sensitive/Naive Individual Used 68
14 2.5.3.4.3 Age/Life Stage/Condition Differences 69
15 2.5.3.4.4 Response by Normal and Sensitive Individuals to
16 Chemical Exposure is Unlikely to Differ for Mechanistic
17 Reasons 69
18 2.5.3.4.5 Mode or Mechanism of Action is Unknown 69
19 2.5.3.4.6 Uncertainty Factors Which Result in AEGL Values That
20 Conflict with Actual Human Exposure Data 70
21 2.6 GUIDELINES/CRITERIA FOR SELECTION OF MODIFYING FACTORS .... 71
22 2.6.1 Definition 71
23 2.6.2 Use of Modifying Factors to Date in the Preparation of AEGL Values .. 71
24 2.7 GUIDELINES/CRITERIA FOR TIME SCALING 72
25 2.7.1 Overview 72
26 2.7.2 Summary of Key Publications on Time Scaling 74
27 2.7.3 Summary of the Approaches that may be Taken for Time Scaling 75
28 2.7.4 Use of Empirical Data that is Available for AEGL-Specified Exposure
29 Durations 76
30 2.7.5 Derivation of Values of n When Adequate Empirical Data are Available for
31 Other than the AEGL-Specified Exposure Durations 76
32 2.7.5.1 Selection of Appropriate Health Effect End Point for Deriving a
33 Value for n 76
34 2.7.5.2 Criteria for Adequate Empirical Data for Deriving Values of n
35 77
36 2.7.5.3 Curve Fitting and Statistical Testing of the Generated Curve . 77
37 2.75.4 Examples of NAC/AEGL Committee Derivations of Values of n
38 from Empirical Data 80
39 2.7.6 Selection of Values of n When Adequate Empirical Data are Not Available
40 to Derive Values for n 80
41 2.7.6.1 Selection of Values of n When Extrapolating from Shorter to
42 Longer Exposure Periods 82
43 2.7.6.2 Selection of Values of n When Extrapolating from Longer to
111
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1 Shorter Exposure Periods 82
2 2.7.7 Special Considerations in the Time Scaling of AEGL-1 and AEGL-2
3 Values 85
4 2.7.8 Time Scaling - Guidelines for NAC/AEGL Committee Approach 86
5 2.7.8.1 Use of Empirical Data to Determine the Exposure Concentration-
6 Exposure Duration Relationship 86
7 2.7.8.2 Estimating the Concentration-Exposure Relationship using a
8 Surrogate Chemical 86
9 2.7.8.3 Estimating the Concentration-Exposure Duration Relationship
10 when Data are not Available to Derive a Value for n and
11 Supporting Data are Available 87
12 2.7.8.4 Determining Concentration-Exposure Relationships when Data
13 are not Available to Derive a Value for n and no Supporting Data
14 are Available 88
15 2.7.8.5 AEGL Exposure Values are Constant Across Time 88
16 2.8 GUIDELINES/CRITERIA FOR ADDRESSING SHORT TERM EXPOSURE
17 KNOWN AND SUSPECT CARCINOGENS 89
18 2.8.1 NRC/NAS Guidance 89
19 2.8.2 Precedents for Developing Short-Term Exposure Limits Based on
20 Carcinogenicity 90
21 2.8.3 Scientific Basis for Credible Theoretical Excess Carcinogenic Risk
22 Assessments for Single Exposures of 8 Hours or Less 91
23 2.8.4 Practical Issues of Using Quantitative, Carcinogenic Risk Assessments for
24 Developing AEGLs 93
25 2.8.5 Current Approach of the NAC/AEGL Committee to Assessing Potential
26 Single Exposure Carcinogenic Risks 94
27 2.8.5.1 Evaluation of Carcinogenicity Data 94
28 2.8.5.2 Methodology Used for Assessing the Carcinogenic Risk of a
29 Single Exposure 95
30 2.8.5.2.1 The Determination of an Adjustment Factor Dealing with
31 the Dose-Dependent Stage of Carcinogenesis 95
32 2.8.5.3 Summary of Cancer Assessment Methodology used by the
33 NAC/AEGL Committee 97
34 2.9 GUIDELINES/CRITERIA FOR MISCELLANEOUS PROCEDURES AND
35 METHODS 99
36 2.9.1 Mathematical Rounding of AEGL Values 99
37 2.9.2 Multiplication of Uncertainty Factors 99
38
39 3. FORMAT AND CONTENT OF TECHNICAL SUPPORT DOCUMENTS 100
40 3.1 FORMAT AND CONTENT OF THE TECHNICAL SUPPORT DOCUMENT
41 (TSD) 100
42 PREFACE 100
43 TABLE OF CONTENTS 100
IV
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1 EXECUTIVE SUMMARY 101
2 OUTLINE OF THE MAIN BODY OF THE TECHNICAL SUPPORT
3 DOCUMENT 103
4 3.2 Potential Inclusion of Graphic Descriptions of Data 107
5
6 4. CURRENT ADMINISTRATIVE PROCESSES AND PROCEDURES FOR THE
7 DEVELOPMENT OF AEGL VALUES Ill
8 4 1 COMMITTEE MEMBERSHIP AND ORGANIZATIONAL STRUCTURE 112
9 4.2 THE AEGL DEVELOPMENT AND PEER REVIEW PROCESS 113
10 4.3 OPERATION OF THE COMMITTEE 116
11 44 ROLE OF THE DIRECTOR OF THE AEGL PROGRAM 117
12 4.5 ROLE OF THE DESIGNATED FEDERAL OFFICER 118
13 4.6 ROLE OF THE NAC/AEGL COMMITTEE CHAIR 118
14 4.7 CLASSIFICATION OF THE STATUS OF AEGL VALUES 119
15 48 ROLE OF AEGL DEVELOPMENT TEAMS 120
16 4 8.1 Role of a Chemical Manager 120
17 4.8.2 Role of a Chemical Reviewer 121
18 4.8.3 Role of an Staff Scientist at the Organization which Drafts Technical
19 Support Documents 122
20 4.9 ROLE OF NAC/AEGL COMMITTEE MEMBERS 122
21 4.10 ROLE OF THE ORGANIZATION THAT DRAFTS TECHNICAL SUPPORT
22 DOCUMENTS 123
23
24 5 REFERENCES 125
25
26 APPENDIX A. NAC/AEGL PROGRAM PERSONNEL A 1
27
28 APPEND1XB. PRIORITY LISTS OF CHEMICALS B 1
29
30 APPENDIX C. DIAGRAM OF THE AEGL DEVELOPMENT PROCESS C 1
31
32 APPENDIX D. GLOSSARY - ACRONYMS, ABBREVIATIONS, AND SYMBOLS D 2
33
34 APPENDIX E. EXAMPLE OF A TABLE OF CONTENTS IN A TECHNICAL SUPPORT
35 DOCUMENT El
36
37 APPENDIX F. EXAMPLE OF AN EXECUTIVE SUMMARY IN A TECHNICAL SUPPORT
38 DOCUMENT F 1
39
40 APPENDIX G EXAMPLE OF THE DERIVATION OF AEGL VALUES APPENDIX IN A
41 TECHNICAL SUPPORT DOCUMENT G 1
42
43 APPENDIX H. EXAMPLE OF A TIME SCALING CALCULATIONS APPENDIX IN A
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1 TECHNICAL SUPPORT DOCUMENT HI
2
3 APPENDIX I. EXAMPLE OF A CARdNOGENICITY ASSESSMENT APPENDIX IN A
4 TECHNICAL SUPPORT DOCUMENT II
5
6 APPENDIX J. EXAMPLE OF THE DERIVATION SUMMARY APPENDK IN A
7 TECHNICAL SUPPORT DOCUMENT J 1
8
9 APPENDIX K. LIST OF EXTANT STANDARDS AND GUIDELINES IN A TECHNICAL
10 SUPPORT DOCUMENT K 1
11
12 LIST OF TABLES
13
14 TABLE 2.7-1. VALUES OF n FROM TEN BERGE ET AL. (1986) 81
15 TABLE 3.2-1 GROUPING DATA INTO CATEGORIES FOR PLOTTING 109
16 TABLE B-l. PRIORITY LIST OF CHEMICALS B 4
17
18
19
20 LIST OF FIGURES
21
22 FIGURE 1-1 HAZARD ASSESSMENT 14
23 FIGURE 2.3-1 ALLOCATION OF STUDY REPORTS DECISION TREE 35
24 FIGURE 2.7-1 EFFECTS OF VARYING n IN THE EQUATION Cn x t = k 84
25 FIGURE 3.2-1 PLOT OF CATEGORIES OF DATA 110
26 FIGURE 4.2-1 THE AEGL DEVELOPMENT PROCESS 115
27 FIGURE C-l THE AEGL DEVELOPMENT PROCESS C 1
28
29
30
31
VI
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30. 2000
1
2 1. OVERVIEW OF CURRENT AEGL PROGRAM AND
3 NAC/AEGL COMMITTEE
4
5
6 HISTORY
7
8 The concerns of EPA, other U.S. federal agencies, state and local agencies, private
9 industry and other organizations in the private sector regarding short-term exposures due to
10 chemical accidents became sharply focused following the accidental release of methyl isocyanate
11 in Bhopal, India in December of 1984. In November 1985, as part of EPA's National Strategy
12 for Toxic Air Pollutants, the agency developed the Chemical Emergency Preparedness Program.
13 This voluntary program identified a list of over 400 acutely toxic chemicals and provided this
14 information, together with interim technical guidance, for the development of emergency
15 response plans at the local community level. At that time the agency adopted the NIOSH
16 Immediately Dangerous to Life and Health (IDLH) exposure values, or an approximation of these
17 values in instances where IDLH values were not published, to serve as the initial airborne
18 concentrations of concern for each chemical.
19
20 During this same period, the U.S. Chemical Manufacturers Association (CMA)
21 developed and implemented the Community Awareness and Emergency Response (CAER)
22 program. This program encouraged chemical plant managers to assist community leaders in
23 preparing for potential accidental releases of acutely toxic chemicals. The program was intended
24 to provide local communities with information on existing chemicals and chemical processes,
25 technical expertise to assist in emergency planning, notification and response, as well as the
26 training of response personnel.
27
28 In October, 1986 as part of the reauthonzation of Superfund, Congress wrote into law an
29 emergency planning program under the Superfund Amendments and Reauthonzation Act (SARA
30 Title HI). Under this act, states were required to have emergency response plans for chemical
31 accidents developed at the local community level. The EPA subsequently adjusted the level of
32 concern values to one-tenth of the IDLH value or its equivalent as an approach to improving the
33 safety of the levels used for the general public. Since that time, the agency and other
34 organizations, including private industry, have been interested in adopting more rigorous
35 methodologies for determining values that would be deemed safe for the general public. During
36 this period, the American Industrial Hygiene Association (AIHA) established a committee, the
37 Emergency Response and Planning Guidelines (ERPG) Committee to develop ERPGs and
38 pioneered the concept of developing three different airborne concentrations for each chemical
39 that would reflect the thresholds for important health effect endpoints. The Committee was later
40 renamed the Emergency Response Planning (ERP) Committee. Although constrained by limited
41 resources, the ERP Committee has managed to develop one-hour exposure limits for more than
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1 70 chemicals during the past 10 years.
2
3 At a workshop hosted by EPA in 1987, it was proposed by EPA that the ERP Committee
4 and scientists from federal and state agencies, as well as scientists and clinicians from academia
5 and public interest groups pool their technical and financial resources and form a single
6 committee comprised of scientists from both the public sector and the private sector to develop
7 Acute Exposure Guideline Levels (AEGL values). EPA conceived the idea to formulate general
8 guidance for developing short-term exposure limits and together with ATSDR subsequently
9 funded a subcommittee of the Committee of Toxicology of the National Research Council, U. S.
10 National Academy of Sciences (NRC/NAS) to develop guidance on the use of procedures and
11 methodologies to establish emergency exposure guideline levels for the general public.
12
13 Since the 1940's, the NRC/NAS Committee on Toxicology has developed emergency
14 exposure guidelines for 41 chemicals of concern to the U. S. Department of Defense (DOD).
15 These values are referred to as "Emergency Exposure Guideline Levels" (EEGLs). Although the
16 EEGLs were developed for use with military personnel, the NAS also developed special
17 exposure guidelines for the general public, termed "Short-term Public Exposure Guidance
18 Levels" (SPEGLs). Based on this extensive experience and the high level scientific and technical
19 expertise continually available to the NAS, this organization was considered the most qualified
20 entity to develop guidance on the methodologies and procedures used in the establishment of
21 short-term exposure limits for acutely toxic chemicals.
22
23 The NAS guidance document, entitled Guidelines for Developing Community Emergency
24 Exposure Levels for Hazardous Substances, was published in 1993. The Community Emergency
25 Exposure Levels (CEELs) and the Acute Exposure Guideline Levels (AEGLs) represent the
26 identical short-term emergency exposure levels. The NAS name (CEELs) has been replaced by a
27 new name (AEGLs) only to convey the broad applications of these values for planning,
28 response, and prevention in the community, the workplace, transportation, the military, and the
29 remediation of superfund sites. A discussion of how AEGLs might be used for emergency
30 planning, response, and prevention appears later in this chapter.
31
32 The efforts to mobilize the federal and state agencies and individuals and organizations in
33 the private sector to form the committee began shortly thereafter. In October, 1995 the
34 committee was formally chartered and the charter filed with the U.S. Congress under the Federal
35 Advisory Committee Act (FACA) with approval by the Office of Management and Budgets
36 (OMB) and concurrence by the General Services Administration (GSA). Due to EPA budgetary
37 constraints, the first meeting of the NAC/AEGL Committee was not held until June, 1996. This
38 meeting represented the culmination of the efforts to solicit stakeholders, identify committee
39 members, form the committee, obtain the technical support of the Oak Ridge National
40 Laboratories (ORNL), and begin the development of the AEGL values.
41
42
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 PURPOSE AND OBJECTIVES OF THE AEGL PROGRAM AND THE
2 NAC/AEGL COMMITTEE
3
4 The primary purpose of the AEGL Program and the NAC/AEGL Committee is to develop
5 guideline levels for once in a lifetime short-term exposures to airborne concentrations of acutely
6 toxic, high priority chemicals. These Acute Exposure Guideline Levels (AEGLs) are needed for
7 a wide range of planning, response, and prevention applications. These applications may include
8 the EPA's SARA Title ffl Section 302-304 emergency planning program, the U. S. Clean Air Act
9 Amendments (CAAA) Section 112(r) accident prevention program, and the remediation of
10 Superfund sites program; the DOE environmental restoration, waste management, waste
11 transport, and fixed facility programs; the DOT emergency waste response program; the DOD
12 environmental restoration, waste management, and fixed facility programs; ATSDR health
13 consultation and risk assessment programs; NIOSH/OSHA regulations and guidelines for
14 workplace exposure; State CAA Section 112(b) programs and other state programs; and private
15 sector programs such as the AIHA-ERPG and the CMA Chemtrec programs.
16
17 A principal objective of the NAC/AEGL Committee is to develop scientifically credible,
18 acute (short-term) once in a lifetime exposure guideline levels within the constraints of data
19 availability, resources and time. This includes highly effective and efficient efforts in data
20 gathering, data evaluation and data summarization, fostering the participation of a large cross-
21 section of the relevant scientific community, and the adoption of procedures and methods that
22 facilitate consensus-building for AEGL values within the Committee.
*>3
^4 Another principal objective of the committee is to develop these AEGL values for
25 approximately 400 to 500 acutely hazardous substances within the next ten (10) years.
26 Therefore, the near-term objective is to increase the level of production of AEGL development to
27 approximately forty (40) to fifty (50) chemicals per year without exceeding budgetary limitations
28 or compromising the scientific credibility of the values developed.
29
30 Further, in addition to determining AEGL values for three different health effect end-
31 points, it is intended to derive exposure values for the general public that are applicable to
32 emergency (accidental) once m a lifetime exposure periods ranging from 10 minutes to 8 hours
33 duration. Therefore, exposure limits will be developed for a minimum of 5 exposure periods (10
34 minutes, 30 minutes, 1 hour, 4 hours, 8 hours). Each AEGL tier is distinguished by varying
35 degrees of severity of toxic effects, as initially conceived by the AIHA ERP Committee and
36 further defined in the NAS' National Research Council report, Guidelines for Developing
37 Community Emergency Exposure Levels for Hazardous Substances, published by the National
38 Academy of Sciences in 1993 (NAS Guidance), and further defined by the NAC/AEGL
39 Committee. These AEGL-1, AEGL-2, and AEGL-3 definitions are presented elsewhere in this
40 SOP manual.
41
42 As stated in the NAS guidelines and described in the AEGL definitions, these exposure
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 limits are intended to protect most individuals in the general population, including those that may
2 be particularly sensitive or susceptible to the deleterious effects of the chemicals. However, as
3 stated in the guidelines and the definitions, it is recognized that certain individuals, subject to
4 unique and idiosyncratic responses, could experience effects at concentrations below the
5 corresponding AEGL.
6
7 An important objective of the NAC/AEGL Committee is the establishment and
8 maintenance of a comprehensive "Standing Operating Procedures" manual (SOP Manual) that
9 adheres to the 1993a NRC/NAS guidelines and supplements, clarifies, interprets or defines these
10 guidelines with regard to the specific use of certain procedures and methods such as the selection
11 of NOAELs, LOELs, etc., use of uncertainty factors, modifying factors, interspecies/intraspecies
12 extrapolation methodologies, time scaling, carcinogenic risk assessment, and other methods and
13 procedures relevant to the development of AEGL values.
14
15
16 COMMITTEE MEMBERSHIP AND ORGANIZATIONAL STRUCTURE
17
] 8 The NAC/AEGL Committee is comprised of representatives of federal, state and local
19 agencies, and organizations in the private sector that derive programmatic or operational benefits
20 from the AEGL values. This includes federal representatives from the U.S. Environmental
21 Protection Agency (EPA), the Department of Energy (DOE), the Agency for Toxic Substances
22 and Disease Registry (ATSDR), the National Institute for Occupational Safety and Health
23 (NIOSH), Occupational Safety and Health Administration (OSHA), the Department of
24 Transportation (DOT), the Department of Defense (DOD), the Center for Disease Control
25 (CDC), the Food and Drug Administration (FDA), and the Federal Emergency Management
26 Agency (FEMA). States providing committee representatives include New York, New Jersey,
27 Texas, California, Minnesota, Dlinois, Connecticut, and Vermont. Private companies with
28 representatives include Allied Signal Corporation, Exxon Corporation, and Olin Chemical
29 Company. Other organizations with representatives include the American Industrial Hygiene
30 Association (AM A), American College of Occupational and Environmental Medicine
31 (ACOEM), American Association of Poison Control Centers (AAPCC), and the AFL-CIO. In
32 addition, the committee membership includes individuals from academia, a representative of
33 environmental justice, and other organizations in the private sector. A current list of the
34 NAC/AEGL Committee members and their affiliations is shown in Appendix A of this SOP
35 manual. At present, the Committee is comprised of 32 members.
36
37 Recently, the Organization of Economic and Cooperation Development (OECD) and
38 various OECD member countries have expressed an interest in the AEGL Program. Several
39 OECD member countries such as Germany and the Netherlands have been participating m the
40 Committee's activities and actively pursuing formal membership on the NAC/AEGL Committee
41 It is envisioned that the Committee and the AEGL Program in general will progressively expand
42 its scope and participation to include the international community.
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 The Director of the AEGL Program has the overall responsibility for the entire AEGL
2 Program and the NAC/AEGL Committee and its activities. A Designated Federal Officer (DFO)
3 is responsible for all administrative matters related to the Committee to insure that it functions
4 properly and efficiently. These individuals are not voting members of the Committee. The
5 NAC/AEGL Committee Chair is appointed by EPA and is selected from among the committee
6 members. In concert with the Program Director and the DFO, the Chair coordinates the activities
7 of the Committee and also directs all formal meetings of the Committee. From time to time, the
8 members of the Committee serve as Chemical Managers and Chemical Reviewers in a
9 collaborative effort with assigned scientist-authors (non-Committee members) to develop AEGLs
10 for a specific chemical. These groups of individuals are referred to as the AEGL Development
11 Teams and their function is discussed in Section 4.8 of this manual..
12
13 SELECTION OF CHEMICALS FOR AEGL DEVELOPMENT
14
15 A master list of approximately 1,000 acutely toxic chemicals was initially compiled
16 through the integration of individual priority lists of chemicals submitted by each U. S. federal
17 agency placing a representative on the Committee. The master list was subsequently reviewed by
18 individuals from certain state agencies and representatives from organizations in the private
19 sector and modified as a result of comments and suggestions received. The various priority
20 chemical lists were compiled separately by each federal agency based on their individual
21 assessments of the hazards, potential exposure, risk, and relevance of a chemical to their
22 programmatic needs. A list of approximately 400 chemicals representing the higher pnonty
23 chemicals was tentatively identified from the original master list. It was acknowledged that this
24 list was subject to change based on the changing needs of the stakeholders.
25
26 On May 21, 1997, a list of 85 chemicals was published in the Federal Register. This list
27 identified those chemicals from the list of approximately 400 chemicals considered to be of
28 highest priority across all U. S. federal agencies and represented the selection of chemicals for
29 AEGL development by the NAC/AEGL Committee for the first two to three years of the
30 program. The Committee has now addressed these chemicals and they are presently in the Draft,
31 Proposed, Interim, or Final stages of development. Certain chemicals did not contain an
32 adequate database for AEGL development and, consequently, are on hold pending decisions
33 regarding further testing This initial "highest" priority list of 85 chemicals is shown in
34 Appendix B.
35
36 A second "working list" of approximately 100 priority chemicals is being selected from
37 (1) the original master list, (2) the intermediate list of approximately 400 chemicals (which is a
38 subset of the master list) and (3) from new, high priority candidate chemicals submitted by U. S.
39 Agencies and organizations and OECD member countries that are planning to participate in the
40 AEGL Program. Although "working lists" will be published in the U. S. Federal Register and
41 elsewhere from time-to-time to indicate the NAC/AEGL Committee's agenda, the priority of
42 chemicals addressed, and , hence, the "working list" is subject to modification if priorities of the
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30,2000
1 NAC/AEGL Committee or individual stakeholder organizations, including international
2 members, change during that period.
3
4
5 SCIENTIFIC CREDIBILITY OF AEGLS
6
7 The scientific credibility of the AEGL values is based on adherence to the National
8 Academy of Sciences 1993a guidelines for developing short-term exposure limits, the
9 comprehensive nature of data collection and evaluation, the consistency of the methods and
10 procedures used to develop the values, the potential of acute toxicity testing in cases of
11 inadequate data, and the adoption of the most comprehensive peer review process ever used to
12 establish short-term exposure limits for acutely toxic chemicals.
13
14 The comprehensive data gathering process involves literature searches for all relevant
15 published data and the mobilization of all relevant unpublished data. Data and information from
16 unpublished sources is obtained through individual companies in the private sector and the
17 cooperation of trade associations. The completeness of the data searches is enhanced through the
18 oversight and supplemental searches conducted by individual Committee members and interested
19 parties during the peer review process.
20
21 Data evaluation and selection is performed by scientists with expertise in toxicology and
22 related disciplines from staff at the organization which drafts Technical Support Documents and
23 the assigned members of the NAC/AEGL Committee. Additionally, input on data evaluation and
24 selection is provided by interested parties who participate in the open meetings of the Committee
25 or who formally comment on the Federal Register notices of Proposed AEGL values
26
27 The work of the NAC/AEGL Committee adheres to the 1993a NRC/NAS publication
28 Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances.
29 Since this guidance document represents a more general guidance for methods and procedures,
30 the NAC/AEGL Committee interprets and develops greater detail related to the methodologies
31 and procedures that it follows. These Standing Operating Procedures (SOPs) are documented by
32 the SOP Workgroup and represent a consensus or two-thirds majority vote of the NAC/AEGL
33 Committee. SOPs also represent concurrence of the National Academy of Sciences'
34 Subcommittee on Acute Exposure Guideline Levels (NAS/AEGL Subcommittee). Therefore,
35 each step of the AEGL development process follows specific methodologies, criteria or other
36 guidelines to insure consistent, scientifically sound values.
37
38 In instances where AEGL values cannot be developed because of poor data or no data, the
39 chemical may be subjected to appropriate acute toxicity testing. The AEGL program is
40 committed to insuring that AEGL values are derived from adequate data and information based
41 on a consensus or two-thirds majority vote of the NAC/AEGL Committee and concurrence of the
42 NAS/AEGL Subcommittee.
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1 To further assure the scientific credibility of the AEGL values and their supporting
2 rationale, the most comprehensive peer review process ever employed in the development of
3 short-term exposure limits has been established (see next section). This review process has been
4 designed to effectively, yet efficiently, encourage and enable the participation of the scientific
5 community and other interested parties from the public and private sectors in the development of
6 the AEGLs. Further, the review process utilizes an expert committee of the National Academy
7 of Sciences, the NAS/AEGL Subcommittee as the final scientific review . Hence, the final
8 judgement of scientifically credible values rests with the United State's ultimate scientific body,
9 the NAS. A detailed summary of the AEGL development process is presented in the next
10 section.
11
12
13 THE AEGL DEVELOPMENT AND PEER REVIEW PROCESS
14
15 The process that has been established for the development of the AEGL values is the
16 most comprehensive ever employed for the determination of short-term exposure limits for
17 acutely toxic chemicals. A summary of the overall process is presented in diagram form in
18 Appendix C. The process consists of four basic stages in the development and status of the
19 AEGLs and they are identified according to the review level and concurrent status of the AEGL
20 values. They include (1) "Draft" AEGLs, (2) "Proposed" AEGLs, (3) "Interim" AEGLs and (4)
21 "Final" AEGLs. The entire development process can be described by individually describing the
22 four basic stages in the development of AEGL values.
23
24
25 Stage 1: "Draft" AEGLs
26
27 This first stage begins with a comprehensive search of the published scientific literature.
28 Attempts are made to mobilize all relevant, non-published data through industry trade
29 associations and from individual companies in the private sector. A more detailed description of
30 the published and unpublished sources of data and information utilized is provided in Section 2.3
31 of this document which addresses search strategies. The data are evaluated following the
32 guidelines published in the NRC/NAS guidance document and this SOP manual and selected
33 data are used as the basis for the derivation of the AEGL values and the supporting scientific
34 rationale. Data evaluation, data selection, and the development of a technical support document
35 are all performed as a collaborative effort among the Staff Scientist at the organization which
36 drafts Technical Support Documents, the Chemical Manager, and two Chemical Reviewers.
37 This group is referred to as an "AEGL Development Team". NAC/AEGL Committee members
38 are specifically assigned this responsibility for each chemical under review. Hence, a separate
39 team comprised of different Committee members is formed for each chemical under review The
40 product of this effort is a technical support document (TSD) that contains "Draft" AEGLs. The
41 Draft TSD is subsequently circulated to all other NAC/AEGL Committee members for review
42 and comment prior to a formal meeting of the Committee. Revisions to the initial TSD and the
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30,2000
1 "Draft" AEGLs are made up to the time of the NAC/AEGL Committee meeting scheduled for
2 formal presentation and discussion of the AEGL values and the documents. Following
3 deliberations during the committee meeting, an attempt is made to reach consensus, or the
4 minimum of a two-thirds majority of a quorum present, to elevate the AEGLs to "Proposed"
5 status. If agreement cannot be reached, the Committee conveys its issues and concerns to the
6 AEGL Development Team and further work is conducted by this group. After completion of
7 additional work, the chemical is resubmitted for consideration at a future meeting. If a consensus
8 or two-thirds majority vote of the Committee cannot be achieved because of inadequate data
9 unrelated to the completeness of the data search, the chemical becomes a candidate for
10 appropriate toxicity studies.
11
12
13 Stage 2: "Proposed" AEGLs
14
15 Once the NAC/AEGL Committee has reached a consensus, or the minimum two-thirds
16 majority vote, on the AEGL values and supporting rationale, they are referred to as "Proposed"
17 AEGLs and are published in the Federal Register for a thirty (30) day review and comment
18 period. Following publication of the "Proposed" AEGLs in the Federal Register, the Committee
19 reviews the public comments, addresses and resolves relevant issues and seeks a consensus or
20 minimum two-thirds majority of those present on the Committee on the original or modified
21 AEGL values and the accompanying scientific rationale.
22
23
24 Stage 3: "Interim" AEGLs
25
26 Following resolution of relevant issues raised through public review and comment and
27 subsequent approval of the Committee, the AEGL values are classified as "Interim". The
28 "Interim" AEGL status represents the best efforts of the NAC/AEGL Committee to establish
29 exposure limits and the values are available for use as deemed appropriate on an interim basis by
30 federal and state regulatory agencies and the private sector. The "Interim" AEGLs, the supporting
31 scientific rationale, and the TSD, are subsequently presented to the National Academy of
32 Sciences (NAS/AEGL Subcommittee) for its review and concurrence. If concurrence cannot be
33 achieved, the NAS/AEGL Subcommittee will submit its issues and concerns to the NAC/AEGL
34 Committee for further work and resolution.
35
36
37 Stage 4: "Final" AEGLs
38
39 When concurrence by the NAS/AEGL Subcommittee is achieved, the AEGL values are
40 considered "Final" and published by the U. S. NAS. Final AEGLs may be used on a permanent
41 basis by all federal, state and local agencies and private sector organizations. It is possible that
42 from time to time new data will become available that challenges the scientific credibility of
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 "Final" AEGLs. If this occurs, the chemical will be resubmitted to the NAC/AEGL Committee
2 and recycled through the review process.
3
4
5 OPERATION OF THE COMMITTEE
6
7 The NAC/AEGL Committee meets formally four (4) times each year for two and one-half
8 (2-1/2) days. The meetings are scheduled for each quarter of the calendar year and are generally
9 held m the months of March, June, September, and December. Based on overall cost
10 considerations, the meetings are generally held in Washington, D.C. However, from time to
11 time, committee meetings may be held at other locations for justifiable reasons.
12
13 At least 15 days prior to the committee meetings, a notice of the meeting is published in
14 the Federal Register together with a list of chemicals and other matters to be addressed by the
15 Committee and provides dates, times and location of the meetings. The agenda is finalized and
16 distributed to committee members approximately one week prior to the meeting. The agenda
17 also is available to other interested parties at that time, upon request, through the Designated
18 Federal Officer (DFO).
19
20 All NAC/AEGL Committee meetings are open to the public and interested parties may
21 schedule individual presentations of relevant data and information by contacting the DFO to
22 establish a date and time. Relevant data and information from interested parties also may be
23 provided to the Committee through the DFO during the period of development of the Draft
24 AEGLs so that it can be considered during the early stage of development. Data and information
25 also may be submitted during the Proposed and Interim stages of AEGL development as well.
26
27 The NAC/AEGL Committee meetings are conducted by the Chair who is appointed by
28 the U.S. Environmental Protection Agency in accordance with the Federal Advisory Committee
29 Act (FACA). At the time of the meeting, both the Chair and all other committee members will
30 have received the initial draft and one or more revisions of the Technical Support Document
31 (TSD) and "Draft", "Proposed", or "Interim" AEGL values for each chemical on the agenda.
32 Reviews, comments, and revisions are continuous up to the time of the meeting and committee
33 members are expected to be familiar with the "Draft", "Proposed", or "Interim" AEGLs,
34 supporting rationale, and other data and information in each TSD and to participate in the
35 resolution of residual issues at the meeting. Procedures for the AEGL Development Teams and
36 the other Committee members regarding work on AEGLs in the Proposed or Interim status are
37 similar to those for Draft AEGLs.
38
39 All decisions of the NAC/AEGL Committee related to the development of Draft,
40 Proposed, Interim, and Final AEGLs and their supporting rationale are made by consensus or a
41 minimum of two-thirds (2/3) majority of a quorum of committee members. A quorum of the
42 NAC/AEGL Committee is defined as fifty-one percent (51 %) or more of the total NAC/AEGL
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1 Committee membership in attendance.
2
3 The highlights of each meeting are recorded by the scientists who draft the Technical
4 Support Documents and written minutes are prepared, ratified and maintained in the
5 Committee's permanent records. Deliberations of each meeting also are tape-recorded when
6 possible and stored in the Committee's permanent records by the Designated Federal Officer
7 (DFO) for future reference as necessary.
8
9 All Proposed AEGL values and supporting scientific rationale are published in the
10 Federal Register. Review and comment by interested parties and the general public are requested
11 and encouraged. The Committee's response to official comments on Federal Register notices on
12 Proposed AEGL values consists of an evaluation of the comments received, discussions and
13 deliberations that take place at Committee meetings regarding the considerations of elevation of
14 AEGLs from "Proposed" to "Interim" status, and changes to the Technical Support Documents
15 as deemed appropriate by the NAC/AEGL Committee. This information is reflected on the tapes
16 and in the minutes of the meetings and will be maintained for future reference.
17
18 As previously mentioned a "Standing Operating Procedures" Workgroup (SOP
19 Workgroup) was established in March, 1997 to document, summarize, and evaluate the various
20 procedures, methodologies, and guidelines employed by the Committee in the gathering and
21 evaluation of scientific data and information and the development of the AEGL values. The SOP
22 Workgroup performs a critical function by continually providing the Committee with detailed
23 information on the Committee's interpretation of the NAS guidelines and the approaches the
24 Committee has taken in the denvation of each AEGL value for each chemical addressed. This
25 documentation enables the Committee to continually assess the basis for its decision-making,
26 insure consistency with the NAS guidelines, and maintain the scientific credibility of the AEGL
27 values and accompanying scientific rationale. This ongoing effort is continuously documented
28 and is identified as the "SOP Manual".
29
30
31 VALUE OF A COLLABORATIVE EFFORT IN THE AEGL PROGRAM
32
33 The value of a collaborative effort in the AEGL Program is related primarily to the
34 pooling of substantial resources of the various stakeholders and the direct or indirect involvement
35 of a significant portion of the relevant scientific community from both the public and private
36 sectors. These factors, in turn, promote greater productivity, efficiency and cost effectiveness of
37 such an effort and greatly enhance the scientific credibility of the Acute Exposure Guideline
38 Levels (AEGLs) that are developed by the Committee.
39
40 The formation of the Federal Advisory Committee for Acute Exposure Guideline Levels
41 for Hazardous Substances (NAC/AEGL Committee) with approximately 30 to 35 members has
42 provided an important forum for scientists, clinicians, and others to develop the AEGLs and
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1 related scientific issues. The composition of the Committee represents a balanced cross-section
2 of relevant scientific disciplines and a balance of U. S. federal and state agencies, academia, the
3 medical community, private industry, public interest groups, and other organizations in the
4 private sector. This mutual participation of stakeholders, including the regulators and the
5 regulated community, in the development of the AEGLs promotes the acceptance of the AEGLs
6 by all parties involved. Additionally, the diverse composition of the committee represents the
7 nucleus of a broad network of scientists, clinicians, and other technical personnel that fosters
8 information and data exchange and the resolution of relevant scientific and technical issues well
9 beyond the committee membership. This network also facilitates the identification of national
10 and international experts with particular expertise that may provide important data, information
11 or insight on a specific chemical or scientific issue.
12
13 The collaborative effort also results in greater scientific credibility of the exposure values
14 developed. The pooling of resources enables a very comprehensive gathering and evaluation
15 effort of both published and unpublished data and information. Collaboration provides a broad
16 base of relevant scientific knowledge and expertise that is highly focused on the chemicals and
17 issues addressed by the Committee. This approach provides sufficient scientific and technical
18 resources for the SOP Workgroup to document and evaluate procedures and methodologies that
19 instill rigor and consistency into the process and the resultant AEGL values. The documentation
20 of these procedures and methodologies are contained in this Standing Operating Procedures
21 Manual (SOP Manual). Finally, the collaborative effort has enabled the establishment of the most
22 comprehensive peer review process ever implemented for the development of short-term
23 exposure limits.
24
25 Recently the AEGL Program has extended invitations to all OECD member countries to
26 participate on the NAC/AEGL Committee and the program activities in general. It is believed
27 that expanding the scope of the AEGL Program to include the international community will be of
28 great benefit. Their participation will provide even greater resources, further broaden the base of
29 scientific and technical expertise, provide new toxicological data and insights, and foster the
30 harmonization of emergency exposure limits at the international level.
31
32 In summary, the establishment of a collaborative effort, with its pooling of resources,
33 represents the most productive, efficient, and cost-effective approach to the development of
34 exposure guideline levels. Further, the effort results in the development of uniform values for a
35 wide range of applications. This eliminates inconsistencies and confusion among individuals and
36 organizations involved in emergency planning, response and prevention of chemical accidents.
37 In global terms, the NAC/AEGL Committee represents an approach to unifying the international
38 community in the development and use of chemical emergency exposure limits. In the interest of
39 multinational companies seeking uniform operating parameters and the mandates placed on
40 federal agencies to achieve international harmonization of standards and guidelines, the
41 participation of the international community in the AEGL Program represents an important goal
42 of the AEGL program.
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1
2 APPLICATIONS OF THE AEGL VALUES
3
4 As previously stated, it is anticipated that the AEGL values will be used for both
5 regulatory and non-regulatory purposes by federal and state agencies in conjunction with
6 chemical emergency prevention, preparedness, and/or response programs. This includes the
7 implementation of these chemical emergency activities at the local community level.
8
9 More specifically, the AEGL values will be used for conducting various risk assessments
10 to aid in the development of emergency preparedness and prevention plans, as well as real-time
11 emergency response actions, for accidental chemical releases at fixed facilities and from transport
12 carriers. The AEGL values, which represent defined toxic endpoints, are used in conjunction
13 with various chemical release and dispersion models to determine geographical areas, or
14 "vulnerable zones", associated with accidental or terrorist releases of chemical substances. By
15 determining these geographical areas, and the presence of human populations and facilities
16 within these zones, the potential risks associated with accidental chemical releases can be
17 estimated. For example, the release and dispersion models, which take into account the quantity
18 and rate of release of the chemical, the volatility of the substance, the wind speed and wind
19 stability at the time of the release, and a consideration of the topographical characteristics in the
20 area of the release, will define the geographical areas exposed, and quantitatively, the airborne
21 concentration of the "plume" or the chemical cloud as it is dispersed. By comparing the
22 projected airborne concentrations of the chemical substance in question with the exposed
23 populations, human health risks associated with a chemical release can be estimated. Using these
24 nsk estimates, emergency response personnel can make effective risk management and risk
25 communication decisions to minimize the adverse impact of the release on human health. Figure
26 1-1 is a summary diagram that indicates the overall effects that are expected to occur above each
27 of the three AEGL threshold tiers, as well as sensory and non-sensory or asymptomatic effects
28 below the AEGL-1 threshold level. Figure 1-1 also indicates the expected increase in occurrence
29 and severity of the various adverse health effects as the airborne concentration increases beyond
30 each of the three AEGLs.
31
32 Because of the complex nature of chemical accidents, the populations at risk, the variable
33 capabilities among emergency response units, and many other considerations related to a specific
34 event, it is beyond the scope of this document to discuss or speculate on specific actions that
35 should or could be taken at any point in tune 01 at a given level of exposure to a specific
36 chemical. However, it is known by emergency responders and planners that vanous options are
37 available, depending upon the circumstances, for reducing or even preventing the adverse
38 impacts of chemical releases. In general they include public notification and instruction,
39 sheltering-in-place, selective of major evacuation procedures, procedures to enable or facilitate
40 medical attention or some combination of these approaches. These are important decisions best
41 left to local emergency planners and responders to be addressed on a case-by-case basis. Further,
42 information regarding the applications of short-term exposure limits such as AEGLs may be
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1 obtained m Technical Guidance for Hazards Analysis (U.S. EPA, 1987).
2
3
4
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30,2000
1 FIGURE 1-1 HAZARD ASSESSMENT
2
Threshold
Levels
HAZARD ASSESSMENT
Effects
DEATH
AEGL-3
Increasing
likelihood of death
DISABLING
-Impairment of ability to escape
-Increasing severity of
irreversible or ofr.er long-lasting
effects
AEGL-2
DISCOMFORT
AEGL-1
-Increase in notable discomfort
-increasing severity of
reversible effects (with or
without signs/symptoms)
DETECTABILITY
Increasing complaints of
objectionable odor, taste,
sensory irritation or other
mild, non-sensory or
asymptomatic effects
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i 2. DERIVATION OF AEGL VALUES
2
3 2.1 DEFINITIONS OF AEGL-1, AEGL-2 AND AEGL-3
4
5 AEGL seventy levels represent short-term exposure values which are a threshold for
6 specific biological effects for the general public and are applicable to specified exposure
7 durations. The values for these specified durations are "... ceiling exposure values for the public
8 (i.e., a ceiling is a concentration of a substance that should never be exceeded)..." (NRC 1993a,
9 p2). Three AEGLs are developed for each of five exposure durations (10 and 30 minutes, 1 hour,
10 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects.
11 AEGLs for 10 minute durations will be developed for the chemicals included in the first
12 publication of AEGLs by the National Academy of Sciences at a future date.
13
14 PREFACE
15
16 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of
17 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
18 Substances (NAC/AEGL Committee) has been established to identify, review and interpret
19 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic
20 chemicals.
21
22 AEGLs represent threshold exposure limits for the general public and are applicable to
23 emergency exposure periods ranging from 10 minutes to 8 hours. AEGL-2 and AEGL-3 levels,
24 and AEGL-1 levels as appropriate, will be developed for each of five exposure periods (10 and
25 30 minutes, 1 hour, 4 hours, and 8 hours) and will be distinguished by varying degrees of seventy
26 of toxic effects. It is believed that the recommended exposure levels are applicable to the general
27 population including infants and children, and other individuals who may be sensitive or
28 susceptible. The three AEGLs have been defined as follows:
29
30 AEGL-1 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
31 which it is predicted that the general population, including susceptible individuals, could
32 experience notable discomfort, irritation, or certain asymptomatic, non-sensory effects.
33 However, the effects are not disabling and are transient and reversible upon cessation of
34 exposure.
35
36 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
37 which it is predicted that the general population, including susceptible individuals, could
38 experience irreversible or other senous, long-lasting adverse health effects, or an impaired ability
39 to escape.
40
41 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
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1 which it is predicted that the general population, including susceptible individuals, could
2 experience life-threatening health effects or death.
3
4 Airborne concentrations below the AEGL-1 represent exposure levels that could produce
5 mild and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic,
6 non-sensory effects. With increasing airborne concentrations above each AEGL level, there is a
7 progressive increase in the likelihood of occurrence and the seventy of effects described for each
8 corresponding AEGL level. Although the AEGL values represent threshold levels for the general
9 public, including sensitive subpopulations, it is recognized that certain individuals, subject to
10 unique or idiosyncratic responses, could experience the effects described at concentrations below
11 the corresponding AEGL level.
12
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1 2.2 EMPIRICAL TOXICOLOGIC ENDPOINTS, AND METHODS FOR
2 DETERMINING EXPOSURE CONCENTRATIONS USED TO DERIVE
3 AEGL-1,2, AND 3 LEVELS
4
5 The selection of the biological endpoints that serve as the thresholds for each of the
6 AEGL severity levels are based on the definitions for the Community Emergency Exposure
7 Levels (CEELs) that were published in the 1993a National Academy of Sciences' (NAS)
8 guidelines for developing short-term exposure limits. The AEGLs address the same defined
9 population as the NAS CEELs. The NAS definitions of the 3 CEEL tiers have been modified
10 slightly by the NAC/AEGL Committee only to improve the clarity of description of the threshold
11 levels. Hence, the defined threshold levels for CEELs and AEGLs are the same.
12
13 The NAS guidelines describe CEELs (or AEGLs) as ceiling exposure values (i.e., a
14 concentration of a substance that should never be exceeded) that are applicable to emergency
15 exposures to hazardous substances for a specified duration (NAS, 1993). The NAS guidance
16 further states that the CEELs (or AEGLs) must be set low enough to protect most of the
17 population that might be exposed, including those with increased susceptibilities such as
18 children, pregnant women, asthmatics and persons with other specific illnesses (NAS, 1993).
19 The NAS definition of CEELs/AEGLs for each of the three different tiers of adverse health
20 effects states that the adverse effects for each CEEL/AEGL tier is not likely to occur below that
21 level for a specified exposure duration, but becomes increasingly likely to occur at concentrations
22 above that level in a general population, including susceptible individuals. For this reason the
23 NAS also refers to the CEELs/AEGLs as threshold levels (NAS, 1993).
24
25 Because the data and methodologies used to derive AEGLs or any other short-term
26 exposure limits are not sufficiently precise to make a distinction between a ceiling value and a
27 threshold value, no distinction has been made with respect to AEGL values. No fine line can be
28 drawn to precisely differentiate between a ceiling level, which represents the highest exposure
29 concentration for which an effect is unlikely to occur, and a threshold level, which represents the
30 lowest exposure concentration for the likelihood of onset of a given set of effects. Hence,
31 AEGLs are not true effect levels. Rather, they are considered threshold levels that represent an
32 estimated point of transition and reflect the best efforts to quantitatively establish a demarcation
33 between one defined set of symptoms or adverse effects and another defined set of symptoms or
34 adverse effects. Therefore, in the development of AEGLs the NAC/AEGL Committee selects the
35 highest exposure level from animal or human data where the effects used to define a given AEGL
36 tier are not observed.
37
38
39 2.2.1 SELECTION OF THE HIGHEST EXPOSURE LEVEL WHERE THE
40 EFFECTS USED TO DEFINE AN AEGL LEVEL WERE NOT OBSERVED
41
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1 Traditionally, when setting acceptable (typically considered "safe") levels of exposure the
2 evaluator will select the highest experimental exposure which does not cause an adverse effect
3 (No Observed Adverse Effect Level - NOAEL) in an experiment which demonstrated a graded
4 exposure response from no effect to adverse effects. In standard nsk assessment practice (NRC,
5 1993a), the exposure level identified as the NOAEL would then be divided by appropriate
6 uncertainty factors and modifying factors to derive an acceptable exposure level for humans
7 However, there are a number of limitations in this methodology. It does not consider the number
8 of animals used in the expenment and the associated statistical uncertainty around the
9 experimental exposure level chosen. It does not consider the slope of the exposure-response
10 relationship and subjects the evaluator to use the possibly arbitrarily selected exposure levels
11 which were chosen in the face of an unknown exposure-response relationship. Under some
12 conditions, especially a small number of animals exposed per exposure, the NOAEL could be a
13 level associated with significant adverse health effects (Leisenring and Ryan 1992). In recent
14 years Crump (1984), Barnes et al. (1995), US EPA (1995a), Faustman et al. (1994), Gaylor et al.
15 (1998), Gaylor et al. (1999), and Fowles et al. (1999) addressed these problems by using the
16 concept of analyzing all of the data to statistically estimate a benchmark concentration (BMC).
17 The BMC is a statistical estimate of an exposure which will cause a specified incidence of a
18 defined adverse health effect. The BMC is commonly defined as the 95% lower confidence limit
19 (LCL) on the exposure causing a specified level of response (typically 1% to 10%). This
20 exposure is intended to replace the NOAEL and is used like the NOAEL when setting acceptable
21 exposure levels.
22
23 The BMC methodology has a number of advantages over the traditional NOAEL
24 approach. The BMC is derived from a statistical analysis of the exposure-response relationship
25 and is not subject to investigator selection of exposure levels. It is a reflection of the exposure
26 response curve. Although the number of animals used in a study will impact the NOAEL and
27 BMC estimates, the BMC, when compared to the maximum likelihood estimate (MLE), will
28 explicitly reflect the variability in the study and the uncertainty around the number of subjects.
29 The greater the variability and uncertainty, the greater the difference between the BMC and the
30 MLE. The BMC calculation allows for the statistical estimation of a BMC in the absence of an
31 empirical NOAEL.
32
33 The data most relevant to the development of AEGL-3 values and most amenable to a
34 benchmark concentration analysis are inhalation LC50 data. Fowles et al. (1999) analyzed 120
35 inhalation animal lethality data sets using the BMC methodology. The analyses provide the basis
36 for the application of the BMC approach used by the NAC/AEGL Committee in the development
37 of AEGL values. Benchmark concentrations (95% LCL) and maximum likelihood estimates
38 were developed for the 1,5, and 10% response levels using log probit and Weibull models.
39 Species tested included rats, mice, guinea pigs, hamsters, rabbits, and dogs. Exposure times
40 ranged from 5 minutes to 8 hours. Each data set consisted of at least 4 data points. The BMC
41 and MLE values were compared with the empirical NOAEL (highest exposure which did not
42 cause death in the experiment) and LOAEL (lowest exposure which killed at least one animal).
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1 The curve generated by the statistical models was subjected to a chi-squared goodness of fit test
2 (P>0.05). For statistical and data presentation reasons, 100 studies were analyzed with the probit
3 analysis and 93 with the Weibull model. Most of the studies reported NOAELs (81/100 which
4 were considered for the probit analysis and 74/93 considered for the Weibull analysis).
5
6 The benchmark concentrations were generally lower than the NOAELs when analyzed
7 with either statistical estimate. The mean NOAEL/BMC ratios for the 1, 5, and 10% response
8 were 1.60,1.16, and 0.99 when using a probit analysis and 3.59, 1.59, and 1.17 when using the
9 Weibull analysis. It is interesting to note that comparable means from a Weibull analysis of
10 developmental toxicity data were considerably greater, the developmental toxicity means of the
11 NOAEL/BMC ratios were 29, 5.9, and 2.9 (Allen et al., 1994).
12
13 The proportion of times that the NOAEL exceeded the BMC for the 1, 5, and 10%
14 response was 89, 65, and 42% for the probit analysis and 95, 80, and 54% for the Weibull
15 analysis. In all cases the LOAEL/BMC ratio exceeded 1 for the probit and Weibull analysis of
16 the 1 and 5% response but not always for the 10% response (99%). For this reason the BMCIO
17 may be too high a response rate to use to predict a NOAEL. In contrast the corresponding 1 and
18 5% response ratios were always greater than 1.
19
20 The ratios of the MLE/BMC were not great, ranging from a mean of 1.39 for a probit
21 analysis of the 10% response to 3.02 for a Weibull analysis of the 10% response. It is important
22 to note that using the probit analysis the LOAEL/MLE ratios were equal to or greater than 1 in
23 99, 94, and 71% of the cases for the 1, 5, and 10% responses. The MLE would probably be
24 protective at the 1% response level but not for the 5 and 10% response levels. Similar numbers
25 of 99, 97, and 76% were observed for the Weibull analysis.
26
27 The BMC approach can provide a more refined assessment of the prediction of the
28 empirical NOAEL. It must be emphasized that even the empirical NOAEL may represent a
29 response level which is not detected. When 5 to 10 animals are used in an experiment a 10 to
30 20% response can be missed (Leisenring and Ryan, 1992) and even a BMC,0 is similar to a
31 LOAEL with dichotomized data (Gaylor, 1996). It is expected that the BMC is less than the
32 empirical LOAEL. In the Fowles et al. (1999) analysis of the data the BMC05 and BMC0, values
33 were always below the empirical LOAEL for the studies analyzed. The probit analysis of the
34 data by Fowles et al. (1999) provided a better fit with the data as measured by the "chi-squared
35 goodness-of-fit test, mean width of confidence intervals, and number of data sets amenable to
36 analysis by the model."
37
38 It is interesting to note that the BMCOJ is very close to the MLEOI in the Fowles et al.
39 (1999) evaluation of inhalation acute toxicity data. Through 1999 the NAC/AEGL Committee
40 has used the MLE0, to estimate the highest exposure at which lethality is not likely to be
41 observed in a typical acute exposure study. Given the analysis by Fowles et al. (1999) and for the
42 above reasons, the NAC/AEGL Committee will generally use the BMC05 (lower 95% confidence
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1 limit (LCL) of the exposure required to produce a 5% response to exposure to chemicals) in the
2 future for this estimate although, the MLE0, will also be calculated and considered. This
3 incorporates the uncertainties due to the number of animals used in an experiment, the
4 experimental variability observed, utilizes all of the data and the slope of the exposure response
5 curve, and provides for a reasonable estimate of a predicted experimental NOAEL. In all cases
6 the MLE and BMC at specific response levels will be considered when setting AEGL levels.
7 Statistical models in addition to the log-probit will also be considered. Since goodness of fit tests
8 consider an average fit, they may not be valid predictors of the fit in the low exposure region of
9 interest. In this case the output of the different models will be plotted and compared visually
10 with the experimental data in selection of the most appropriate model.
11
12 It should be emphasized that these methodologies will generally be considered for an
13 acute lethal endpoint. Their use to set AEGL-1 and AEGL-2 levels will be considered on a
14 chemical-by-chemical basis. Different endpoints may require the use of different data sets in
15 different or the same species, a different benchmark dose approach, or identification of a
16 different response level. These factors will be considered for specific chemicals and
17 toxicological endpoints.
18
19 The preferred approach will be to use the BMC approach to identify the highest exposure
20 at which the toxicologic effects used to define an AEGL tier were not observed. If the data are
21 insufficient to use that approach then the level will be determined empirically from experimental
22 data.
23
24 2.2.2 SELECTION OF HEALTH EFFECTS ENDPOINTS FOR AEGL-1,
25 AEGL-2, AND AEGL-3
26
27 In addition to the working definitions of the three AEGL tiers, this section includes a
28 summary of the specific biologic endpoints used to establish the AEGL levels for individual
29 chemicals. Also included are general principals for selection of AEGL health effect endpoints
30 that have been derived from the Committee's selections on a chemical-by-chemical basis. Since
31 ideal data sets for certain chemicals are not available, extrapolation methods and the
32 Committee's scientific judgement are often employed to establish threshold values. In the
33 absence of adequate data, no AEGL value is established. The basis for this decision is the failure
34 to achieve a minimum two-thirds majority of a quorum of the Committee that is in favor of
35 establishing a value, or a formal decision by two-thirds of the Committee not to establish a value.
36
37
38 Under ideal circumstances the specific health effects would be identified that determine
39 each of the AEGL levels. A search of the published literature would be performed for data on
40 the chemical, and AEGL levels would be generated from that data. However, data relating
41 exposure and effect do not always follow an ideal paradigm and may lead to apparent
42 mconsistences in the use of endpoints to set AEGL levels. The general principles laid down in
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1 the NRC (1993a) guidance for evaluating data and selecting appropriate health effects, combined
2 with professional judgement, are used to establish AEGL levels. From the evaluations of the first
3 5 chemicals in this publication, and experience with data sets on chemicals currently under
4 review, the following refinements to the NAS guidelines have been adopted by the NAC/AEGL
5 Committee to set AEGL levels. Following the guidelines are elements of the rationale to capture
6 in the Technical Support Document.
7
8 For the reasons discussed in the introduction to this section, the NAC/AEGL Committee
9 generally selects the highest experimental concentration that does not elicit the symptoms or
10 effects defined by the AEGL tier in question. This concentration represents the starting point for
11 AEGL development. In instances where appropriate data are available, the BMC methodology
12 may be considered and used to select the AEGL endpoints.
13
14
15 2.2.2.1 AEGL-1 Endpoints
16
17 The NRC 1993a guidelines discuss the definition of the AEGL-1 endpoint on pages 10,
18 12, and 21. Above the AEGL-1 level, discomfort becomes increasingly likely. Below the
19 AEGL-1 level (detectability) "Exposure insufficient to cause discomfort or adverse health effects
20 might be perceived nevertheless by means of smell, taste, or sensations (mild sensory irritation)
21 that are not uncomfortable. The awareness of exposure might lead to anxiety and complaints and
22 constitutes what is termed here detectability." (NRC, 1993a, p21).
23
24 Thus at concentrations below the AEGL-1 level there may be specific effects such as the
25 perception of a disagreeable odor, taste, or other sensations (mild sensory irritation). In some
26 people that could result in mild lacrimation or coughing. Since there is a continuum in which it
27 is difficult to judge the appearance of "discomfort" in animal studies and human experiences, the
28 NAC/AEGL Committee has used its best judgement on a case by case basis to arrive at
29 appropriate and reasonable AEGL-1 values.
30
31 One additional factor to consider is that the three tiers of AEGL values "...provide much
32 more information than a single value because the series indicates the slope of the dose-response
33 curve" (NRC, 1993a). If an accident occurs and people smell or otherwise "detect" a chemical,
34 the extent of the concentration range between the AEGL-1 and AEGL-2 levels provides
35 information and insight into the estimated margin of safety between a level of detection or mild
36 sensory irritation (AEGL-1) and a level that may impair escape or lead to a serious long-term or
37 irreversible health effect (AEGL-2). In cases where the biological criteria for the AEGL-1 value
38 would be close to, or exceed the AEGL-2 value, the conclusion is reached that it is "Not
39 Recommended" (NR) to develop AEGL-1 values. In these cases, "detectability" by itself would
40 indicate that a serious situation exists. In instances where the AEGL-1 level approaches or
41 exceeds the AEGL-2 level, it might erroneously be believed that people experiencing mild
42 irritation are not at risk when in fact they have been exposed to extremely hazardous or possibly
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1 lethal concentrations.
2
3 Since a comparison of the AEGL-1 and AEGL-2 levels indicates the slope of the dose-
4 response curve which may be of value in emergency response, planning, or prevention, the
5 NAC/AEGL Committee also attempts to establish AEGL-1 endpomts for adverse effects that are
6 asymptomatic or non-sensory. Examples of such effects include significant (measurable) levels
7 of methemoglobin, elevated blood enzyme levels, or other biological markers related to exposure
8 to a specific chemical. By establishing an AEGL-1 value in these instances, important
9 information on the toxicological behavior of a specific chemical is available to emergency
10 responders and planners.
11
12 The following criteria have been used by the NAC/AEGL Committee to select
13 endpoints for use in setting the AEGL-1 values.
14
15 2.2.2.1.1 No Value Established - AEGL-1 Exceeds AEGL-2
16
17 1. What aspects of the chemical toxicity profile make it inadvisable to generate an
18 AEGL-1 value.
19
20 For example, the AEGL-1 value was not established because levels which are
21 "detectable" are close to, or exceed, an AEGL-2 level. These materials have poor warning
22 properties.
23
24 2.2.2.1.2 No Value Established - Insufficient Data
25
26 Insufficient data were available.
27
28 2.2.2.1.3 Highest Experimental Exposure Without an AEGL-1 Effect
29
30 1. State the species, effect, and concentration and exposure time to cause the effect.
31 2. Describe the toxicologic endpoint of concern.
32
33 The highest experimental exposure levels which did not cause sensory irritation,
34 pulmonary function, and narcosis in humans have been used to set AEGL-1 levels.
35
36 2.2.2.1.4 Effect Level for a Response
37
38 1. State the species, effect, and concentration and exposure time to cause the effect.
39 2. Describe the toxicologic endpoint of concern
40
41 For example, levels for odor detection in humans, mild sensory irritation, asymptomatic
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1 or non-sensory effects such as methemoglobin formation (22%), and pulmonary function
2 (transient changes in clinically insignificant pulmonary functions of a sensitive individual) have
3 been used as AEGL-1 endpoints.
4
5 2.2.2.2 AEGL-2 Endpoints
6
7 NRC (1993a) discussed the AEGL-2 definition on pages 10,12, and 21. The AEGL-2
8 exposure level is the threshold between reversible effects which cause discomfort, and serious or
9 irreversible health effects or effects which impair escape. Above the AEGL-2 level there is an
10 increasing likelihood people may become disabled or are increasingly likely to experience serious
11 or irreversible health effects. "The term disability is used here to indicate the situation where
12 persons will require assistance or where the effects of exposure will be more severe or prolonged
13 without assistance." (NRC, 1993a, p21). In developing AEGL-2 levels the NAC/AEGL
14 Committee has defined a NOEL for serious or irreversible effects or effects which impair escape.
15 It must be emphasized that reversible clinical toxiciry may be observed below the AEGL-2 level.
16 If minor reversible effects are seen at one level of exposure and disabling effects at a higher
17 exposure, the former is used to set the AEGL-2 level. If the exposure associated with disabling
18 effects cannot be determined from experimental data, then the highest level causing reversible
19 effects/discomfort may be used to set the AEGL-2 level.
20
21 The following criteria have been used by the NAC/AEGL Committee to date to select
22 endpoints for use in setting the AEGL-2 values.
23
24 2.2.2.2.1 Highest Experimental Exposure Without an AEGL-2 Effect
25
26 1. State the species, effect, and concentration and exposure time to cause the effect.
27 2. Describe the toxicologic endpoint of concern.
28
29 The highest experimental exposure levels which did not cause decreased hematocrit,
30 kidney pathology, behavioral changes or lethality (effects observed at higher exposures were
31 above the definition for AEGL-2) have been used as the basis for determining AEGL-2 levels.
32
33 2.2.2.2.2 Effect Level for a Toxic Response Which was Not Incapacitating or
34 Not Irreversible
35
36 1. State the species, effect, and concentration and exposure time to cause the effect.
37 2. Describe the toxicologic endpoint of concern.
38
39
40
41
**- a-rwiawijiiyv ui^« LisyvJtsl/llsgll' 1*I1U£JWU1L Ul VU111/&111.
For example, strong irritation, dyspnea, pulmonary function, provocation of asthma
episodes, pathology (respiratory tract, mild narcosis, methemoglobin formation (41%) have been
used to set AEGL-2 levels.
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1 2.2.2.2.3 A Fraction of the AEGL-3 Level
2
3 1. State the rationale for using a fraction of the AEGL-3.
4 2. State why the specific fraction chosen is scientifically justified.
5
6 In the absence of specific data used to determine an AEGL-2 value, 1/3 of the AEGL-3
7 value has been used to establish the AEGL-2 level. This approach can only be used if the data
8 indicate a steep exposure-response relationship from serious to no-effects.
9
10 2.2.2.3 AEGL-3 Endpoints
11
12 NRC, (1993a) discussed the AEGL-3 definition on pages 10, 12, and 21. The AEGL-3
13 tier is the threshold exposure level between serious long lasting or irreversible effects or effects
14 which impair escape and death or life-threatening effects. Above the AEGL-3 there is an
15 increasing likelihood of death or life threatening effects occurring. In determining AEGL-3
16 levels, the NAC/AEGL Committee defined the highest exposure which does not cause death or
17 life threatening effects. It must be emphasized that severe toxicity will be observed at the AEGL-
18 3 level. In cases where data to determine the highest exposure level which does not cause life-
19 threatening effects are not available, levels which cause severe toxicity without producing death
20 have been used.
21
22 The following criteria have been used by the NAC/AEGL Committee to date to
23 select endpoints for use in setting the AEGL-3 values.
24
25 2.2.2.3.1 Highest Exposure Level Which Does Not Cause Lethality -
26 Experimentally Observed Threshold (AEGL-3 NOEL)
27
28 1. State the species, effect, and concentration and exposure time to cause the effect.
29 2. Describe the toxicologic endpoint of concern.
30
31 Where experimental lethality data have been insufficient to statistically determine a
32 benchmark concentration, the highest experimental exposure which did not cause lethality in an
33 experiment in which death was observed was used to set the AEGL-3 level.
34
35 2.2.2.3.2 Highest Exposure Level Which Does Not Cause Lethality - Estimated
36 Lethality Threshold - 1/3 of the LC50
37
38 1. State the species, effect, and concentration and exposure time to cause the effect.
39 2. Describe the toxicologic endpoint of concern.
40 3. If an exposure which does not produce death is estimated by dividing an LC50 value by
41 3 (or some other divisor), give the slope of the exposure response curve or enough
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 data points to support the division by 3 (or some other divisor).
2
3 Where experimental lethality data have been insufficient to statistically determine an LC0,
4 value, but an LC50 value was determined, and all exposure levels caused lethality, a fraction of
5 the LC50 value was used to estimate the threshold for lethality. In all cases the exposure response
6 curve was steep and the LCSO value was divided by three. The Fowles et al. (1999) analysis of
7 inhalation toxicity experiments revealed that for many chemicals, the ratio between the LCSO and
8 the experimentally observed non-lethal level was on average a factor of approximately 2, the 90th
9 percentile was 2.9, and the 95th percentile was 3.5. There was a range of ratios from 1.1 to 6.5.
10
11 2.2.2.3.3 Highest Exposure Level Which Does Not Cause Lethality -
12 Benchmark Exposure Calculation of the 5 % and 1% Response
13
14 1. State the species, effect, and concentration and exposure time to cause the effect.
15 2. Descnbe the toxicologic endpoint of concern.
16 3. State the statistical methodology used to derive a BMC05 and the MLE01.
17
18 Where sufficient information was available, the preferred method through 1999 was a
19 probit analysis (Finney, 1971) to determine the LC01. Actual calculations were performed using
20 the Number Cruncher Statistical System - Version 5.5. This is a probit analysis of the response -
21 log exposure curve. The Maximum Likelihood Estimate (MLE) was used for the LC0, value.
22 The method of Litchfield and Wilcoxon (1948) has also been used.
23
24 In the future both the BMC05 and MLE01 for lethality will be determined, presented and
25 discussed. Results from the above models will be compared with the log probit U. S. EPA
26 (2000) Benchmark Dose Software (http://www.epa.gov/ncea/bmds.htm). In all cases the MLE
27 and BMC at specific response levels will be considered. Other statistical models such as the
28 Weibull may also be considered. Since goodness of fit tests consider an average fit, they may not
29 be valid predictors of the fit in the low exposure region of interest. In this case the output of the
30 different models will be plotted and compared visually with the experimental data to determine
31 the most appropriate model. The methodology which results in values consistent with the
32 experimental data and the shape of the exposure-response curve will be selected for AEGL
33 derivations.
34
35 Because of uncertainties that may be associated with extrapolations beyond the
36 experimental data range, the estimated values are compared with the empmcal data. Estimated
37 data which conflicts with the empirical data will generally not be used.
38
39 2.2.2.3.4 Effect Level for a Response
40
41 1. State the species, effect, and concentration and exposure time to cause the effect.
42 2. Describe the toxicologic endpoint of concern.
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1 Where the data were insufficient to estimate the highest exposure which does not cause
2 lethality, exposures which caused severe intoxication in the absence of lethality were used in the
3 selection of exposure levels to set AEGL-3 values. The endpoints of concern included decreased
4 hematocrit, methemoglobin formation (70-80%), cardiac pathology, and severe respiratory
5 pathology.
6
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 2.3 GUIDELINES/CRITERIA FOR THE SEARCH STRATEGY,
2 EVALUATION, SELECTION AND DOCUMENTATION OF KEY DATA
3 AND SUPPORTING DATA USED FOR THE DERIVATION OF AEGL
4 VALUES
5
6 2.3.1 Search Strategy
7
8 The literature search strategy focuses on three general sources of information: (1)
9 electronic databases, primarily peer-reviewed journals and government databases, (2) published
10 books and documents from the public and pnvate sectors of the U. S. and foreign countries,
11 including references on toxicology, regulatory initiatives, and general chemical information; (3)
12 data from private industry on other pnvate sector organizations. The search strategy also
13 includes the use of search terms to enhance the relevance of the electronic databases identified
14 and retrieved.
15
16
17 (1) ELECTRONIC DATABASE COVERAGE
18
19 The following databases are searched:
20
21 TOXLINE database (1981 - Current) from U. S. National Library Medicine's TOXNET:
22 TOXLINE covers the toxicological effects of chemicals, drugs and physical agents on
23 living systems. Among the areas covered are adverse drug reactions, carcmogenesis,
24 mutagenesis, developmental and reproductive toxicology, environmental pollution and food
25 contamination.
26
27 TOXLINE65 database (1965-1980)
28 Subject coverage is identical to TOXLINE, for tune periods that precede that of
29 TOXLINE.
30
31 HAZARDOUS SUBSTANCES DATA BANK (HSDB) (Current) from TOXNET:
32 HSDB is a comprehensive factual and numeric chemical profile. Each chemical profile is
33 peer reviewed for completeness and accuracy to reflect what is known the about the chemical.
34
35 PUBLIC MEDLINE (PUBMED):
36 PUBMED includes MEDLINE and PREMEDLINE. MEDLINE, the U. S. National
37 Library of Medicine's (NLM) premier bibliographic database covers medicine, nursing, dentistry,
38 veterinary medicine, health care systems, and the preclimcal sciences The above-mentioned
39 TOXLINE searches include MEDLINE citations. PREMEDLINE, also produced by NLM,
40 provides citation and abstract information before full records are added to MEDLINE. For a
41 short period of time, this information is only available in PUBMED.
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS).
2 RTECS, compiled by NIOSH (U. S. National Institute of Safety and Health), is a
3 comprehensive database of basic toxicity information and toxic-effects data on more than
4 100,000 chemicals.
5
6 U. S. NATIONAL TECHNICAL INFORMATION SERVICE (NTIS)
7 The NTIS database provides access to the results of US government-sponsored research,
8 development and engineering, plus analyses prepared by federal agencies, their contractors, or
9 grantees. It is a means through which unclassified, publicly available, unlimited distribution
10 reports are made available from such U. S. agencies as NASA, DDC, DOE, HUD, DOT and
11 some 600 other agencies. In addition, some state and local government agencies contribute their
12 reports to the database. NTIS also provides access to the results of government-sponsored
13 research and development from other countries.
14
15 U.S. INTEGRATED RISK INFORMATION SYSTEM (IRIS)
16 Data from US EPA in support of human health risk assessment, focusing on hazard
17 identification and dose-response assessment for specific chemicals.
18
19 U.S. FEDERAL RESEARCH EN PROGRESS (FEDRIP)
20 FEDRIP provides access to information about ongoing U.S. government funded research
21 projects in the fields of physical sciences, engineenng, and life sciences.
22
23 U. S. DEFENSE TECHNICAL INFORMATION CENTER (DTIC)
24 The central U. S. Department of Defense facility for access to scientific and technical
25 information. The DTIC database includes technical reports, independent research and
26 development summaries, technology transfer information, and research and development
27 descriptive summaries. The scope of the DTIC collection includes areas normally associated
28 with Defense research such as military sciences, aeronautics, missile technology, and nuclear
29 science. The collection also includes information on biology, chemistry, environmental sciences,
30 and engineenng.
31
32 U S. ORNL IN-HOUSE DATABASES
33
34 CHEMICAL UNIT RECORD ESTIMATES (CURE)
35 The CURE database contains selected information from the U.S. Environmental
36 Protection Agency Office of Health and Environmental Assessment documents
37 and Carcinogen Risk Assessment Verification Effort (CRAVE) and Reference
38 Dose (RfD) work groups. Although the groups are not currently active, this
39 database is a valuable compilation of historic information.
40
41 TOXICOLOGY AND RISK ANALYSIS (TARA) DOCUMENT LIST
42 This database lists all types of documents written by TARA staff over the past
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1 fifteen years. These range from Toxicity Summaries to journal articles. This list
2 provides good references for chemicals which overlap the AEGL priority list
3
4 (2) PUBLISHED BOOKS AND DOCUMENTS FROM THE PUBLIC AND PRIVATE
5 SECTORS
6
7 GENERAL REFERENCES FOR TOXICOLOGY AND CHEMICAL INFORMATION
8
9 U. S. ATSDR (Agency for Toxic Substances and Disease Registry) Toxicological
10 Profiles.
11 Chemfmder, Chemical Searching and Information Integration by CambridgeSoft
12 Corporation
13 Current Contents, Life Sciences edition
14 HEAST (Health Effects Assessment Summary Tables)
15 Kirk-Othmer Encyclopedia of Chemical Technology
16 IARC (International Agency for Research on Cancer) Monographs on the Evaluation of
17 the Carcinogenic Risk of Chemicals to Humans
18 Low-dose Extrapolation of Cancer Risks, S. Olin, et al. (editors)
19 Merck Index
20 U. S. NTP (National Toxicology Program) Div. of Toxicology Research and Testing,
21 published reports.
22 Patty's Industrial Hygiene and Toxicology
23 Respiratory System, Monographs on the Pathology of Laboratory Animals, T.C. Jones, et
24 al. (editors)
25 Synthetic Organic Chemicals, U.S. International Trade Commission
26 Toxicology of the Nasal Passages, C.S. Barrow (editor)
27 U.S. Air Force Installation Restoration Program Toxicology Guide
28
29 GENERAL REFERENCES FOR REGULATORY INFORMATION AND STANDARDS
30
31 U. S. AIHA (American Industrial Hygiene Association) Emergency Response Planning
32 Guidelines
33 (ERPGs) and Workplace Exposure Level Guides (WEELs)
34 U. S. ACGIH (American Conference of Government and Industrial Hygienists) Threshold
35 Limit
36 Values for Chemical Substances and Physical Agents and Biological Exposure Indices
3 7 ACGIH Documentation of Threshold Limit Values
38 U. S. NAAQS National Ambient Air Quality Standards
39 U.S. NIOSH Documentation of IDLH's
40 U. S NIOSH (National Institute for Occupational Safety and Health) Pocket Guide to
41 Chemical Hazards
42 U. S. NIOSH Recommendations for Occupational Safety and Health, Compendium of
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1 Policy Documents and Statements
2 U. S. OSHA (Occupational Safety and Health Administration) Limits for Air
3 Contaminants
4 U. S. SMACS Spacecraft Maximum Allowable Concentrations for Selected Airborne
5 Contaminants, Committee on Toxicology, Commission on Life Sciences, and
6 National Research Council, sponsored by NAS
7 U. S. EPA Health Effects Documents
8
9 (3) UNPUBLISHED DATA FROM PRIVATE INDUSTRY AND OTHER PRIVATE
10 SECTOR ORGANIZATIONS OF ALL NATIONS
11
12 Reports and data not published in peer reviewed scientific journals that is relevant to the
13 development of AEGLs. Most often this represents acute toxicity data from controlled inhalation
14 exposure studies available from private industry or other organizations in the private sector of all
15 nations that may or may not be published in a peer reviewed journal at some later date.
16
17 SEARCH TERMS
18
19 The U. S. Chemical Abstract Services (CAS) Registry number of the chemical is used as
20 the first choice. Chemical nomenclature or common chemical names and synonyms are used if
21 the CAS Registry number is unknown.
22
23 The CAS Registry number alone is used as the first step. If there are approximately 300
24 citations, then all are retrieved for review. If less than approximately 300 references are found,
25 conduct searches using chemical nomenclature and common chemical name(s) in addition to the
26 CAS number. Searches by chemical name(s) also should be made if limited data of high quality
27 are found, irrespective of the number of citations found.
28
29 If more than 300 citations are found using any form of chemical identification, the
30 references may be enriched in relevance and quality by adding any number of the following
31 characterizations of the desired data to the search strategy:
32
33 short-term
34 threshold limit
35 permissible exposure
36 acute
37 ocular terms
38 inhalation terms
39 dermal terms
40
41 If the number or quality of single exposure toxicity studies found is not deemed to be
42 adequate, multiple exposure studies may be considered but might not achieve a consensus of the
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1 NAC/AEGL Committee. If a consensus or 2/3 majority of the Committee cannot agree on the
2 adequacy of the data, the chemical may be placed in a cue for future acute toxicity testing.
3
4 2.3.2 Evaluation, Selection and Documentation of Key and Supporting Data
5
6 As a detailed interpretation and supplementation of the U. S. NAS (NAS, 1993a)
7 guidelines, U. S. EPA's National Advisory Committee on Acute Exposure Guideline Levels
8 (NAC/AEGL Committee) has developed guidelines for evaluating the quality of studies to be
9 used in the calculation of proposed AEGL values. The proposed evaluation and documentation
10 procedure created by the AEGL Committee is intended to provide technical support document
11 (TSD) writers, reviewers, committee members, interested parties and the public with a clear and
12 consistent list of elements that must be considered in their evaluations. The proposed evaluation
13 and documentation system will add technical validity and administrative credibility to the process
14 by providing a transparent, logical and consistent method for selecting key studies used to
15 calculate an AEGL value. Additionally, the system will allow linkage to uncertainty factors and
16 modifying factors in a consistent and logical manner. The process is designed to allow
17 maximum flexibility in professional judgment while promoting scientific uniformity and
18 consistency and providing a sound administrative foundation from which Committee members
19 can function. The NAC/AEGL Committee has the concurrence of the U. S. National Academy
20 of Sciences (NAS) on these guidelines, as well as all other guidelines published in this manual.
21
22 Many toxicology studies used in the development of an AEGL were not designed to meet
23 current regulatory guidelines and are not necessarily consistent in protocol or scientific
24 methodology. As a result, these valuable investigations cannot be judged solely on the basis of
25 currently accepted experimental design criteria for such studies. Current U. S. EPA and OECD
26 guidelines are used as the basis for future studies conducted on behalf of the NAC/AEGL
27 Committee, but lack of consistency of older studies requires evaluation and qualification of each
28 data set for scientific validity within the context of AEGL documentation. A study can be
29 valuable in the derivation of AEGL values without conforming completely to a standard of
30 detailed methodology, data analysis and results reporting. The aim of the subject procedure is to
31 provide specific criteria in the selection and use of specific data sets for development of
32 defensible values, yet retain the ability to use logical scientific thinking and competent
33 professional judgment in the data selection process. If a study or some portion of a study 1) uses
34 scientifically valid methods, 2) contains adequate and reliable data and 3) presents defensible
35 conclusions relevant to the AEGL process, it may be included in the technical support document
36 and used to support the AEGLs.
37
38 It is important to emphasize that only toxicity data obtained directly from a primary
39 reference source is used as the basis for "key" toxicity studies from which the AEGL values are
40 derived. Additionally, all supporting data and information important to the derivation of an
41 AEGL value is obtained solely from the primary references. This includes data used to provide a
42 "weight-of-evidence" rationale in support of the AEGL value derived. Secondary references may
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1 be used to provide data and information on commercial uses, production volumes, chemical and
2 physical properties and other non-toxicological or epidemiological information on a chemical.
3 Secondary references also may be used to present background information on the toxicity or
4 toxicological characteristics of a chemical and any other information not important or directly
5 relevant to the actual derivation of, or the supporting rationale for, the AEGL values. Finally,
6 data and information from secondary references should not be included in data summary tables
7 presented in the Technical Support Documents.
8
9 The evaluation guidelines are more credible if they are drawn from a widely accepted
10 prescription for study protocol design. The list of guidelines for AEGL study evaluation should
11 be based upon the scientific methodologies, but not be so restrictive that it precludes competent
12 professional judgment. Current Good Laboratory Practice (GLP) guidelines provide a basis for
13 selection of a robust list of study elements that, in concert with the professional experience and
14 judgment of the AEGL Development Team and NAC/AEGL Committee members in general, are
15 used to qualify the data which support the AEGLs. Consequently the NAC/AEGL Committee
16 has used NRC (1993a), the OECD's Guidelines for the Testing of Chemicals, and U. S. EPA
17 (Health Effects Test Guidelines) as a basis for selection.
18
19 The NAS (1993a) guidance provides only limited guidance on the use of toxicological
20 data from routes of exposure other than inhalation. The guidance states that the bioavai lability
21 and differences in the pharmacokinetics from the different exposure routes of the chemical in
22 question must be considered. Because of these complex biological phenomena and the paucity of
23 data to enable credible evaluation and consideration, the NAC/AEGL Committee to date has
24 selected and used only inhalation toxicity data to derive AEGL values. Further, toxicity data
25 from alternate routes of exposure will not be included in discussions in the Technical Support
26 Documents unless it is considered important for the support of relevant pharmacokinetics or
27 metabolism data or mechanisms and observed effects of toxicity. In the absence of inhalation
28 data to derive an AEGL value, the NAC/AEGL Committee may use toxicity data from other
29 exposure routes if there are adequate data to perform scientifically credible route-to-route
30 extrapolations. In the absence of acceptable data, the Committee will refer the chemical for
31 toxicity testing.
32
33 Each key and supporting study is evaluated using all listed Elements for Evaluation as
34 guidance. A "Key Study" is defined as the human and/or animal study from which a
35 toxicological value is obtained for use in AEGL calculations. "Supporting Studies" are the
36 human and/or animal studies which are used to support the toxicological findings and values
37 obtained from the Key Study and their use is consistent with the "weight-of-evidence" approach
38 to scientific credibility. While all Elements for Evaluation listed below are considered when
39 evaluating a study, only Elements for Evaluation from key and supporting studies which are
40 relevant to the derivation of the AEGL values will be discussed in the TSD as they impact the
41 derivation. In evaluating a study, a variety of measurement endpoints are preferred. However, a
42 study measuring, for example, only one endpoint may be selected for development of an AEGL if
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1 other studies have shown that other known inhalation toxicology endpoints are less sensitive,
2 provided the data are considered to be reliable. The list of Elements for Evaluation also is used
3 for initial review of all studies evaluated for possible inclusion in the TSD in instances where
4 they are germane to the selection of studies.
5
6 The NAC/AEGL Committee is dependent upon existing human studies published in the
7 literature for data on humans Many of these studies do not necessarily follow current guidelines
8 on ethical standards which require that effective, documented, informed consent from
9 participating humans subjects be required. Further, recent studies which followed such
10 guidelines may not include that fact in the publication. Although human data may be important
11 in deriving AEGL values that protect the general public, utmost care must be exercised to insure
12 first of all that such data have been developed in accordance with ethical standards. No data on
13 humans known to be obtained through force, coercion, misrepresentation, or any other such
14 means will be used in the development of AEGLs. The NAC/AEGL Committee will use its best
15 judgement to determine whether the human studies were ethically conducted and that the human
16 subjects were likely to have provided their informed consent. Additionally, human data from
17 epidemiological studies and chemical accidents may be used. However, in all instances
18 described here, only human data, documents and records will be used from sources that are
19 publicly available or if the information is recorded by the investigator in such a manner that
20 subjects cannot be identified directly or indirectly. These restrictions on the use of human data
21 are consistent with the Common Rule as published in the Code of Federal Regulations (40 CFR
22 Part 26 [The Common Rule], 2000).
23
24 In addition to the discussion of the Elements for Evaluation in the individual studies
25 section of the Technical Support Document (TSD), a section entitled "Data Adequacy and
26 Research Needs" is included in the text of the TSD. A summary of the data adequacy discussion
27 is also included in the Derivation Summary Tables in the appendix of the TSD and in the
28 Executive Summary of the TSD. The text of the TSD relates the studies used to derive, or
29 support the derivation of, the AEGL values to the discussion of the adequacy of the available
30 data. Brief summaries of this discussion are included in the Executive Summary and Derivation
31 Summary Tables. The data adequacy section also presents and integrates the weight-of-evidence
32 by considering all information as a whole for each AEGL developed. In addition to considering
33 the Elements for Evaluation as relevant in the discussion, a number of other factors must be
34 considered. These include repeatability of experiments between laboratories, consistency of data
35 between experiments and laboratories, types and number of species tested, variability of results
36 between species, and comparison of AEGL values with the valid human and animal data. Every
37 data set is a unique, chemical-specific source of information which reflects the investigations
38 conducted on the chemical and the properties of the chemical. This section reflects a "best
39 professional judgement" approach in the evaluation of the data adequacy and future research
40 needs.
41
42 A diagram of the decision process for the selection of key studies and supporting studies
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 is shown on the following page. A summary of the elements or criteria used to select key studies
2 and supporting studies, and to evaluate their adequacy in deriving AEGL values follows.
3
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FIGURE 2.3-1 ALLOCATION OF STUDY REPORTS DECISION TREE
ALLOCATION OF STUDY REPORTS
DECISION TREE
Non-published,
Non-peer Reviewed
Industry Data
Published
Literature
Search
Other
Data / Information
Sources
Special Toxicity
Studies
\t
V
Identification and
Selection of Relevant
Data / Information
Evaluate Data and
Information
Retain
Incorporation in Whole
or in Part into TSD?
Yes
_L
Consider for AEGL
Derivation?
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
Not Included in TSD
Background Information
Supporting Study
Yes
Selected as Key Study
Derivation of one or more
Acute Exposure Guideline Levels
2
3
4
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35
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1 Elements for the Evaluation of Key and Supporting Data and Studies
2
3 1. Only toxicity data and information obtained directly from a primary reference source may be
4 used as the basis for "key" lexicological studies. All other studies important to the
5 derivation of an AJEGL value, or that serve as a "weight-of-evidence" rationale are
6 obtained from a primary source.
7
8 2. Secondary references may be used for non-toxicological data such as physical/chemical
9 properties, production locations, quantities and background information on the toxicity of
10 a chemical, provided the information is not directly used in the derivation of the AEGL
11 values.
12
13 3. Only human data from studies that meet the ethical standards discussed in the Evaluation,
14 Selection and Documentation of Key and Supporting Data section of this SOP Manual
15 will be used in the derivation of AEGL values.
16
17 4. Route of exposure. The inhalation route is preferred. Where the endpomt of concern is
18 systemic intoxication and the first pass effect is not significant, oral exposure may be
19 considered. In the absence of scientifically sound data with high confidence in a valid
20 route-to-route extrapolation, routes of exposure other than inhalation will not be used for
21 AEGL derivation.
22
23 5. Scientifically credible exposure concentration and exposure duration are provided.
24
25 6. Analytical procedures used to determine chamber concentration for inhalation exposure in
26 controlled studies and detailed, scientifically credible methods, procedures, and data used
27 to measure chemical concentration in epidemiological or anecdotal cases (accidental
28 chemical releases). For oral exposure, dose may be determined from the amount of test
29 chemical placed into the subject.
30
31 7. Number of subjects. The number is not rigid; e.g., a general rule uses 5-10 rodents/sex/group
32 as a valid measure, but as few as 2-3 primates or dogs/sex/group may be used. The
33 acceptable number of subjects per group is influenced by the relationship between the
34 within group variability and the degree of change that is considered to be detrimental.
35 Smaller numbers per group may be acceptable by increasing the number of treatment
36 groups.
37
38 8. Species studied. Humans are most relevant. Rats, mice, rabbits, guinea pigs, ferrets, dogs or
39 monkeys are acceptable. Other species require evaluation on a case-by-case basis. It is
40 important to use a species for which there are historical control data and relevance to
41 humans.
42
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 9. Presence of a concurrent control group composed of the same species as that in the treatment
2 groups. The control subjects should be housed and cared for in the same manner as
3 exposed animals.
4
5 10. Concentration/dose selection that establishes a clear dose-response relationship.
6
7 11. Observation period. The period is variable based on the time of onset of the toxic effect. If
8 it is rapid (minutes to 2-3 hours) and associated with quick recovery, an observation
9 penod of 3-4 days may be sufficient. For effects that are slow in onset (2-3 days) and
10 delayed in time, a minimum observation period of 14 days is recommended.
11
12 12. Signs and symptoms of intoxication noted during and after exposure and reported separately
13 by sex and concentration or dose.
14
15 13. For animal studies, body weights should recorded throughout the study.
16
17 14. For repeated concentration/dose studies, establishment of the highest estimated or
18 experimental (empirical) level of no effect for the specific AEGL endpoint of concern.
19
20 15. Toxicity data from routes of exposure other than inhalation generally will not be used as key
21 or supporting data. Data from alternate routes are considered in the absence of inhalation
22 data if sufficient data are available to perform a credible route-to-route extrapolation.
23
24 16. Number of concentrations or doses used.
25
26 17. If a NOEL is selected or derived as the endpoint for an AEGL seventy level of concern,
27 identifying both the highest dose at which the effect is not seen, and the lowest dose at
28 which it is seen, for each AEGL severity level strengthens the confidence in the study.
29
30 18. Record of time of death if applicable.
31
32 19. For animal studies, necropsy conducted with at least gross effects noted.
33
34 20. As available, data (e.g. histopathological changes, clinical chemistry and hematology) may
35 reduce uncertainty.
36
37 21 Recovery group included in the study and data generated are sufficient to determine the
38 degree of reversibility.
39
40 22. Statistical treatment of data generated from study.
41
42 23. An evaluation of all relevant data should be performed and summarized in the Technical
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1 Support Document in order to present an integrated "weight-of-evidence" picture for all
2 information considered as a whole.
3
4 2.3.3 Elements for Discussion on Data Adequacy and Research Needs
5
6 The adequacy of the key and supporting data selected for AEGL derivation should be
7 discussed in Section 8.3 of the TSD (Data Adequacy and Research Needs) Because of the
8 different toxic endpoints used for the three AEGL tiers and the use of different data and/or
9 studies for each tier, the data adequacy should be addressed separately for AEGL-1, -2, and -3
10 In addition to any discussion regarding the elements for evaluating key and supporting studies
11 listed in this section of the TSD, the discussion should consider in general terms: (1) repeatability
12 of experiments between laboratories, (2) consistency of data between experiments and
13 laboratories, (3) types and number of species tested, and, (4) comparisons of the AEGLs with
14 valid human and animal data.
15
16 A summary of the discussion in the TSD section "Data Adequacy and Research Needs"
17 also should be included in the Executive Summary and the Derivation Summary Tables. The
18 summary statements also should address the adequacy of the data by AEGL tier.
19
20
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1 2.4 DOSIMETRY CORRECTIONS FROM ANIMAL TO HUMAN
2 EXPOSURES
3
4 When extrapolating from observed responses in animals to predicted human responses,
5 the relationship between nominal exposure concentration and delivered dose to the target tissue
6 is often an issue of concern. For inhaled toxicants the target tissue is either some component of
7 the respiratory system and/or other tissue or organ. A number of methods have been proposed to
8 adjust for differences in the dose to target tissue in the respiratory system (U.S. EPA, 1994b) and
9 those located systemically (U. S. EPA, 1994b; NRC, 1993a). The concern has been the lack of
10 validated methodologies that would provide scientifically sound values for gases, vapors and
11 aerosols. This is particularly true where the methodology may predict levels for humans that may
12 not be sufficiently protective. Both methodologies referenced above have not been validated for
13 gases with experimental data, especially in the higher dose ranges required to produce toxicity
14 with acute exposures. Another possible dosimetry correction, using the inhaled dose against the
15 body weight raised to the 3/4 power has support based upon an analysis of chronic toxicity
16 studies (U.S. EPA, 1992). However, this adjustment may not be relevant for acute lethality
17 studies (Wolff and Rhomberg, 1998). Therefore, no dosimetry adjustments have been made to
18 date by the NAC/AEGL Committee for attaining human-equivalent doses in the development of
19 AEGLs for gases, vapors and aerosols.
20
21 If AEGL values are developed for particulates, the methodology developed by the U. S.
22 Environmental Protection Agency, and validated with experimental data on particulate matter,
23 will be reviewed and applied on the basis of the individual material (U. S. EPA, 1994b). Where
24 specific data and validated models are available for chemicals inhaled as gases, a dosimetry
25 correction will be made by the NAC/AEGL Committee.
26
27
28 2.4.1 Discussion of Potential Dosimetry Correction Methodologies for Gases
29
30 2.4.1.1 The Respiratory System as a Target Organ
31
32 The RfC (Reference Concentration) methodology for chronic exposure to gases was
33 proposed by U.S. EPA (1994b) as an approach to the dosimetry correction for effects on the
34 respiratory system. This method has not been used by the NAC/AEGL Committee for the
35 following reasons: (1) The RfC dosimetry corrections from animal to man are based upon
36 theoretical constructs which have not been confirmed and validated with experimental data; (2)
37 Some of the RfC assumptions are questionable and can have a significant impact upon the
38 calculated dosimetry correction between animal and human. Below is a discussion of two key
39 examples and their impact upon the dosimetry adjustment. The assumptions are the requirement
40 of uniform deposition in compartments and equivalent percent of deposition in animals and
41 humans
42
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1 For Category 1 gases (highly water soluble and/or rapidly irreversibly reactive) the RfC
2 methodology assumes that for each respiratory compartment (extrathoracic, tracheobroncial, and
3 pulmonary), the deposition of chemical is equivalent throughout the compartment. This fails to
4 take into account major differences in anatomical structure and deposition (dose) as the gas,
5 vapor or aerosol progresses from proximal to distal regions within any one compartment. The
6 dosimetric adjustment from rodent to man for the extrathoracic region predicts a 5-fold higher
7 delivered dose to humans compared to rodents at equivalent exposures. However, a number of
8 investigators have shown that treating the entire extrathoracic region as a single homogeneous
9 compartment is incorrect. The use of sophisticated computational fluid dynamics computer
10 modeling, correlated with analysis of patterns of lesions induced by chemical exposure,
11 demonstrate that the degree of deposition of chemicals vanes greatly in different extrathoracic
12 regions in rats (Kimbell et al., 1993; Kimbell et al., 1997a; Kimbell et al., 1997b) and the
13 monkey (Kepler et al., 1998). Specific areas such as the olfactory epithelium will receive
14 different regional doses in the rat and humans because of differences in surface area, susceptible
15 location, and degree of ventilation (Frederick, et al., 1998). A recent estimate of a dosimetnc
16 adjustment for vinyl acetate toxicity to the olfactory epithelium was performed using multiple
17 compartments and a physiologically based pharmacokinetic model (PBPK). Bogdanffy et al.
18 (1999) predicted that a time adjusted exposure of 8.7 ppm in the rat would result in the same
19 damage in a human exposed to 10 ppm. In this case the application of the RfC methodology
20 overestimates the risk to humans.
21
22 In the RfC methodology the proportion deposited in each region for Category 1 gases is
23 assumed to be the same in animals and humans. Where the deposition is less than 100% this
24 assumption is incorrect when one considers a rodent breathing at 100 times a minute vs 15
25 breaths a minute for a human. The residence time for the chemical in a rodent lung is
26 approximately 0.6 seconds while it is approximately 4 seconds in a human or about 6 times as
27 long. All things being equal, the longer residence time in the human respiratory system will
28 mean that the human extracts a greater percent of inspired chemical per breath than a rodent.
29 Another factor to consider is that at high exposure levels, a steady state can be rapidly achieved
30 in which relatively little chemical is deposited in each breath so that the concentration becomes
31 the determining factor.
32
33 Of concern is the fact that when dosimetry adjustments are made between rodents and
34 humans for toxicity to the pulmonary region, the delivered dose to the human is predicted to be
35 about 3-times less than the mouse for an equivalent nominal exposure concentration. Using this
36 methodology in the absence of supporting empirical data could seriously underestimate human
37 sensitivity. For example, at lethal concentrations fluorine toxicity is due to pulmonary
38 intoxication in all species tested (Keplinger and Suissa, 1968) Further, the empirically derived
39 LC50 values for the mouse, rat, rabbit, and guinea pig are essentially identical. However, the
40 minute volume to surface area ratio for the pulmonary region of the guinea pig closely resembles
41 the human. If the RfC dosimetry procedure were correct, the LC50 for the guinea pig should be 2-
42 3 times higher than that observed for the rat and mouse, yet the empirical data were essentially
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1 identical for all three species. Using the RfC methodology to extrapolate a dosimetric correction
2 to humans in this case would seriously underestimate the nsk by a factor of 3 from the mouse
3 data. This problem is compounded by the fact that the RfC methodology calls for the use of a
4 lower interspecies uncertainty factor when the dosimetry correction is used.
5
6 2.4.1.2 Systemic Toxicity
7
8 Most systemic toxicants would fall under the definition of a Category 2 gas in the EPA
9 methodology (U.S. EPA, 1994b). Category 2 gases are moderately water soluble and
10 intermediate in their reactivity such that they would be distributed throughout the respiratory tract
11 and absorbed readily into the blood stream. In the case of Category 2 gases, the RfC dosimetry
12 procedure predicts that the human receives a dose ranging from 6,000 to 50,000 times higher
13 than a rodent (depending upon the species) for an equivalent exposure. These numbers do not
14 appear to be biologically reasonable or scientifically credible. Because of the potential errors, the
15 methodology for category 2 gases has not been used. When a corrected methodology is
16 published it will be evaluated for use by the NAC/AEGL Committee.
17
18 For systemic toxicants, the NRC (1993a), proposed that dosimetry correction be
19 conducted by adjusting for minute volume to body weight ratios. It is assumed for this
20 calculation that 100 percent of the chemical, or that equal percentages of the chemical, are
21 absorbed. Given that assumption, the correction is a reasonable approach and may be valid for
22 low concentrations of chemicals. Most animal to human extrapolation is done using mouse or rat
23 data. Using certain typical minute volume and body weight parameters, it is possible to calculate
24 an adjustment factor or multiplier in order to derive an equivalent dose in a human from animal
25 data. The multiplier is approximately 6 for the mouse and 3.5 for the rat. Thus, if the exposure
26 of interest in mice or rats is 100 ppm, then an equivalent internal dose in humans would be
27 predicted to be induced by exposure to 600 ppm and 350 ppm from these two species
28 respectively. Therefore, in order to induce an acutely toxic systemic effect in humans, people
29 would have to be exposed to a concentration 6 times greater and 3.5 times greater than the
30 nominal exposure required to induce the effect in mice or rats respectively.
31
32 If, on the other hand, less than 100 percent of the inspired chemical is absorbed with each
33 breath, the human and animal would absorb a different fraction of the chemical in each minute
34 (see discussion above). As the percent absorbed approaches 0 the multiplier would approach 1.
35 In the example above the multiplier for human dosimetry correction would go from 6 to 1 in the
36 case of mice and 3.5 to 1 in the case of rats as the percent absorbed approaches 0.
37
38 AEGL-2 and AEGL-3 levels represent relatively high exposure concentrations where
39 absorption may not be complete. If the minute volume to body weight correction for dosimetry
40 which assumes 100 percent absorption were used in these cases, the estimated human exposure
41 equivalent to the rodent would be too high, leading to an underestimate of the toxicity and the
42 derivation of AEGL values that are not protective to the human population
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1 Another approach to dosimetry correction might be that used by the U.S. Environmental
2 Protection Agency when extrapolating from animal cancer bioassays to theoretical excess human
3 cancer risk levels for lifetime exposures (U.S. EPA, 1992) The cross species scaling factor used
4 is based upon an equivalence of mg/kg^/day. There is reasonable scientific support for utilizing
5 this approach based upon an analysis of a number of multiple exposure studies across a number
6 of animal species (U.S. EPA, 1992) One might assume that the total amount of chemical
7 inhaled is equivalent to the dose (NRC, 1993a) and adjust that across species using the
8 equivalence of mg/kg^/day. However, Vocci and Farber (1988) point out the power law of
9 (body weight)3'4 holds for the ventilation rate such that on a weight to weight basis, the rat
10 receives about 4 times the delivered dose of a human for the same exposure concentration.
11 When this adjustment for breathing rate is combined with the adjustment for toxicity (U.S. EPA,
12 1992), the two cancel each other out and one is left with the conclusion that equivalent exposure
13 concentrations result in equivalent outcomes in animals and humans.
14
15 The situation is further complicated by an analysis of oral acute toxicity experiments by
16 Rhomberg and Wolff (1998) using pair-wise comparisons of LD50 values for different species for
17 a large number of chemicals on the RTECS database. Their findings contrast with the U.S. EPA
18 (1992) findings, which largely evaluated multiple exposure studies, in that the best
19 correspondence of toxicity across species for LD50 values was found when doses were expressed
20 as mg/kg. This finding might argue for the NRC (1993a) recommendation to scale doses across
21 species based upon minute volume to body weight ratios. However, this conclusion would be
22 based upon an evaluation of oral toxicity studies, most of which were probably by gavage. Bolus
23 doses result in a high peak body dose, in contrast to the inhalation of a chemical over a number
24 of hours with a more constant body burden over time. The question then becomes, does
25 inhalation exposure on the order of hours mimic the toxic response seen with multiple exposures
26 (U.S. EPA, 1992) or the acute bolus doses used in the Rhomberg and Wolff (1998) analysis? If
27 the former situation prevails then the rationale by Vocci and Farber would argue for no dosimetry
28 corrections being made. On the other hand, the latter case would argue for the use of the NRC
29 (1993a) methodology.
30
31 2.4.2 Current Approach of the NAC/AEGL Committee to Dosimetry
32 Corrections
33
34 Given the large amount of uncertainty surrounding this issue, and the fact that the use of
35 no dosimetry corrections for gasses across species would be the most conservative approach, the
36 NAC/AEGL Committee has chosen not to use dosimetry corrections across species. However, as
37 the science surrounding this issue progresses the NAC/AEGL Committee will continue to re-
38 evaluate it's conclusions. If data are available, on a chemical-by-chemical basis, which would
39 scientifically support dosimetry corrections for gases in the development of AEGL values, they
40 will be used to do so.
41
42 As AEGL values are developed for particulates, the methodology developed by the U. S
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1 Environmental Protection Agency, and validated with experimental data on particulate matter,
2 will be reviewed and applied on the basis of the individual material (U. S. EPA, 1994b).
3
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1 2.5 GUIDELINES/CRITERIA FOR SELECTION OF UNCERTAINTY
2 FACTORS TO ADDRESS THE VARIABILITY BETWEEN ANIMALS
3 AND HUMANS AND WITHIN THE HUMAN POPULATION
4
5 2.5.1 Introduction
6
7 The variation in the toxicological response of organisms to chemical exposures is well
8 known. This variability can be expressed across species and among individuals within the same
9 species. Lack of knowledge about the range of variability introduces uncertainties into any
10 estimate of AEGL values based upon biological data. To account for known and unknown
11 variability in response, the value derived from experimental data is adjusted by a value that
12 reflects the degree of uncertainty. This value is referred to here and by most agencies and
13 organizations as the uncertainty factor (UF). If an extrapolation is being made from animal data
14 to humans the total UF is a composite of an mterspecies UF to account for possible differences
15 between animal and human response to the chemical, and an mtraspecies UF to account for
16 differences in response to the chemical within the human population. The mtraspecies UF is
17 needed to account for possible variabilities in response by "... those at either extreme of age,
18 those with poor nutritional status, those with preexisting diseases, such as certain heart diseases,
19 that are fairly widespread in the general population, those with enhanced hereditary
20 susceptibility, or those who are overexposed because of unusual physical exertion." (NRC 1993a,
21 p88).
22
23 Inter- and intraspecies uncertainty factors have been used in the development of "safe" or
24 threshold exposure levels for chronic, non-cancer toxicity by health organizations throughout the
25 world. Examples include the acceptable daily intake (ADI) (Lu, 1988; Truhaut, 1991; Lu and
26 Sielken, 1991), the tolerable daily intake (TDI) or tolerable concentration (TC) (Meek et al.,
27 1994; IPCS, 1994), the minimal risk level (MRL) (Pohl and Abdin, 1995), the reference dose
28 (R.fD) (Barnes and Dourson, 1988; Dourson, 1994), and the reference concentration (RfC) (U. S.
29 EPA, 1994b; Jarabeck, 1994). The importance of using distribution based analyses to assess the
30 degree of variability and uncertainty in risk assessments has been emphasized in recent trends in
31 risk analysis. This will enable risk managers to make more informed decisions and better inform
32 the public about possible risks and the distribution of those risks among the population (Hattis
33 and Anderson, 1999). These techniques can be used to assess variability from differences in
34 individual exposure and susceptibility for specific risk assessments in order to reduce the
35 uncertainty in estimating the real variability which exists in a population (Hattis and Burmaster,
36 1994; Hattis and Barlow, 1996).
37
38 The use of uncertainty factors in the development of AEGL values is designed to protect
39 the general public, including sensitive subpopulations, from short-term exposures to acutely toxic
40 chemicals. However, it is recognized that certain individuals, subject to unique or idiosyncratic
41 responses, could expenence adverse effects at concentrations below the corresponding AEGL
42 level. "In the case of CEEL-2 (AEGL-2), uncertainty factors must be balanced against the
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1 Barnes and Dourson (1988) described the U.S. EPA's approach and rationale to assessing
2 non-carcinogenic health risks from chronic chemical exposure. The U. S. EPA approach follows
3 the general format as set forth by the National Research Council (NRC, 1983). The conceptual
4 difference between "safety" and "uncertainty" is discussed within the context of the terms safety
5 factor (SF) versus uncertainty factor (UF) and acceptable daily intake (ADI) versus reference
6 dose (RfD). The authors state that "safety factor" suggests the notion of absolute safety and that
7 the ADI is generally and erroneously interpreted as a strict demarcation between what is
8 "acceptable" and what is "safe" in terms of chronic exposure. In reality, the ADI represents an
9 estimate of a level where the probability of adverse effects is low but a level where the complete
10 absence of all risk to all people cannot be assured. Consequently, the RfD and UF terminology
11 was developed and adopted by the U. S. EPA. The U. S. EPA considers the RfD to be an
12 estimate (with uncertainty spanning perhaps an order of magnitude of a daily exposure to a
13 human population, including sensitive subpopulations), that is likely to be without an appreciable
14 nsk of deleterious effects during a lifetime.
15
16 Dourson, et al. (1992) conducted an analysis of chronic and subchronic toxicity data on
17 69 pesticides obtained from EPA's Integrated Risk Information System (IRIS) to determine the
18 potential impact of missing studies on the quality of the RfD values derived. Certain of these
19 data proved useful in determining interspecies variations in toxic response to long term oral
20 ingestion of a wide range of pesticides. The authors' analyses of 1- to 2- year studies indicated
21 that the probability of the rat NOAEL for each of 67 pesticides exceeding the dog NOAEL by
22 greater than 3.16-fold was 28 percent and the probability of the rat NOAEL exceeding the dog
23 NOAEL by greater than 10-fold was 10 percent. Also, the probability of the dog NOAEL in the
24 same studies exceeding the rat NOAEL by greater than 3.16-fold was 19 percent and the
25 probability of the dog NOAEL exceeding the rat NOAEL by greater than 10-fold was 4 percent.
26 These data support the value of using uncertainty factors (UFs) derived from data in developing
27 RfDs and suggests that UFs between species may be significantly less than 10-fold for a wide
28 range of structurally diverse chemicals.
29
30 Renwick (1993) considered the expression of toxicity to be the combined result of
31 toxicokinetics (all processes contributing to the concentration and duration of exposure of the
32 active chemical toxicant at the target tissue) and toxicodynamics (mode or mechanism of action
33 of the active toxicant at the target tissue site). Therefore, he reasoned that since both
34 toxicokinetics and toxicodynamics contribute quantitatively to the uncertainty factor, it is
35 necessary to subdivide each of the 10-fold UFs (inter- and intraspecies) into these two
36 components to effectively accommodate differences in contributions made by toxicokmetic and
37 toxicodynamic factors. Hence, for any chemical, appropriate data may be used to derive a
38 specific data-derived factor for that component. The overall inter-and intraspecies UFs would
39 subsequently be determined as the product of the known data-derived factor or factors and the
40 "default" values for the remaining unknown factors. The author evaluated published data for
41 parameters that measure interspecies differences in plasma kinetics (physiological changes,
42 differences in rates of absorption, biotransformation, and elimination) in laboratory animals and
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1 little or no evaluation of scientific data to support or reject the use of this value. Today there is
2 greater knowledge and insight and defined methods to evaluate sensitivity or variability in
3 responses and selecting or deriving more scientifically credible UFs.
4
5 Dourson and Stara (1983) introduced the concept that empirical data are available to
6 support the use of UFs for both inter- and intraspecies adjustment. This was followed by the
7 publication of an analysis of the chronic and subchronic toxicity data obtained from U. S. EPA's
8 Integrated Risk Information System (IRIS). Certain of these data proved useful in determining
9 the extent of interspecies variations in toxic response to long-term oral ingestion of a wide range
10 of pesticides. More recently the concept of data-derived UFs has been introduced (Renwick,
11 1993; Dourson et al., 1996). Finally, the concept of dividing, evaluating, and quantifying
12 separately the toxicokinetic and toxicodynamic factors from each of the inter- and intraspecies
13 UFs has been proposed (Renwick, 1993).
14
15 One important consideration in the selection or derivation and use of UFs for the
16 development of AEGLs is the nature of the toxicant and the exposure period. Much of the data,
17 information, and emphasis to date on non-carcinogenic and non-mutagenic substances has
18 addressed chronic effects from long-term or life-time exposures. Certain of the reports
19 discussing the toxicokinetic and toxicodynamic factors as related to variability of response have
20 drawn on carcinogenic or mutagenic mechanisms as a basis for scientific support. By contrast,
21 the AEGL values address relatively high concentration, short-term exposures to threshold effects
22 of acutely toxic chemicals. In attempting to draw on the scientific foundations upon which UFs
23 are being selected for use in developing chronic guideline levels such as RfDs and RfCs, it is
24 important to maintain an awareness of certain potential differences when considering acute
25 guideline levels such as AEGLs. Responses to chronic exposures may be greater between
26 species or between individuals as compared to responses to acute exposures. For example, the
27 impact of individual differences in absorption, excretion, metabolism, rate of repair or
28 accumulation of unrepaired damage may be magnified through exposure to lower concentrations
29 over extended time periods. The higher concentrations associated with acute exposure may tend
30 to overwhelm existing defense mechanisms, possibly ameliorating certain differences in response
31 among species and among individuals within the same species. The higher concentrations
32 associated with single exposures, together with the short-term nature of the exposure period, may
33 nullify existing differences in absorption, metabolism, and excretion of a substance, as well as
34 differences in repair mechanism rates, and other factors. Hence, acute exposure to acutely toxic
35 substances in some instances may reduce the variability in response between species and among
36 individuals of the same species depending upon the mode of action of the chemical.
37 Additionally, the fact that AEGLs are based on, and intended for, inhalation exposure adds one
38 more important dimension to the complexity of differences between individuals and species.
39
40 Based on the considerations presented above, the acceptance and use of default UFs based
41 upon chronic exposure data should be carried out only after careful evaluation of chemical
42 specific data for single exposures. However, the concepts, ideas, and approaches to developing
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1 UFs that have emanated from the chronic exposure studies of the past 10 years is of substantial
2 value in the development of AEGLs and will be employed as appropriate m the selection or
3 derivation of UFs used in the AEGL program.
4
5 2.5.3.1 Interspecies Uncertainty Factors - Use in the Development of AEGL
6 Values - Discussion
7
8 Where data are insufficient to determine the relative sensitivity of animals to man, an
9 uncertainty factor of 10 has been used by U. S. EPA, U. S. ATSDR, Health Canada, International
10 Program on Chemical Safety (IPCS), and Rijksinstituut voor Volksgesondheid en Milieu
11 (RTVM) when developing the equivalent of reference doses for chronic exposure to chemicals
12 (Dourson et al, 1996). When extrapolations are made from animals to humans based upon mg/kg
13 of body weight the factor of 10-fold is usually adequate to account for differences in response.
14 Dourson and Stara (1983) found that a factor of 10 accounted for many of the animal to human
15 differences observed when the dose was adjusted for differences between human and animal
16 body weights and body surface areas.
17
18 Brown and Fabro (1983) compared the lowest effective dose to cause teratogemcity in
19 animals (mouse, rat, rabbit, cat, monkey) and humans for 8 chemicals (methyl mercury, diethyl
20 stilbesterol, methotrexate, aminoptenn, PCBs, thalidomide, phenytoin, alcohol). The LOAEL
21 ratios ranged from 1.8 to 50 with a geometric mean of 7. Humans were generally more sensitive
22 on an administered oral dose/body weight basis but by less than an order of magnitude. This
23 analysis is complicated by the fact that the criteria and confidence in determining the lowest
24 effective dose are not discussed, and the 8 chemicals may represent potent developmental
25 toxicants in humans since their effect in humans represented the basis for their selection. The
26 potency estimates in humans may represent only the sensitive part of the distribution of human
27 response to exposure. The animal response dose may be closer to the mean response level, and
28 therefore presents a higher LOAEL for the species. However, the retrospective nature allows the
29 choice of the most sensitive animal species. In most instances the animal database is incomplete.
30 Thus, this analysis may represent the spectrum of results in which humans are more sensitive
31 than animals to developmental toxicants.
32
33 Renwick 1993 subdivided the inter- and intraspecies UFs into two components to address
34 toxicokinetics and toxicodynamics separately. Although the supporting data for this concept is
35 from chronic animal feeding studies and in vitro cell cultures, the concept of considering the
36 kinetics and dynamics separately across species has relevance to UFs for AEGLs. Renwick
37 proposed specific quantitative values of 4-fold and 2.5-fold for the kinetics and dynamics
38 components, respectively. Although this approach has merit, the NAC/AEGL Committee does
39 not make such a precise quantitative differentiation. To date the NAC/AEGL Committee uses
40 only general information on the kinetic and dynamic components of toxicity to adjust the
41 interspecies uncertainty factor from 10 to 3 or 1. This approach is also consistent with the
42 recommendation by Dourson et al. (1996) to use data-denved uncertainty factors when
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1 appropriate data are available. This approach is in keeping with the U. S. EPA's general
2 approach in the development of RfDs. For example in the case of Aroclor 1016 the default
3 tnterspecies UF of 10 was reduced to 3 because of the similarity with which monkeys and
4 humans respond to, and metabolize PCBs (toxicokinetics) and the physiologic similarity
5 (toxicokinetics) between the two species (U. S. EPA, 1996b).
6
7 Comparisons of the current approach to determine UFs for AEGLs with other short-term
8 exposure limits has not altered the current thinking of the NAC/AEGL Committee. In the
9 development of Emergency Exposure Guideline Levels (EEGLs) by the National Research
10 Council (NRC, 1986) a factor of 10-fold was used for mterspecies extrapolation. However, no
11 EEGLs have been developed in the last 15 years so it is not known if different uncertainty factors
12 might be used in light of the more recent concepts and data on interspecies differences.
13
14 The NAS Guidelines for Developing Spacecraft Maximum Allowable Concentrations for
15 Space Station Contaminants (SMACs) states that uncertainty factors between 1- and 10-fold are
16 used for each source of uncertainty (NRC, 1992a). The sources include intraspecies (human)
17 response variabilities, interspecies variabilities, the extrapolation of a LOAEL to a NOAEL, and
18 the extrapolation from an inadequate or incomplete data base. For 1 hour SMACs the NAS
19 employed an overall (combined intra- and interspecies) UF of 10-fold when only animal data
20 were available or when the route of human exposure differed from the study. However, the
21 population for which SMACs is intended does not include infants, children, the elderly, or the
22 infirm and is, therefore, a more homogeneous and healthier subpopulation.
23
24 The National Research Council (NRC, 1993a) recommended the use of an interspecies
25 uncertainty factor (UF) within the range of 1- to 10-fold to account for differences between
26 animals and humans. The guidance suggests that the UF should be based on the quality of the
27 data available. In this regard, the NAC/AEGL Committee evaluates data on a chemical-by-
28 chemical basis, considers the weight of evidence, and uses scientific judgement in the selection
29 of interspecies UFs. As data become available, the NAC/AEGL Committee will use data-derived
30 interspecies uncertainty factors.
31
32 Information bearing on the toxicokinetics and toxicodynamics of the chemical under
33 consideration, as well as structurally related analogues and/or chemicals which act by a similar
34 mechanism of action, will be used to derive an appropriate interspecies factor which may range
35 from 10 to 3 or 1. In the absence of information on a subject, or analogous, chemical to set data-
36 derived uncertainty factors, the use of a default uncertainty factor of 10 is considered to be
37 protective in most cases. As always, all information on the chemical, its mechanism of action,
38 structurally related chemical analogs, and informed professional judgement will be used when
39 determining appropriate uncertainty factors and evaluating the resultant AEGL values.
40
41
42 2.5.3.2 Interspecies Uncertainty Factors - NAC/AEGL Committee Guidelines
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1
2 General guidelines followed by the NAC/AEGL Committee to select UFs are presented
3 below. In each section there is a list of questions which should be addressed to support the
4 rationale for the choice of the uncertainty factor used. The guidelines are organized into
5 categories for convenience. However, more than one guideline may be applied to the selection of
6 any one uncertainty factor.
7
8 2.5.3.2.1 Most Appropriate Species Used
9
10 In cases where there is little interspecies variability (e.g., within a factor of 3), and/or the
11 most sensitive species is selected, and/or a species closely related to humans was selected, the
12 interspecies uncertainty factor is typically reduced from 10 to 3. It should be noted that m these
13 cases the mechanism of action can be identified and there is evidence that it is not expected to
14 vary significantly between species.
15
16
17 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
18 1. The species tested.
19 2. The toxicologic endpoint used for the AEGL derivation.
20 3. The qualitative and quantitative range of response of the species tested.
21 4. Discussion of why the species/study chosen was the most appropriate.
22 5. Discussion of the variability among studies with the same species or among strains.
23
24 2.5.3.2.2 Most Sensitive Species Not Used
25
26 In instances where the most sensitive species is not used, an uncertainty factor of 10 is
27 generally used.
28
29
30 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
31 1. The species tested.
32 2. The toxicologic endpoint used for the AEGL derivation.
33 3. The qualitative and quantitative range of responses of the species tested.
34 4. Discussion of why the most sensitive species was not used, and/or why the less
35 sensitive species was selected.
36
37 2.5.3.2.3 Mechanism of Action is Unlikely to Differ Among Species
38
39 If evidence is available indicating the mechanism of action, such as direct acting irritation
40 or alkylation is not expected to differ significantly between species an interspecies uncertainty
41 factor of 3 is generally used.
42
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1 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
2 1. A description of the mechanism of action.
3 2. A discussion of why the mechanism of action is unlikely/likely to differ? Is
4 bioavailability/metabolism/detoxification/elimination likely to be an issue?
5
6
7 2.5.3.2.4 Mechanism of Action is Unknown
8
9 In cases where the mechanism of action is unknown, or insufficient data between species
10 are available, or there are likely to be substantial (but inadequately quantified) differences in
11 metabolic and physiological response between species, an interspecies uncertainty factor of 10 is
12 applied.
13
14 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
15 1. Description of the toxicological effects observed.
16 2. Description of the range of uncertainty in toxicologic response and how that relates to
17 this assessment.
18 3. Discussion of what is known/unknown about the mechanism of action.
19 4. Discussion of the extent of data available among species.
20
21 2.5.3.2.5 Variability in Response Between Species
22
23 When there is a wide degree of variability between species, or strains or experiments
24 which cannot be adequately explained, an interspecies uncertainty factor of 10 is applied.
25
26 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
27 1. Description of the response.
28 2. Discussion of the differences or similarities in pharmacokinetic parameters
29 (absorption/metabolism/detoxification/elimination) among species.
30 3. Discussion of the range of dose-dependent response(s) of the species tested and the
31 qualitative and quantitative aspects of the data.
32
33 2.5.3.2.6 Humans More Sensitive than Animals
34
35 Where published data show humans are more sensitive than animals, an interspecies
36 uncertainty factor of 10 is used unless published results demonstrate otherwise.
37
38 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
39 1. Description of the toxicologic endpomts for which humans and animals show
40 differential sensitivity.
41 2. Discussion of the factors where humans are thought to be more/less sensitive than
42 animals.
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1 3. State which species were tested.
2 4. Discussion of the range of response of the species tested. This discussion should
3 address qualitative and quantitative aspects of the data.
4 5. Discussion of why humans are more susceptible than test animals.
5
6 2.5.3.2.7 Use of an Uncertainty Factor of 10
7
8 The uncertainty factor for interspecies response adjustment is 10 when there is
9 insufficient information about the chemical or its mechanism of action to justify a lower UF, or if
10 data are available suggesting a high degree of variability between species
11
12 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
13 1. Discussion of why an uncertainty factor of 10 is chosen. For example, the analysis
14 may depend upon data collected in only one species, high variability of response,
15 uncertainties in exposure measurement, etc. This statement could point to data
16 gaps which could be filled if the need exists.
17
18
19 2.5.3.2.8 A Selected Uncertainty Factor Applied to Animal Data Would Drive
20 the AEGL-2 or -3 Level to a Value Which Humans can Tolerate without
21 Lethal or Serious Adverse Effects
22
23 Where the application of an interspecies uncertainty factor of 10 reduces the AEGL-3
24 level, the threshold for lethality, or the AEGL-2 level, the threshold for irreversible or disabling
25 effects, to an exposure concentration which humans are known to tolerate without adverse effect,
26 the interspecies uncertainty factor is reduced to 3 or 1.
27
28 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE-
29 1. Citations and explanations of the human data and how it relates to the AEGL value
30 denved with an UF selected on the basis of the existing guidelines.
31
32 2.5.3.2.9 A multiple exposure study was used to set the level.
33
34 In cases where a single exposure AEGL value is denved from a multiple exposure study
35 because the acute data set for a single exposure is lacking, the multiple exposure data are
36 considered an inherently conservative estimate because a biological organism is expected to have
37 greater tolerance to a single exposure as compared to multiple exposures to the same chemical.
38 If the adverse effect identified in the multiple exposure study is cumulative for the AEGL level of
39 concern, the interspecies uncertainty factor used to adjust the multiple exposure animal data
40 might be reduced to 1 or 3. Careful judgement should be used when making this assessment. If
41 a chemical is cleared very rapidly, or there is evidence that the concentration causing the effect
42 does not vary with duration or number of exposures, then the animal may be able to sustain
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1 repeated insult at a level close to a single acutely toxic exposure. Thus in these instances the
2 reduction of the uncertainty factor based on multiple exposures versus a single exposure would
3 not be justified.
4
5 THE RATIONALE FOR THE SELECTION OF AN UF SHOULD INCLUDE:
6 1. A description of the study.
7 2. Discussion of the known or suspected clearance rate and other toxicokinetic properties
8 of the chemical. For example, does the concentration causing the effect vary significantly with
9 time or number of exposures?
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l 2.5.3.3 Intraspecies Uncertainty Factors - Use in the Development of AEGL
2 Values - Discussion
3
4 Intraspecies uncertainty factors (UFs) are used to address the variability in biological
5 response that exists within a human population exposed to a toxic agent. Their use represents an
6 important step in the AEGL development methodology and is designed to account for the
7 differences which can occur within the general population.
8
9 The National Research Council, National Academy of Sciences' guidelines for developing
10 emergency exposure limits state that the exposure limits are "designed to protect almost all
11 people in the general population..." (NRC, 1993a). The NRC guidelines state that, although the
12 levels "...are designed to protect 'sensitive' individuals, some hyper-susceptible individuals might
13 not be protected...". This distinction is based on the premise that emergency exposure limits
14 must be set low enough to protect the general population but must also be set at levels that
15 minimize the risks associated with inappropriate or unwarranted response to chemical
16 emergencies as a result of rare or exceptional circumstances. Consequently, the AEGL values
17 may not be expected to necessarily protect certain individuals with unique or idiosyncratic
18 susceptibilities. This consideration is clearly communicated in the NAC/AEGL Committee's
19 definition of the AEGLs.
20
21 When data are insufficient to determine the relative sensitivity of individuals in a human
22 population exposed to a specific chemical, a default uncertainty factor of 10 has been used by U.
23 S. EPA, U. S. ATSDR, Health Canada, IPCS, and RIVM when developing the equivalent of
24 reference doses for chronic exposure to chemicals (Dourson et al, 1996). This value of 10 is
25 generally applied to the NOAEL (the highest observed or calculated dose which did not cause an
26 adverse effect in an experiment). A number of studies have tried to address the issue of the
27 reasonableness or validity of this factor. Under ideal circumstances an analysis would provide
28 information on the ratios of the experimentally observed NOAELs for different human groups
29 within a population for a wide range of defined exposures to chemicals. Groups would be
30 identified based upon biochemical or physiological differences which might cause members of
31 the group to respond to chemical exposure in a fundamentally different manner - either
32 quantitatively or qualitatively. Sample sizes would be large and include a wide variety of genetic
33 backgrounds. Such examples would include differences among newborns, infants, children,
34 adults, the elderly, the infirm, and those compromised by illness, including asthmatics. The
35 NOAELs also would represent a distinct relationship between dose level and response. These
36 data would encompass all variables due to the toxicokinetics and toxicodynarrucs factors. Such
37 data are not available, even in carefully controlled, double blind clinical trials for new therapeutic
38 drugs. However, surrogates have been developed which provide information on the
39 reasonableness of the choice of the intraspecies uncertainty factor of 10 or less. This approach is
40 referred to as the use of data-derived uncertainty factors.
41
42 Dourson and Stara (1983) analyzed the slopes of 490 adult p.o. rat LD50 studies reported
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1 by Weil (1972). They calculated the intraspecies adjustment factor required to reduce the dose 3
2 standard deviations below the median LDSO response using a probit, log-dose analysis. This gives
3 a z value of 0.4987 from the mean or a calculated response of 1.3/1000 (Spiegel, 1996). This
4 was used to predict the response of a sensitive subgroup in the population. An adjustment factor
5 of 10 was adequate to reduce the response from a dose killing 50% of the animal population to a
6 level which would kill only the most sensitive members of the inbred rat population in 92% of
7 the chemicals studied. These data support the contention that a 10-fold uncertainty factor is
8 adequate in many instances to account for intraspecies differences in response to acute exposures.
9 However, in some instances this UF may not protect the more sensitive members of the
10 population. The extrapolation reported here represents a measure of 3 standard deviations from
11 the median response data points. Statistically, an extrapolation of 3 standard deviations from the
12 mean includes more than 99 percent of the population in question, or approximately 999
13 individuals out of a population of one thousand. The extrapolation of three standard deviations
14 as performed by Dourson and Stara (1983) includes a similar proportion of the population in
15 question, 998.7 out of 1000. It is interesting to note that the Fowles et al. (1999) analyses of
16 inhalation toxicity experiments revealed that for many chemicals, the ratio between the LCJO and
17 the experimentally observed non-lethal level was on average a factor of approximately 2, the 90*
18 percentile was 2.9, and the 95th percentile was 3.5. There was a range of ratios from 1.1 to 6.5.
19 Therefore, the use of an UF of 3-fold with a NOAEL for lethality can achieve the same reduction
20 in acute lethality as that reported by Dourson and Stara (1983). The 490 LD50 studies with rats
21 were undoubtedly based on a wide range of chemical substances exhibiting many different
22 toxicological mechanisms. Hence, the variability due to chemical-specific properties was
23 included in this evaluation and was accounted for by an adjustment factor of 10-fold in 92
24 percent of the chemicals tested. This type of statistical analysis makes the untested hypothesis
25 that the slope of the dose response was the same in the experimental dose range and at the
26 untested tails of the experiment. It also reflects the response in a homogeneous (inbred) adult
27 animal population and does not measure the difference in values between potentially sensitive
28 subgroups such as adult vs newborn.
29
30 A number of authors have presented data and analyzed adulf.newborn LD50 ratios to
31 assess the differential sensitivity of young and adult animals. Done (1964 as cited in NRC,
32 1993b) compiled LDSO ratios between immature and mature animals. He found that for 34 of 58
33 chemicals the immature animals were more sensitive that adults, and for 24 of 58 chemicals the
34 adults were more sensitive than the immature animals (NRC, 1993b). A similar compilation of
35 newbom/neonate and adult LD50 ratios for rat and mouse was done by Goldenthal (1977) on data
36 submitted to FDA in drug applications. This included a broad range of chemicals such as
37 analgesics, bronchodilators, CNS depressants and stimulants, anti-depressants, tranquilizers, etc.
38 NRC (1993b) analyzed these data and found that about 225 of the compounds were more toxic to
39 neonates and 45were more toxic to adults. Almost all of the age related differences from the
40 Done (1964 as cited in NRC 1993b) and Goldenthal (1977) data collections were within a factor
41 of 10 of each other and most of the ratios were within a factor of 3 (NRC, 1993b). Sheenan and
42 Gaylor (1990) analyzed adult:newbom LDSO ratios for 238 chemicals. The median ratio of the
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1 LDJO values between age groups was 2.6. Approximately 86% of the ratios were less than 10
2 indicating that this factor is adequate to account for differences in response to chemical exposure
3 between adult and young in most cases but may be insufficient for 14% of the cases. In these
4 studies the comparison was made from the median response.
5
6 Another indirect approach to quantify biological uncertainty is to measure the observed
7 variability in human populations. Calabrese (1985) examined a number of parameters related to
8 toxicokinetics (metabolism, binding of chemicals to protein and DN A, and activity levels of.
9 enzymes). In studies which included between 10 and 349 subjects he concluded that generally
10 75-95% of the population fell within a range of 10-fold. However, his conclusion was based on
11 the supposition that the 10-fold factor was to account for the total range of human variability as
12 opposed to the range from an experimental NOEL to the most sensitive person. In a similar
13 study, Hattis et al. (1987) evaluated toxicokinetic parameters in 101 data sets (5 or more healthy
14 adults) on 49 chemicals (primarily drugs). They found that 96% of the variation was within a
15 factor of 10. However, this analysis also measured the total range of human variability. These
16 analyses measured the range of responses for toxicokinetic parameters and give some sense of
17 the variability in an adult population only and not in a potentially sensitive subpopulation. They
18 do not measure how far the tail for response goes beyond the lowest dose/activity in the
19 population measured, nor the response of different populations. Another consideration is the fact
20 that these data represent measures of toxicokinetic variables which may not directly reflect the
21 threshold of toxicologic response to chemical exposure.
22
23 Ideally, one would like to be able to compare NOAEL levels observed in an experiment
24 to the tail of the NOAEL distribution in order to assess the actual frequency of response in the
25 total human population when the intraspecies uncertainty factor of 10 is applied and obtain a
26 measure of the sensitive person. Determining the experimental NOAEL is fraught with problems
27 of sample size and dose selection. The response of the sensitive population at a dose 10 fold
28 lower than the experimental NOAEL will never be known. Hattis et al. (1999) performed
29 statistical modeling analyses designed to determine the efficacy of applying the intraspecies
30 uncertainty factor of 10 to a NOAEL. They statistically analyzed clinical studies on humans
31 which measured parameters related to toxicokinetics and toxicodynamics. The studies had at
32 least 5 subjects each and included approximately 2700 data points for the toxicokinetic
33 endpoints. They demonstrated that the population distribution of the data were lognormal in the
34 data region and assumed that they were lognormally distributed out to the extreme tails. From
35 the data, and assuming a lognormal distribution, they calculated the dose required to produce an
36 incidence in 5% of the population. This is essentially an experimental NOAEL which is divided
37 by the intraspecies uncertainty factor when a risk assessment is performed. The dose at the 5%
38 incidence level was divided by 10 and the response at that dose calculated, assuming a lognormal
39 distribution of data, to the extreme tails. This approach was used to assess the response rate
40 when a 10 fold uncertainty factor is applied to a NOAEL. They found that "...acting by itself, a
41 10-fold reduction in dose from a 5% effect level could be associated with effect incidences
42 ranging from slightly less than one in ten thousand for a median chemical/response to a few per
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1 thousand for chemicals and responses that have more human interindividual variability than 19
2 out of 20 typical chemicals/responses." The analysis did not include sensitive subpopulations so
3 the variability seen could be greater. This type of analysis assumes a lognormal distribution of
4 the data to the extreme tails. It does not allow for a threshold which is generally assumed to be
5 true for non-cancer effects. Thus, the calculated response at doses 10-fold less than the 5%
6 response level may be overly conservative. There are no data, human or animal, that far out in
7 the tail of the distribution curve. The analysis by Hattis et al. (1999) indicates that a human
8 intraspecies UF of 10 would be protective of sensitive individuals and may be overly
9 conservative in many instances.
10
11 Another approach to measuring variability between different groups of a human
12 population is to compare maximum tolerated doses (MTDs) OT effect levels between groups.
13 Reports comparing the MTDs of chemotherapeutic agents in child and adult cancer patients
14 indicate that most of the substances studied were tolerated as well, and, in many instances,
15 tolerated better by children than by adults when the dose was expressed as mg/kg body weight or
16 mg/m2 (Glaubiger et. al., 1982; Marsom, et. al., 1985). In those instances where children
17 demonstrate a greater response at equivalent dose to these substances, the differences were less
18 than a factor of two-fold. Although MTDs are not entirely a precise measure of a toxicological
19 threshold, they represent a credible parameter by which relative toxicities between groups can be
20 measured in humans. It is important to acknowledge that although the substances studied
21 represent a diverse group of chemical classes, these substances exhibit similar mechanisms of
22 cytotoxicity. Therefore, the results observed cannot be applied to a large number of other
23 chemicals with different mechanisms of action. In addition, only MTDs were reported, not the
24 variability within each group in response to the drugs. Thus, this type of study gives a measure
25 of response between groups within a population but not the variability within each group.
26
27 Other studies regarding differences in sensitivities between specific groups in humans to
28 various anaesthetic gases have been reported. These studies indicate children, particularly
29 infants, are more resistant than adults to the effects of various volatile anesthetics (Gregory, et.
30 al, 1969; Katoh and Dceda, 1992; Lerman et. al., 1983; Matthew, et al., 1996; Stevens, et ah,
31 1975; LeDez and Lerman, 1987). The susceptibility of individuals of different ages has been
32 extensively studied in the anesthesia literature where the concentrations of various anesthetic
33 gases in the lung which produce "anesthesia" (ie lack of movement) have been measured. The
34 results are usually reported as the Mean Alveolar Concentration (MAC) which produces lack of
35 movement in 50% of persons exposed to that concentration. Occasionally the ED9S - the alveolar
36 concentration which prevents movement in 95% of those exposed is also reported. MACs for
37 several anesthetic gases have been measured as a function of age. The results consistently show
38 a pattern with maximal sensitivity (lowest MAC values) in newborns, particularly prematures,
39 pregnant women, and the elderly. The least sensitive (highest MAC values) occur in older
40 infants, toddlers and children as compared to adults. The total range of sensitivity was 2-3 fold.
41 Many organic solvents for which AEGLs are developed can also produce anaesthesia in humans
42 at high doses. As previously stated, this type of study gives a measure of response between
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1 groups within a population but not the variability within each group.
2
3 Intraspecies uncertainty factors (UFs) are used to address the variability in biological
4 response that exists within a human population exposed to a toxic agent. Their use is designed to
5 account for the range of response to exposure by individuals within the general population. As
6 the studies above demonstrate, an uncertainty factor of 10 is adequate to account for variability m
7 the majority of cases and a factor of 2-3 is often adequate.
8
9 It has been proposed that data on the differences in kinetics and dynamics be used to
10 modify the uncertainty factors from defaults of 10 (Renwick, 1993; Dourson et ah, 1996).
11 Renwick (1993) proposed dividing inter- and intraspecies uncertainty factors into two
12 components. Toxicity is considered to be the combined function of toxicokinetics (all processes
13 contributing to the concentration and duration of exposure of the active chemical toxicant at the
14 target tissue) and toxicodynamics (mode or mechanism of action of the active toxicant at the
15 target tissue site). If data are available on the differences between or within species on one or
16 both of these two processes, then it should be possible to reduce the total uncertainty factor by
17 developing a data derived uncertainty factor. This approach has in fact been taken by the U.S.
18 Environmental Protection Agency in the examples below.
19
20 The U. S. EPA (I996b) reduced the default intraspecies uncertainty factor of 10 to 3 for
21 Aroclor 1016 because data from animal and human studies indicate that infants who were
22 exposed transplacentally represent a sensitive subpopulation and this information (toxicity in
23 monkeys) was used to derive the RfD value (toxicodynamics).
24
25 In the case of methyl mercury toxicodynanucs data were used to reduce the intraspecies
26 UF to 3 (U. S. EPA, 1995b). The RfD was based upon a benchmark dose computed lower 95%
27 confidence limit on the 10% increase over the background for human childhood neurological
28 abnormalities (this level has been used to represent the NOAEL) in the sensitive subpopulation
29 (the developing fetus). Therefore, the default intraspecies uncertainty factor of 10 was reduced to
30 3. Since the sensitive subpopulation had been identified, the toxicodynamic part of the
31 uncertainty factor had been addressed. However, variability due to toxicokinetics was
32 main tamed with the use of the 3 fold uncertainty factor.
33
34 For styrene the default intraspecies UF of 10 was reduced to 3 in the calculation of the
35 RfC value because the lower 95% limit of the exposure extrapolation for a NOAEL in a human
36 cross-sectional study was used and the biological exposure index had been shown to account for
37 variation in pharmacokinetic and physiological measures such as the alveolar ventilation rate (U.
38 S.EPA, 1993).
39
40 In the absence of information to set data derived uncertainty factors, an uncertainty factor
41 of 10 is considered to account for intraspecies variability in most cases. When information is
42 available about the response of a sensitive population, mechanism of action in different species
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1 and/or subgroups within an exposed population, toxicokinetics or toxicodynamics, it will be
2 factored into the development of a data derived uncertainty factor which may vary between 10, 3,
3 or 1. All information on the chemical, its mechanism of action, structurally related chemical
4 analogs, a discussion of the weight of evidence and informed professional judgement are used
5 when determining appropriate uncertainty factors.
6
7
8 2.5.3.3.1 Range of Susceptibility
9
10 The National Research Council, National Academy of Sciences' guidelines for developing
11 emergency exposure limits state that the exposure limits are "designed to protect almost all
12 people in the general population..." (NRC, 1993a). The NRC guideline levels "...are designed to
13 protect 'sensitive1 individuals, some hyper-susceptible individuals might not be protected...".
14 This distinction is based on the premise that emergency exposure limits must be set low enough
15 to protect most of the general population but must also be set at levels that minimize
16 over-response to chemical emergencies as a result of rare or exceptional circumstances.
17 Consequently, the AEGL values may not necessarily protect certain individuals with unique or
18 idiosyncratic susceptibilities. This consideration is clearly communicated in the definitions of
19 the three AEGL tiers.
20
21 The definition, and intended application of AEGL values make distinctions between
22 susceptible and "hypersusceptible" individuals. It is important to characterize these two terms
23 and the potential subpopulations they may represent for purposes of uncertainty factor selection .
24 It is also important to distinguish between these two populations for purposes of risk
25 communication to emergency planners, emergency responders, and to the public.
26
27 Individual susceptibility within a population will vary according to both individual
28 determinants and the specific properties of a given chemical. The origins of susceptibility are
29 multifactorial and distributed across populations. According to the U. S.
30 Presidential/Congressional Commission of Risk Assessment and Risk Management, "Genetic,
31 nutritional, metabolic, and other differences make some segments of a population more
32 susceptible than others...susceptibility is influenced by many factors" (P/CC, 1997). The factors
33 are based on intrinsic and/or acquired differences among individuals and may include age,
34 gender, genetic factors, ethnicity and race, quality of life and life-style considerations. The latter
35 considerations may be further classified as preexisting illnesses, prior exposure(s), nutritional
36 status, personal behavior (e.g. occupation, smoking, alcohol, obesity, etc.), and socio-economic
37 factors. The NRC also characterizes such determinants: "[S]ome of the individual determinants
38 of susceptibility are distributed bimodally...other determinants seem to be distributed more or
39 less continuously and unimodally" (NRC, 1994).
40
41 Hypersusceptibility describes extreme examples of responses. Hypersusceptibility may
42 represent biological reactions that are unique, idiosyncratic and/or stem from determinants that
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1 are generally discontinuous with, and lay outside of, the range of distributions expected for the
2 general population.
3
4 The determination of susceptibility entails the presence of observable changes in
5 biochemical or physiological processes reflecting dose-response relationships unique to a
6 chemical (e.g., sulfur dioxide) or class of chemicals (e.g., acid aerosols). Susceptibility and
7 hypersusceptibility are not meaningful concepts outside of the context of specific exposures;
8 "Dose-response relationships are chemical-specific and depend on modes of action; people are
9 not hyper-susceptible to all kinds of exposures" (P/CC, 1997).
10
11 Susceptibility and hypersusceptibility may reflect transient, rather than permanent states.
12 For example, infants are susceptible to some chemicals (e.g. ingested nitrates and nitrites as a
13 result of their relatively high gastric pH), but lose that susceptibility as they mature. Susceptible
14 populations may also experience transient penods of hypersusceptibility. For example,
15 asthmatics represent 5 to 10 percent of the general population and can be more susceptible than
16 non-asthmatics to challenge by respiratory irritants. Moreover, at any given time some
17 asthmatics may be suffering acute asthmatic attacks, which might lead to a hypersusceptible
18 condition, just prior to an irritant exposure. Based on the transient condition, these individuals
19 might not be accounted for in the published AEGL values. Similarly, otherwise normal
20 individuals may suffer transient periods of hypersusceptibility during penods of illness. For
21 example, following very severe, acute respiratory infections, many non-asthmatic individuals will
22 experience several weeks or more of bronchiolar hyper-reactivity and bronchospasm following
23 non-specific exposure to respiratory irritants. This condition can be considered an example of
24 transient hypersusceptibility. In general, since there is little or no information regarding the
25 responses of transiently hypersusceptible individuals to chemical exposures, the corresponding
26 AEGL values might not be protective for this group.
27
28 During the past 15 years, a wide range of symptoms and complaints in patients thought to
29 be related to extreme sensitivity to low-levels of diverse and often non-quantifiable chemical
30 exposures have been reported by clinicians and researchers. This syndrome has been referred to
31 as "Multiple Chemical Sensitivity" or MCS (Cullen, 1987). MCS has been characterized as the
32 heightened, extraordinary, or unusual response of individuals to known or unknown exposures
33 whose symptoms do not completely resolve post exposure and/or whose sensitivities seem to
34 spread to other chemicals (Ashford, 1999). The syndrome is thought by Ashford to be a 2-step
35 process with an initial acute exposure to high concentrations of a substance and the subsequent
36 triggering of symptoms at extraordinarily low-levels of exposure to the same substance or
37 different substances. He believes that repeated or continuous lower level exposures may also
38 lead to the same type of sensitization. Ashford and Miller (1998) also postulate that this
39 sensitivity may be the consequence of a variety of disease processes resulting from "toxicant-
40 induced loss of tolerance" (TILT) - described as "a new theory of disease providing a
41 phenomenological description of those disease processes".
42
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1 In response to the increasing public demand for government attention to a problem
2 frequently identified as MCS, the Environmental Health Policy Committee (EHPC) of the U.S.
3 Public Health Service (USPHS), formed the Interagency Workgroup on MCS in 1995 to address
4 this issue. The workgroup's charge was to review the scientific literature on MCS, consider the
5 recommendations from various expert panels on MCS, review current and past federal actions,
6 and make recommendations to policy makers and researchers at government agencies concerned
7 with evaluating public health issues that might relate to MCS-like syndromes. The Workgroup
8 comprised scientists from the U. S. federal agencies, including, ATSDR, DOD, DOE, DVA,
9 NCEH (CDC), NEEHS (NIH), and EPA. The original draft report was peer reviewed by 12
10 independent experts in occupational and/or environmental medicine, toxicology, immunology,
11 psychology, psychiatry, and physiology. A Predecisional Draft Report was issued for public
12 comment on August 24,1998 (U. S. PHS, 1998). Although a final report has not yet been issued,
13 the Draft Report concluded that MCS remains a poorly defined problem where the experts
14 disagree on possible causes (e.g., physical or mental) while the sufferers complain of a wide
15 range of symptoms (not associated with any "end-organ" damage) that may result from a
16 disruption of homeostasis by environmental stressors.
17
18 In addition to the EHPC Interagency Workgroup on MCS, the U. S. National Academy of
19 Sciences (NRC, 1992b, 1992c), professional organizations (ACOEM [McLellan et al., 1999];
20 AAAJ, 1986; AAAA1, 1999;), and others (Kreutzer, et al., 1999; Kipen and Fiedler, 1999;
21 Graveling, et al, 1999) have attempted to address this issue. Despite these attempts, the
22 diagnosis, treatment and etiologic assessment of MCS has remained a troublesome medical and
23 social concern for individuals, physicians, government and organizations (McClellan et al.,
24 1999). No consensus has yet been reached for a case definition (U. S DHHS, 1995; ACOEM
25 [McLellan et al., 1999]; Graveling, et al, 1999), diagnostic methods (U. S. DHHS, 1995;
26 AAAAI, 1999; ACOEM [McLellan et al., 1999], or treatment (AAAAI, 1999). Further, despite
27 extensive literature on the existence of MCS, "there is no unequivocal epidemiological evidence;
28 quantitative exposure data are lacking; and qualitative exposure data are patchy" (Graveling et
29 al., 1999). Although most reviewers contend that symptoms characteristic of chemical
30 sensitivities exist, they agree that symptoms may be exaggerated and may be "differentially
31 precipitated by psycho social events or stress, or by different physical or chemical exposures"
32 (Ashford, 1999). All researchers and clinicians familiar with the problem agree more work must
33 be done to understand the unexplained symptoms that are attributed to MCS (Kipen and Fiedler,
34 1999).
35
36 The American College of Occupational and Environmental Medicine (ACOEM), the
37 American Academy of Allergy, Asthmatics, and Immunology (AAAAI) and the International
38 Programme on Chemical Safety (IPCS) have all recommended that the term "idiopathic
39 environmental intolerance" be used to replace the term MCS (McClellan et al., 1999; IPCS,
40 1996; AAAAI, 1999). These authors believe that the term MCS incorrectly implies that the
41 condition affects the immune system and that chemical exposure is its sine qua non (McLellan et
42 al., 1999). No immunological dysfunction has been identified in these patients (Graveling, et al.,
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1 1999; AAAAI, 1999). Further, they concur with other prominent medical organizations in
2 maintaining that evidence does not exist to define MCS as a distinct entity (ACOEM [McLellan
3 etal., 1999]).
4
5 While some clinicians hold that MCS occurs as a result of environmental exposures,
6 mechanism(s) by which this may take place have not been proven scientifically. No single
7 widely accepted test of physiologic function can be shown to correlate with observed symptoms
8 (U. S. PHS, 1998; Brown-DeGagne and McGlone, 1999; AAAAI, 1999; McLellan et al., 1999).
9 Immunologic, allergic, neuropsychological, and traditional psychiatric disorders have all been
10 postulated to cause MCS, but to date, they have not been supported by well designed studies (U.
11 S. PHS, 1998; McLellan et al., 1999; Brown-DeGagne and McGlone, 1999).
12
13 As a result of the considerations presented here, it is not believed that MCS represents a
14 viable scientific basis for developing AEGL values, including further adjustments for sensitive
15 subpopulations, at this time. However, the need for scientific research on this proposed
16 syndrome that may help explain and describe its features, enable scientifically valid approaches
17 to hazard or risk assessment, and define appropnate clinical interventions is recognized. Also,
18 the NAC/AEGL Committee will remain vigilant and will consider any new data or information
19 that is scientifically credible and relevant to the development of AEGL values.
20
21
22 2.5.3.3.2 Selection of Intraspecies Uncertainty Factors
23
24 To meet the AEGL definitions that protect susceptible individuals but not necessarily
25 hypersusceptible individuals, the NAC/AEGL Committee evaluates two separate considerations
26 regarding susceptibility. First, evidence is reviewed to attempt to distinguish "susceptible" from
27 "hypersusceptible" individuals for each chemical of concern. Second, estimation of the range of
28 response variability in the general population that includes susceptible (but not necessarily
29 hypersusceptible) individuals and selection of appropriate intraspecies uncertainty factor(s) for
30 development of the AEGL values(s) is carried out.
31
32 2.5.3.3.3 Distinguishing Susceptible and Hypersusceptible Individuals
33
34 A clear distinction between susceptible and hypersusceptible individuals in all cases for
35 all chemicals is not achievable with the clinical and lexicological information available to date.
36 However, the NAC/AEGL Committee has identified specific categories and populations that may
37 be considered sensitive and part of the general population that the AEGL values are intended to
38 protect. These categories include children and infants, the elderly, asthmatics, pregnant women
39 and the fetus, and individuals with preexisting illnesses, diseases or metabolic disorders who
40 would not ordinarily be considered in a severe or critical medical condition. Examples of
41 sensitive individuals based on preexisting illnesses include those with compromised pulmonary
42 function (typical respiratory infections, smokers, immunologically sensitized due to prior
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1 exposures, etc.), hepatic function (alcoholism, hepatitis, prior chemical exposures, etc.), cardiac
2 ftmction (dysrhythmias), and those with impaired renal function.
3
4 Hypersusceptible individuals are considered as those individuals whose reactions to
5 chemical exposure are unique and idiosyncratic, lie outside of the range of distributions expected
6 for the general public, including sensitive individuals, and constitute a relatively small
7 component of the general public. For example, the AEGLs are intended to be protective of mild
8 to moderate asthmatics, but may not necessarily be protective of severe asthmatics. Additionally,
9 there are some asthmatics who, at any given time, could be coincidentally suffering acute
10 asthmatic episodes at the time of a chemical emergency. Such individuals may be considered
11 transient hypersusceptible individuals and would not necessarily be protected by the published
12 AEGLs. Examples of hypersusceptible individuals might include those with severely debilitating
13 pulmonary, hepatic, or renal disorders or diseases, the elderly with serious debilities of primary
14 physiological systems, and those individuals with unique hypersensitivities to specific chemicals
15 or chemical classes such as the isocyanates.
16
17 Certain otherwise healthy individuals in the general population also may suffer transient
18 periods of hypersusceptibility as a result of highly severe, but reversible, short-term illnesses.
19 For example, during recovery from a severe episode of acute upper respiratory infection, many
20 non-asthmatic individuals will expenence several weeks or more of bronchiolar hyper-reactivity
21 and bronchospasm following non-specific exposure to respiratory irritants. This reversible
22 condition is considered an example of transient hypersusceptibility and it is acknowledged that
23 the AEGL values may not be protective of individuals in such circumstances.
24
25 The nature of the dose-response relationships among sensitive and hypersensitive
26 individuals is highly complex and not well-understood. In almost all instances there is no clear
27 line of demarcation that distinguishes susceptible individuals from hypersusceptible individuals
28 and there is no generic or medical guidance that can be followed for a wide range of chemical
29 exposures. However, since most biological responses are chemical-specific and are dependent
30 on the mode of action of the substance in question, the issue of identifying and protecting groups
31 or populations of sensitive individuals is addressed by the NAC/AEGL Committee on a
32 chemical-by-chemical basis. The Committee uses all available data on the properties of the
33 chemical and their relationship to both normal and compromised biochemical, physiological, and
34 anatomical systems in humans to identify and protect sensitive populations. In the absence of
35 data on the chemical in question, the use of structurally related chemicals and scientific
36 judgement may be employed to select uncertainty factors that provide protection for the public
37 health.
38
39 2.5.3.3.4 Estimating the Range of Variability in a Human Population
40
41 The NAC/AEGL Committee estimates the range in variability of response to specific
42 chemical exposures primarily on the basis of quantitative human data. Acceptable experimental
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1 data are more likely to be available for AEGL-1 and AEGL-2 endpomts than for AEGL-3
2 endpoints. For example, numerous studies have considered induction of bronchospasm after
3 controlled exposures to sulfur dioxide in asthmatics and non-asthmatics. There is marked
4 individual variability in the severity of reaction to inhalation of low concentrations of sulfur
5 dioxide. Asthmatics, individuals with hyper-reactive airways, smokers and those with chronic
6 respiratory or cardiac disease react to relatively lower concentrations (Aleksieva, 1983; Simon,
7 1986). Susceptibility may also be increased in people over 60 years of age, but reports have not
8 been consistent (Rondinelli et al., 1987; Koenig, et al., 1993). By contrast, comparable human
9 data for AEGL-3 tier concentrations are limited to anecdotal case reports.
10
11 For example, during the course of the Committee's deliberations on phosphine AEGL
12 development, the possibility that children are more susceptible to phosphine exposure was
13 suggested by two case reports describing the deaths of children, but not adults, after
14 "comparable" phosphine exposures. As with most case reports, the exposure concentrations were
15 not quantified. However, both the children and the adults in question were present in somewhat
16 restricted environments, suggesting comparable exposure levels. Based on these case reports, the
17 Committee concluded that children may be more sensitive to phosphine exposure and selected
18 uncertainty factors that would provide additional protection for children.
19
20 In cases where quantitative human data are lacking for specific chemicals, but adequate
21 data can be found for structurally or mechanistically similar agents, uncertainty factors may be
22 selected by analogy to structurally similar chemicals and/or mechanism of action. For example,
23 asthmatics are particularly sensitive to sulfur dioxide. Declines of >20% in FEV1 have been
24 documented after inhalation of 0.4-1 ppm for 2-15 minutes. The effects of sulfur dioxide
25 exposure are enhanced in normal and asthmatic individuals by moderate exertion (ventilation
26 >40 1/m with mouth breathing), hyperventilation, and use of oral airways (Horstman, et al., 1988;
27 Frank, 1980; Koenig, et al., 1981; Koenig, et al., 1982; Balmes, et al., 1987; Linn, et al., 1987;
28 Roger, et al., 1985). Duration of bronchospasm is generally limited and these patients may
29 develop tolerance with prolonged or repeated exposure. These studies suggest that
30 mouth-breathing asthmatics exposed to sulfur dioxide develop bronchospasm at levels of
31 approximately 33 percent of comparably exposed non-asthmatics. Accordingly, the Committee
32 generally has used an uncertainty factor of 3 when considering the differences in human
33 susceptibility to most respiratory irritants. However, the NAC/AEGL Committee is aware that
34 the variation in response of asthmatics may differ among respiratory irritants ranging from mild
35 to severe in their effects. The most appropriate uncertainty factor will be considered based upon
36 the degree of severity of the imtant chemical and the biological data available, for known or
37 suspected differences among humans.
38
39 Children and infants are often considered as susceptible populations. There is a general
40 belief that children and infants are more susceptible to the effects of toxic substances than adults.
41 Much of this belief is predicated upon the fact that children, and particularly infants, possess
42 immature or developing biochemical, physiological, and anatomical systems that are not
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I adequate to combat the adverse affects of toxic chemicals. Further, it is believed that in certain
2 instances, the toxic effects of chemicals may permanently damage or alter the growth and
3 function of developing organs and organ systems in the young. The potential for greater
4 sensitivity to chemical substances by children and infants has been reviewed by the National
5 Research Council of the National Academy of Sciences (NRC, 1993b). The report indicates that
6 there are limited data on the relative toxiciry of pesticides and other xenobiotic compounds in
7 immature and mature humans. Consequently, the NRC focused on laboratory animal studies,
8 age-related pharmacokinetic and pharmacodynamic differences, and pharmacological data from
9 controlled clinical investigations with humans. The NRC concluded that the mode of action is
10 generally similar in mammalian species and across age and development stages within species.
11 They also concluded that children may be more sensitive or less sensitive than adults to pesticide
12 toxicity, depending on the chemical, but that the quantitative differences in toxicity between the
13 age groups are usually less than a factor of approximately 10-fold.
14
15 Although many reports have been published on the pharmacokinetic differences of
16 pharmacologic agents and other chemicals in children and adults, the data cannot be translated
17 into meaningful dose-response relationships to make valid quantitative comparisons in the
18 absence of specific biologically relevant endpoints. Bruckner and Weil (1999) summarized the
19 biological factors which may influence the responses of adolescents to chemical exposure.
20
21 Based on the limited data available, the extent to which significant differences in the
22 susceptibility of children/infants and adults exists is largely unknown. However, the difference is
23 generally considered to be within a factor of 10-fold (NRC, 1993b) with most of the differences
24 in susceptibility on the order of 2-3 fold. It is highly probable that any differences are
25 chemical-specific and also related to specific developmental stages of children and infants.
26 Within the context of the AEGL program, this issue is further complicated by the consideration
27 of once-in-a-lifetime inhalation exposures of 1 hour or less to 8 hours. The discussion at the
28 beginning of this section indicates that there is a paucity of data on age related differences and
29 the young can be more or less susceptible than adults to exposure to chemicals, depending upon
30 the chemical or chemical class in question. However, it is believed that uncertainty factors
31 applicable to other sensitive subpopulations are adequate to protect children and infants with
32 decisions based on a weight-of-the-evidence on a chemical-specific basis. It is important that all
33 of the relevant information on the chemical be considered when making judgements about
34 selection of the appropriate uncertainty factors for age differences and all other factors that
35 contribute to differences in susceptibility.
36
37 In summary, the maximum variation in responses of susceptible populations are believed
38 to generally range within 3 to 10-fold of a for healthy individuals. All information on the
39 chemical, including its mechanism of action, the biological responses, and data on structurally
40 related chemical analogs is considered as well as informed professional judgement when
41 determining appropriate uncertainty factors. Information about similarities and differences in
42 toxicokinetics and toxicodynarmcs are used where available to modify as necessary the
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1 qualitatively and quantitatively as compared to non-sensitive individuals.
2
3 2.5.3.4.3 Age/Life Stage/Condition Differences
4
5 When available data indicate certain age groups may be uniquely sensitive as contrasted
6 to the general population, an intraspecies uncertainty factor of 10 is generally used.
7
8 THE RATIONALE FOR THE SELECTION OF THIS UF SHOULD INCLUDE:
9 1. Description of the toxicologic endpoints which differ between humans of different age
10 groups.
11 2. Discussion of the magnitude of this difference. For example, quantitatively, how
12 much does the response differ, or what qualitative information indicates there may
13 be differences among age groups?
14
15
16 2.5.3.4.4 Response by Normal and Sensitive Individuals to Chemical
17 Exposure is Unlikely to Differ for Mechanistic Reasons
IS
19 In cases where the mode or mechanism of action is such that the response elicited by
20 exposure to the chemical by different subpopulations is unlikely to differ, an intraspecies
21 uncertainty factor of 3-fold is generally used. Typically this involves a direct acting mechanism
22 of toxicity where metabolism is unlikely to play a major role. A steep dose response curve may
23 also be an indication of little variation within a population, and is factored into the weight-of-
4 evidence considerations for UF determination.
25
26 THE RATIONALE FOR THE SELECTION OF THIS UF SHOULD INCLUDE:
27 1. Description of the mechanism of action.
28 2. Discussion of why the response to chemical exposure is unlikely to differ and whether
29 metabolism/detoxification is likely to be an issue.
30
31
32 2.5.3.4.5 Mode or Mechanism of Action is Unknown
33
34 When the mode or mechanism of toxic action is uncertain, or unknown metabolic factors
35 may play an important role, and/or a broad range of responses to chemical exposure is observed,
36 there is concern that there may be large differences in susceptibility between individuals. In
37 these cases an intraspecies uncertainty factor of 10 may be applied.
38
39 THE RATIONALE FOR THE SELECTION OF THIS UF SHOULD INCLUDE:
40 1. Description of the toxicity reported and the uncertainty associated with the chemical's
41 mechanism of action or other factors.
42 2. Statement as to why the effects seen add uncertainty to the assessment.
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1
2 2.5.3.4.6 Uncertainty Factors Which Result in AEGL Values That Conflict
3 with Actual Human Exposure Data
4
5 When AEGL values are initially proposed, the candidate range of values are compared to
6 the known spectrum of supporting data on the chemical. In a weight-of-the-evidence approach,
7 conflicts between the candidate AEGLs (generally derived from animal data) and the supporting
8 data (either animal data or human data) may lead to the conclusion that the uncertainty factors
9 utilized in the calculations are inappropriate because they conflict with other specific and highly
10 relevant data. In this case, the candidate AEGLs are revised to reflect the supporting data. In
11 other cases where the AEGL may conflict with an existing standard or guideline, the comparative
12 basis of the two values may be evaluated to see if the discrepancy is justified or resolvable.
13
14 THE RATIONALE FOR THE SELECTION OF THIS UF SHOULD INCLUDE:
15 1. A statement on why the use of uncertainty factors initially selected conflict(s) with the
16 published evidence.
17
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1 2.6 GUIDELINES/CRITERIA FOR SELECTION OF MODIFYING
2 FACTORS
3
4 2.6.1 Definition
5
6 In addition to the uncertainty factors discussed above, an additional Modifying Factor
7 may be necessary when an incomplete data base exists. Hence, the modifying factors represent
8 an adjustment for uncertainties in the overall database or for known differences in toxicity among
9 structurally similar chemicals. The modifying factor "... reflects professional judgment of the
10 entire data base available on the specific agent" and is applied on a case by case basis (NRC,
11 1993a, p88). The Modifying Factor may range from Ito 10-fold. The default value is 1-fold.
12
13 2.6.2 Use of Modifying Factors to Date in the Preparation of AEGL Values
14
15 Modifying factors have been used for chemicals currently published "Final" by the U. S.
16 National Academy of Sciences. Modifying factors of 2 or 3 are under consideration for
17 chemicals currently undergoing review to account for (1) a limited data set, (2) instances where
18 the adverse effects used to set the AEGL level are more severe than those described in the AEGL
19 definition, and (3) to account for the differential toxicity of chemical isomers.
20
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1 2.7 GUIDELINES/CRITERIA FOR TIME SCALING
2
3 Acute Exposure Guideline Levels (AEGLs) are derived for 30-minute, 1-hour, 4-hour,
4 and 8-hour exposure durations to meet a wide range of needs for government and private sector
5 organizations. AEGLs for 10 minute exposure durations will be developed for all future
6 chemicals addressed by the NAC/AEGL Committee, and 10 minute AEGLs will be developed
7 for the first six chemicals published by the U. S. NAS in the near future. Experimental animal
8 and controlled human exposure-response data and data from human exposure incidents often
9 involve exposure durations differing from those specified for AEGLs. Therefore, extrapolation
10 from the reported exposure duration and chemical concentration of a toxic endpoint to an
11 equivalent concentration for an AEGL-specified period is usually required. The discussion in
12 this section covers the concept, the published scientific literature, the methodologies used for
13 extrapolation, and examples of the application of these methodologies to specific chemicals for
14 the development of AEGL values.
15
16 2.7.1 Overview
17
18 In accordance with the needs of stakeholders, AEGLs are derived for 30-minute, 1-hour,
19 4-hour, and 8-hour exposure durations. Stakeholders have requested that the NAC/AEGL
20 Committee also develop 10 minute AEGL values. AEGL values for 10 minute durations will be
21 developed for chemicals in future U. S. NAS publications. Experimental exposure-response
22 data from animal studies or human exposure incidents often involve exposure durations differing
23 from AEGL-specified durations or may coincide with only one or two AEGL exposure durations.
24 Therefore, extrapolation from a reported toxic endpoint concentration and exposure duration to
25 an equivalent concentration for an AEGL-specified exposure period is usually required.
26
27 The 1993a NRC/NAS guidelines for developing short-term exposure limits address the
28 extrapolation of the effects of genotoxic carcinogens from long-term to short-term exposures.
29 Only limited NRC/NAS guidance is provided for approaches or methodologies for the
3 0 extrapolation of reported acutely toxic effects to shorter or longer durations of exposure.
31 Therefore, the NAC/AEGL Committee and ORNL have reviewed the scientific literature related
32 to time exposure relationships and current approaches and methodologies used for time-scaling.
33 Documented here are the NAC/AEGL Committee's approaches to making exposure duration
34 adjustments to develop of AEGL values from 10 minutes to 8 hours. This approach also has
35 been reviewed by scientists representing certain OECD-member countries.
36
37 The relationship between dose and time for any given chemical is a function of the
38 physical and chemical properties of the substance and the unique lexicological and
39 pharmacological properties of the individual substance. Historically, the relationship according
40 to Haber (1924), commonly called Haber's Law (NRC, 1993a) or Haber's Rule (i.e., Cxt-k,
41 where C = exposure concentration, t = exposure duration, and k = a constant) has been used to
42 relate exposure concentration and duration to effect (Rinehart and Hatch, 1964). This concept
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1 states that exposure concentration and exposure duration may be reciprocally adjusted to
2 maintain a cumulative exposure constant (fc) and that this cumulative exposure constant will
3 always reflect a specific quantitative and qualitative response. This inverse relationship of
4 concentration and time may be valid when the toxic response to a chemical is equally dependent
5 upon the concentration and the exposure duration. However, an assessment by ten Berge et al.
6 (1986) of LCJO data for certain chemicals revealed chemical-specific relationships between
7 exposure concentration and exposure duration that were often exponential. This relationship can
8 be expressed by the equation C" x t = k, where n represents a chemical specific, and even a toxic
9 endpomt specific, exponent. The relationship described by this equation is basically the form of
10 a linear regression analysis of the log-log transformation of a plot of C vs t (see Curve Fitting and
11 Statistical Testing of the Generated Curve below). Ten Berge et al. (1986) examined the airborne
12 concentration (C) and short-term exposure duration (t) relationship relative to death for
13 approximately 20 chemicals and found that the empirically derived value of n ranged from 0.8 to
14 3.5 among this group of chemicals (See Table 2.7-1). Hence, these workers showed that the
15 value of the exponent («) in the equation C1 x t = k quantitatively defines the relationship
16 between exposure concentration and exposure duration for a given chemical and for a specific
17 health effect endpoint. Haber's Rule is the special case where n = 1. As the value of n increases,
18 the plot of concentration vs time yields a progressive decrease in the slope of the curve.
19
20 In cases where adequate data are available, the NAC/AEGLCommittee conducts an
21 analysis of chemical-specific toxicity and exposure data to denve a chemical-specific and health
22 effect-specific exponent (n) for use in extrapolating available exposure data to AEGL-specified
23 exposure durations. If data are not available for empirically deriving the exponent n, the
4 NAC/AEGL Committee identifies the most appropriate value for n by comparing the resultant
^5 AEGL values derived using n=l and n=3. The value of n=l has been used historically by others
26 and results in rapid reductions in concentrations when extrapolations are made to longer
27 exposure periods and rapidly increasing concentrations when extrapolated to shorter exposure
28 periods. Based on the work often Berge et. al. (1986), 1 represents the estimate of the lower
29 boundary of the value of n. The value of n=3, an estimate of the upper boundary of the value of n
30 (ten Berge, 1986), results in less rapid rates of decrease in estimated effect concentrations when
31 extrapolations are made to longer exposure periods and to less rapid rates of increase in
32 estimated effect concentrations when extrapolated to shorter exposure periods. This range of
33 values in n from 1 to 3 encompasses approximately 90 percent of the chemicals examined by ten
34 Berge et al. (1986). In selecting a value for n when the derivation of n is not possible, the
35 NAC/AEGL Committee evaluates the resultant AEGL values determined with either the upper or
36 the lower boundary value of n (1 or 3) within the context of other supporting data to determine
37 the reasonableness of the extrapolated AEGL value. A value of n=l is used when extrapolating
38 from shorter to longer exposure durations and a value of n=3 when extrapolating from longer to
39 shorter durations. The resultant AEGL value is then compared to supporting data to determine
40 the scientific reasonableness of the derived AEGL value. A consensus of the Committee
41 generally favors the use of a value for n that results in an AEGL value that best fits the
42 supporting data.
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1 In summary, analyses of relevant data, together with scientific judgement are used to
2 determine the extent of temporal extrapolation and its validity in AEGL derivations. For
3 example, extrapolation of 10-minute exposure data to a 4 or 8-hour AEGL value requires more
4 supporting data and or/assumptions than the extrapolation of 10-minute exposure data to a 30-
5 minute or 1-hour AEGL. Errors in the estimated exposure concentration-exposure duration
6 relationship (i.e., the value of n) will progressively increase the magnitude of the error of the
7 derived AEGL value as the time from the empirical data point to the extrapolated data point
8 increases. Since toxicity data are often not available for any or all of the AEGL-specified time
9 periods, temporal extrapolation is usually necessary to generate scientifically credible values for
10 the AEGL time points.
11
12 2.7.2 Summary of Key Publications on Time Scaling
13
14 Several investigators have studied the relationship of exposure duration and exposure
15 concentration as related to the toxic response to airborne chemicals (Haber, 1924; Flury, 1921;
16 Rinehart and Hatch, 1964; ten Berge et al., 1986; ECETOC, 1991, and Pieters and Kramer,
17 1994).
18
19 Based on observations and studies with chemical warfare gases such as phosgene, Haber
20 (1924) found that for certain chemicals the product of the exposure duration multiplied by the
21 exposure concentration was constant for a specific response or toxic endpoint (i.e., lethality). In
22 experiments with cats, Haber found that a specific concentration x time product would result in
23 100% lethal response and that as long as this product value was maintained, regardless of the
24 specific exposure concentration or duration, the response was consistent. This linear relationship
25 became known as Haber's Rule; or Cx t = k where C = concentration of the chemical of the
26 chemical in question, / = exposure duration, and k = a cumulative exposure constant. Similarly,
27 Flury (1921) found that inhalation of phosgene exhibited a linear relationship, Cx t = E, where
28 £ represents the onset of pulmonary edema. Obviously, the cumulative exposure constant may
29 relate to any number of responses or toxic endpoints. However, the information reported by
30 Haber is limited to a small number of chemicals or chemical classes and substantial quantitative
31 data derived from controlled studies is lacking.
32
33 Historically Haber's Rule has been used for time concentration extrapolations U. S. EPA
34 (1994b). This relationship assumes that each unit of damage is irreversible, that no repair takes
35 place during the exposure period and, therefore, that each unit of exposure is 100 percent
36 cumulative. However, this is generally not the case for acutely toxic responses to short-term
37 exposures. The relationship between concentration and duration of exposure as related to
38 lethality was examined by ten Berge et al. (1986) for approximately 20 irritant or systemically-
39 acting vapors and gases. The authors subjected the entire individual animal data set to probit
40 analysis with exposure duration and exposure concentration as independent variables. They used
41 the methodology of Finney (1971) to investigate the fit of the data into a probit model on the
42 basis of a maximum likelihood estimate. In re-evaluating the raw data for these chemicals, it was
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1 found that the linear relationship described by Haber's, C x t = k, was not always a valid
2 predictor of lethality. An exponential function (C1 x t = k), where the value of n ranged from 0.8
3 to 3.5 for different chemicals, was a more accurate quantitative descriptor These authors
4 derived empirically-based, chemical-specific regression coefficients for exposure duration and
5 exposure concentration, as well as chemical-specific values for n. The values for n for the 20
6 chemicals studied ranged from 0.8 to 3.5. The analyses indicated that the concentration-duration
7 relationship for lethality was described more accurately by the exponential function (C1 x t = K)
8 and that Haber's Rule was appropriate for only a limited number of the chemicals. Based upon
9 the results of the analyses, ten Berge et al. (1986) concluded that the concentration-time
10 relationship (i.e., value for n) should be determined empirically from acute inhalation exposure
11 toxicity data on a chemical-specific basis.
12
13 2.7.3 Summary of the Approaches that may be Taken for Time Scaling
14
15 A tiered approach to generating toxicity values for time scaling is taken by the
16 NAC/AEGL Committee to derive AEGL values from empirical data. This approach is
17 summarized below. Each of the approaches and the circumstances under which they are, or
18 could be, used are discussed subsequently in this section of the SOP Manual.
19
20 (1) If appropriate lexicological data for the exposure concentration-exposure duration
21 relationship of a specific health effect endpoint are available for the AEGL-specified
22 exposure periods, use the empirical data directly.
23
24 (2) If empirical exposure concentration-exposure duration relationship data are available,
25 albeit they do not coincide with AEGL - specified exposure periods, use the available
26 data to derive values of n and extrapolate the AEGL values using the equation C" x t = k.
27
28 (3) If no empirical exposure concentration-exposure duration relationship data are
29 available to derive a value of n, a value of n=l for extrapolating from shorter to longer
30 exposure durations, and a value of n=3 for extrapolating from longer to shorter exposure
31 durations, should be selected initially. The scientific reasonableness of the selection of
32 the estimated lower and upper boundaries of n (n=l and n=3) is then evaluated by
33 comparing the resultant AEGL values with all other supporting data. If appropriate, the
34 final value(s) of n may be modified to reconcile differences between extrapolated AEGL
35 values and the supporting data.
36
37 (4) If there are no supporting data to evaluate selected values of n, a value of n=l for
38 extrapolating from shorter to longer exposure periods and a value of n=3 for extrapolating
39 from longer to shorter exposure periods should be selected. In the absence of other data,
40 the resultant AEGL values are thought to be protective and scientifically credible.
41
42 The balance of this section of the guidance will provide more detailed information on the
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1 approaches stated above.
2
3 2.7.4 Use of Empirical Data that is Available for AEGL-Specified Exposure
4 Durations
5
6 If toxicity data are available for all four AEGL-specified exposure periods, there is no
7 need to derive values of n and the data for each exposure period can be used directly. However,
8 it is rare that toxicity data are sufficiently comprehensive to encompass all of the AEGL-
9 specified exposure periods from 10 minutes to 8 hours. Further, there are instances where
10 empirical data are not available to estimate n and predict the exposure concentration-exposure
11 duration relationship using Cn x t = k. Therefore, the sequential approaches used by, or available
12 to the NAC/AEGL Committee to establish AEGL values for the specified exposure periods are
13 discussed in the following sections.
14
15 2.7.5 Derivation of Values of n When Adequate Empirical Data are Available
16 for Other than the AEGL-Specified Exposure Durations
17
18 A key element in the procedure of time-scaling is the use of a value or values for n in the
19 equation C" x t = k. If empirical data for exposure durations other than the AEGL-specified
20 exposure periods are available to quantify the exposure concentration - exposure duration
21 relationships for a health effect endpomt, including lethality, the value of n should be derived
22 using the method of calculation described in this section. It is believed empirically derived
23 values of n are scientifically more credible than simply choosing n=l (Haber's Rule) or
24 attempting to select some other value of n.
25
26 2.7.5.1 Selection of Appropriate Health Effect End Point for Deriving a Value
27 for n
28
29 The first step in any time scaling methodology is the selection of the health effect
30 endpoint of concern. Clearly the health effect endpoint selected should be consistent with the
31 definition of the AEGL tier being determined. Further, the endpoint should be unambiguous and
32 consistently observed at all reported exposure durations. For example, death is an unambiguous
33 endpoint and a quantitatively determined index of toxicity, the LC50, is a response rate which can
34 be compared reliably among exposures at different time periods. The use of the LC50 as an index
35 of toxicity is ideal because it is a statistically derived concentration which is not subject to the
36 vagaries of dose selection and exhibits less variability in response than any other experimental
37 endpoint. Death is included in the AEGL-3 definition and is used for estimating the value of n.
38
39 A comparable endpoint for the AEGL-1 and AEGL-2 tiers would be an ED50 (the dose
40 which causes a specific response in 50 percent of the animals) for a precisely defined toxic or
41 health effect endpoint that is consistent with the definition of the AEGL tier in question. The
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1 actual endpoint is often difficult to determine in most experiments because the observed effects
2 are often a continuum from mild to severe and generally not precise enough to determine an ED50
3 value with reliability. Further, incidence data for non-lethal effects is not always reported. For
4 these reasons, the concentration/response relationship and the value of n derived from lethality
5 data have often been applied to both the AEGL-3 and the AEGL-2 exposure period
6 extrapolations. However, in instances where the mechanism of toxicity causing the health effect
7 of concern at the AEGL-2 tier is thought to be different than that which causes lethality, the value
8 of n derived from LCSO data should not be used. Under these circumstances, AEGL-2 values can
9 be developed by selecting the upper and lower boundaries of n (n=3 and n=l) for extrapolation
10 from longer to shorter and shorter to longer exposure periods, respectively. The resultant AEGL-
11 2 values should be evaluated within the context of other supporting data to evaluate the
12 reasonableness of the values of n selected. In the absence of supporting data, the AEGL values
13 determined using n=3 and n= 1 should be utilized.
14
15 Selection of appropriate endpoints for AEGL-1 values per se represents a unique and
16 often difficult task. Based on the NAC/AEGL Committee's experience to date, no rigorous data
17 for any chemical have been available from which values of n could be denved for the AEGL-1
18 type of endpoints. The derivation of AEGL-1 values is discussed later in this section.
19
20 2.7.5.2 Criteria for Adequate Empirical Data for Deriving Values of n
21
22 After determining the health effect endpoint to be used in deriving the value(s) for n, the
23 next step is to evaluate the quality and the quantity of the data to be used in the derivation.
24 Obviously, two data points will define the slope of a curve descnbing the exposure
25 time/exposure concentration relationship. However, the validity and, hence, the value(s) of n
26 will depend on many factors including the scientific soundness of the concentration exposure-
27 duration data, the length of the empirical exposure duration(s) relative to the AEGL-specified
28 exposure periods, and the known or perceived similarities in effects and mechanism of action of
29 the chemical at the reported exposure concentrations and durations. Generally three empirical
30 data points will improve the scientific validity of the slope and the estimated values(s) for n, and
31 the validity is likely to increase with an increase in the number of empirical data points used to
32 derive n, provided that there is a reasonable fit of these data points.
33
34 2.7.5.3 Curve Fitting and Statistical Testing of the Generated Curve
35
36 Once the health effect endpoint and data points describing the concentration-exposure
37 duration relationship have been selected, the values are plotted and fit to a mathematical equation
38 from which the AEGL values are developed. There may be issues regarding the placement of the
39 exponential function in the equation describing the concentration-exposure duration relationship
40 (e.g. C'xt = kvsCxfn = k2vsC*x? = k}). It is clear that the concentration-exposure duration
41 relationship for a given chemical is directly related to its pharmacokmetic and pharmacodynamic
42 properties. Hence, the use and proper placement of an exponent or exponents to quantitatively
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1 describe these properties is highly complex and not well understood.
2
3 The quantitative description of actual empirical data of this relationship can be expressed
4 by any of a number of linear regression equations. In the assessment of empirical data reported
5 by ten Berge et al. (1986) these workers quantified the concentration-exposure duration
6 relationship by varying the concentration to the nlh power. Since raising c or t or both to a power
7 can be used to quantitatively define the same relationship or slope of the curve, and to be
8 consistent with data and information presented in the peer reviewed scientific literature, the
9 equation C" x t = k is used for extrapolation. It must be emphasized that the relationship between
10 C and t is an empirical fit of the log transformed data to a line. No conclusions about specific
11 biological mechanisms of action can be drawn from this relationship.
12
13 The preferred method is to use a statistical methodology which utilizes all of the
14 individual animal data and generates a maximum likelihood estimate with 95% confidence
15 limits. Where individual animal data are available, the NAC/AEGL Committee will explore
16 using the methodology of Finney (1971). This methodology has been incorporated into a
17 computer program and provided to the Committee by Dr. ten Berge from the Netherlands.
18
19 Unfortunately, the individual animal data are often not available and only LC50 values are
20 listed. In this case a linear regression analysis of the log-log transformation of the
21 concentration/time data will be performed as described below.
22
23 When time-concentration data are plotted on a log-log plot, they generally fall along a
24 straight line. For that reason a simple linear regression (Alder and Roessler, 1968) is run on the
25 data to generate the mathematical curve. The basic linear regression equation is in the form:
26
27 Y = a + bX
28
29 where Y is the predicted value of the dependent variable, X is the value of the independent
30 variable, a is the Y intercept and b is the slope of the line.
31
32 This is the form of the log-transformation of the nonlinear C" * t = k equation to a linear
33 equation (see below):
34
35 log C = (log k)/n + (-1/n)* log t
36
37 where C is the predicted value of the concentration to cause an effect at exposure duration t. The
38 (logk)/n is the Y intercept of the plot of logC against logT", and -1/n is the slope of the plot of
39 logC against Iog7.
40
41 C"*t = k
42 logfC1 * t) = log k
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1 n*logC + logt = log k
2 n*logC-logk- log t
3 logC= (log k)/n - (log t)/n
4 log C = (log k)/n - (1/n) * log t
5
6 The regression coefficient or slope, b, returns the slope of the linear regression line
7 through data points X and Y. The slope (rate of change along the regression line) is the distance
8 between the Y values of the two points divided by the distance between their respective X values.
9 The regression coefficient is calculated as:
10
11
, _ N^XY - (LX) (LY) where N = the number of observations
19 or
20
NLflog t)(log C) - (Llog t) (Llog Q
_1/n =
NL(logtf-(Llog(?
21 The above is solved in a spreadsheet for n.
28
29 The validity of the derived value(s) of n is dependent on the degree of correlation among
30 the various concentration/time data points used to construct the curve and the equation.
3 1 Normally a coefficient of determination (r2) is calculated as a measure of how well the generated
32 curve (linear in this case) fits the data points. If r2 = 0 the data do not fit a linear relationship. If
33 r2 = 1 the data exhibit a strong linear relationship. If the number of data points are 3 and the real
34 value of r = 0 "... the chance of obtaining a fairly high correlation coefficient for the sample is
35 greater than the chance of obtaining a small correlation coefficient." (Alder and Roessler 1968,
36 p!91) If the number of data points are 4 "... the chance of obtaining a particular correlation
37 coefficient is equal to that of obtaining any other." (Alder and Roessler 1968, pi 91). Since the
38 number of data points typically available are only in the range of 3 or 4 values, the use of r2 to
39 measure how well the data fit the generated curve is not a meaningful test to perform. Therefore
40 informed professional judgement is exercised by the NAC/AEGL Committee.
41
42 Given the fact that the distribution of r for low numbers of observations (typically 3 or 4
43 data points for time scaling) cannot be fit to a normal curve, meaningful statistical tests of the fit
44 of the regression line (used to derive n) to the data cannot be performed. Even with these
45 shortcomings, a regression analysis of the data as previously described gives the best fit of a line
46 to the data. A visual inspection of the regression line vs the data also will show the
47 reasonableness of the fit and, hence, the reasonableness of the derived value for n. This is
48 generally the best approach empirical data are used to derive n values for developing AEGL
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1 values for specified exposure durations. As stated earlier, it must be emphasized that: When
2 deriving or selecting a value for n, the NAC/AEGL Committee evaluates the resultant
3 AEGL values within the context of other supporting data to determine the reasonableness
4 of the extrapolated values. This is true even when the value of n is derived from empirical
5 data that describes the concentration-exposure duration relationship. The NAC/AEGL
6 Committee uses a value for n that results in AEGL values that best fit the supporting data.
7 Therefore, there is no substitute for informed professional judgement based on careful review,
8 evaluation and discussion of all available data.
9
10 2.7.5.4 Examples of NAC/AEGL Committee Derivations of Values of n from
11 Empirical Data
12
13 During the course of AEGL development, the NAC/AEGL Committee has used
14 empirically-based derivations of n in the equation C" x t = k for time-scaling to AEGL-specified
15 exposure penods. Guidelines have been developed from this experience and are presented in the
16 final part of this section.
17
18
19 2.7.6 Selection of Values of n When Adequate Empirical Data are Not
20 Available to Derive Values for n
21
22 When adequate data describing concentration-exposure duration period relationships for a
23 specific chemical and toxic endpomt of interest are not available, an alternative approach to
24 quantitatively estimating this relationship must be followed. The approach used by the
25 NAC/AEGL Committee involves the application of the equation Cn x t = k and the selection of a
26 value or values of n that results in AEGL values that best fit the supporting data for the chemical
27 and toxic endpoint in question. It is important to distinguish the difference between the
28 derivation of values of n as described in the preceding section and the selection of values of n as
29 described in this section.
30
31 An evaluation of the analysis of values of n by ten Berge et al. (1986) served as the basis
32 to select the limits used by the NAC/AEGL Committee.
33
34 Table 2.7-1 is a summary of the airborne concentration-exposure duration relationships
35 for 20 chemicals based on their LC50 values.
36
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1 TABLE 2.7-1. VALUES OF n FROM TEN BERGE ET AL. (1986).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
§i
33
34
35 The lowest value of n was 0.8 and the highest value of n was 3.5. Approximately 90
36 percent of the values of n range between n=l and n=3. Consequently, these values were selected
37 as the reasonable lower and upper bounds of n.
38
39 In the absence of data to derive a value for n, the NAC/AEGL Committee selects values
40 for n of 1 and 3, depending on an extrapolation from shorter to longer durations or longer to
41 shorter durations. The value of n is then used in the equation Cn x t = k to extrapolate from
42 empirically reported concentration and exposure durations to the AEGL-specified exposure
43 duration(s). The Committee then selects the derived AEGL values in accord with the supporting
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SYSTEMIC CHEMICALS
HCN
H2S
methyl t-butyl ether
methylenechlorobromide
ethylenedibromide
tetrachloroethylene
trichloroethylene
carbon tetrachloride
acrylonitrile
Value of n(ave)
2.7
2.2
2
1.6
1.2
2
0.8
2.8
1.1
IRRITANTS
ammonia
HC1
chlorine pentafluoride
nitrogen dioxide
chlorine
perfluoroisobutylene
crotonaldehyde
HF
ethylene inline
bromine
dibutylhexamethylenediamine
Range of n # Chemicals/range
0.8-1.5 8
1.51-2.0 6
2.01-2.5 2
2.51-3.0 2
3.01-3.5 2
2
1
2
3.5
3.5
1.2
1.2
2
1.1
2.2
1
Cumulative # chemicals
8
14
16
18 90%withn<3
20
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 data.
2
3
4 2.7.6.1 Selection of Values of n When Extrapolating from Shorter to Longer
5 Exposure Periods
6
7 As discussed previously, a value of n=l represents the lower range of the concentration-
8 exposure period relationship. If the exponent n=l is used in the equation C"xt = k, there is a
9 rapid decrease in extrapolated values when extrapolations are made from shorter to longer
10 exposure periods (see Figure 2.7-1). The extrapolated values are lower and, hence, represent a
11 conservative estimate of the AEGL value. A value of n=3 represents a value in the upper range
12 for the concentration-exposure duration relationship and results in a less rapid rate of decrease
13 when extrapolating from shorter to longer exposure periods. Therefore, the extrapolated AEGL
14 values for longer exposure periods are higher and, hence, less conservative in terms of protecting
15 human health. See Figure 2.7-1.
16
17 When data are not available for deriving a value of n, the NAC/AEGL Committee
18 develops tentative AEGL values from shorter to longer exposure durations using n=l in the
19 equation C1 x t = k and evaluates these values with all other supporting data to determine their
20 scientific reasonableness. Therefore a "weight of evidence" test is applied to the tentative
21 AEGLs by comparing these values to the supporting data to determine the most scientifically
22 credible AEGL values. In instances where the supporting data indicate that the tentative AEGL
23 developed using a value of n=l is too low or too high, the AEGL may be adjusted to
24 scientifically accommodate the supporting data. If there are no supporting data indicating that
25 the derived AEGL should be adjusted, a value of n=l is used to account for the uncertainty of the
26 concentration-endpoint relationship at longer exposure durations.
27
28 2.7.6.2 Selection of Values of n When Extrapolating from Longer to Shorter
29 Exposure Periods
30
31 When extrapolating from longer to shorter exposure durations using the equation Cn x t =
32 k and a value of n=l, there is a relatively rapid increase in the extrapolated values (see Figure
33 2.7-1). Under these circumstances, the derived AEGL value represents a relatively high estimate
34 of the toxic endpomt concentration at shorter exposure durations and is, therefore, a less
35 conservative value. When extrapolating from longer to shorter exposure durations using a value
36 of n=3, there is a less rapid rate of increase in the derived AEGL value. As a result, the
37 extrapolated AEGL value is more conservative when selecting a value of n=3. See Figure 2.7-1.
38
39 Under circumstances where the NAC/AEGL Committee selects a value for n to derive
40 AEGL values from empirical data for longer exposure periods, tentative AEGLs are derived
41 using values for n of 3 and then compared to the derived values with all other relevant data.
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1 Again, this represents a "weight of evidence" approach to selecting a value of n for the most
2 scientifically credible AEGL values. In instances where the supporting data indicate that the
3 tentative AEGL developed using a value of n=3 is too high or too low, the AEGL may be
4 adjusted to scientifically account for the supporting data. If there are no supporting data
5 indicating that the derived AEGL should be adjusted, a value of n=3 should be used to
6 accommodate for the uncertainty of the concentration-exposure duration relationship for the
7 shorter exposure durations.
8
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Extrapolation from a 60 minute value of 100 ppm to
30 and 480 minutes with different values of n
200
150 --
O
E 100 --
CL
o.
50 --
200
126
* * —
t = k
n=3
n=2
n=1
50
35
12.5
0 60 120 180 240 300
Minutes (t)
360
420
480
1
2
3
4
5
6
7
8
9
10
11
12
FIGURE 2.7-1 EFFECTS OF VARYING n IN THE EQUATION C" x t = k
SHORT TO LONG DURATION EXTRAPOLATIONS: Note that when extrapolating from 60 minutes 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=l yields a more conservative value than
any value of n that is >1
LONG TO SHORT DURATION EXTRAPOLATIONS. Conversely, when extrapolating from 60 minutes
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
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1 2.7.7 Special Considerations in the Time Scaling of AEGL-1 and AEGL-2
2 Values
3
4 The previous descriptions of approaches to time scaling for toxic end-point
5 concentrations are most applicable to the derivation of AEGL-3 values. This is because
6 unequivocal data relating the concentration required to cause an effect to the time duration of
7 exposure are LC50 data. Lethality is an unambiguous end-point which does not involve
8 gradations of seventy or incidence which are often difficult to quantify (e.g., lung congestion,
9 lung edema, irritation in the respiratory tract involving variations in both degree and area
10 affected). With respect to AEGL-2 values, it is far more difficult to quantify and achieve
11 consensus on gradations in non-lethal toxic effects with respect to severity and incidence in a
12 manner that readily results in a simple, quantitative toxic end-point concentration - exposure
13 duration relationship. Further, the LC50 is a statistically derived value in the mid-point of the
14 dose-response curve which is less subject to the vagaries in response at the extremes of the
15 exposure regimen. For these reasons, the NAC/AEGL Committee primarily has used LC50 data
16 in the derivation of exposure-time scaling relationships. These quantitative relationships have
17 then subsequently been used to derive both the AEGL-2 and the AEGL-3 values, and
18 occasionally the AEGL-1 values. This is believed to be a scientifically credible approach if the
19 mechanism of toxicity for AEGL-2 and AEGL-3 is known or thought to be similar.
20
21 It is recognized that the time scaling relationship observed with a lethality AEGL-3
22 endpoint may not accurately describe the irreversible effects or impairment of escape endpoint
23 used for the AEGL-2 endpoint. However, the NAC/AEGL Committee compares the AEGL-2
24 values against the supporting data to assess the reasonableness of the AEGL-2 determinations.
25 Based on this assessment, adjustments are made to better fit the supporting data If there are data
26 that suggest different lexicological mechanisms for lethal effects and AEGL-2 health effects,
27 selected values of n should be used for the development of the AEGL values. The upper and
28 lower bounds of n=3 and n=l should be used for extrapolation from longer to shorter and from
29 shorter to longer exposure periods, respectively. The resultant AEGL-2 values should then be
30 evaluated using all supporting data and adjusted or maintained accordingly.
31
32 A difficult application of time scaling is encountered when attempting to derive AEGL-1
33 values. The AEGL-1 value defines the air-borne concentration that distinguishes detection from
34 discomfort. As a result, the difficulty in attempting to quantify this often subjective level with
35 respect to severity and incidence in a manner sufficient to derive a concentration-exposure
36 duration relationship is greater than in the case of the AEGL-2. This is further complicated by
37 the nature of the biological end-point that one is attempting to quantify. For example, the
38 concentration level for odor detection in a group of individuals may actually decrease over time
39 due to olfactory fatigue. With respect to mild sensory effects, they generally are not cumulative
40 over a range of exposures of 10 minutes to 8 hours. Hence, the same AEGL-1 value may be
41 assigned to all AEGL-specified exposure periods. In certain instances, where experimental data
42 suggest that the sensory effects may increase due to the cumulative dose over time, the 10
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1 minute, 30 minute and 1 hour values may be constant, yet differ from a lower but constant
2 AEGL-1 value that is established for the 4 hour and 8 hour AEGL exposure durations.
3
4 In the case of certain sensory irritants, the AEGL values may be constant across all AEGL
5 time periods because this end-point is considered a threshold effect and prolonged exposure will
6 not result in an enhanced effect. In fact individuals may adapt to sensory irritation by these
7 chemicals over these exposure periods such that the warning properties are reduced.
8
9
10 2.7.8 Time Scaling - Guidelines for NAC/AEGL Committee Approach
11
12 This section is a compilation of time scaling guidelines which are used when deriving
13 AEGL values for different time penods.
14
15
16 2.7.8.1 Use of Empirical Data to Determine the Exposure Concentration-
17 Exposure Duration Relationship
18
19 THE RATIONALE FOR THE SELECTION OF AN EMPIRICALLY BASED TIME SCALING
20 APPROACH SHOULD INCLUDE:
21
22 1. The health effect used.
23 2. The exposure durations for which data were available.
24 3. Description of the statistical methodology used. If no methodology was used then
25 describe how the value of n was derived.
26 4. Description of the data used, including durations or the concentration/time values used
27 for extrapolation. Include the formula used.
28 5. Description of the different values of n that were used from one or more studies and
29 why a specific derived value of n was used.
30 6. The value of k calculated from C" x t = k after the uncertainty and modifying factors
31 have been applied to C.
32 7. If the value of n is based upon an analysis of the combined data from a number of
33 different studies then provide a description of how the different
34 time/concentration values were combined and why they were used.
35
36
37 2.7.8.2 Estimating the Concentration-Exposure Relationship using a
38 Surrogate Chemical
39
40 THE RATIONALE FOR THE SELECTION OF THIS TIME SCALING APPROACH SHOULD
41 INCLUDE:
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1 1. Description of the structure/activity relationships between the two chemicals.
2 2. The health effect endpomt used.
3 3. The exposure durations for which data were available.
4 4. The statistical methodology used or a statement of how the value of n was derived
5 5. Description of the data from the surrogate chemical used to derive the concentration-
6 exposure duration relationship. If a derived value of n is used, the equation
7 should be included.
8 6. A description of how the different time/concentration values were combined and why
9 they were used if the value of n is based upon an analysis of the combined data
10 from a number of different studies.
11 7. The value of k calculated after uncertainty and modifying factors have been applied.
12
13 2.7.8.3 Estimating the Concentration-Exposure Duration Relationship when
14 Data are not Available to Derive a Value for n and Supporting Data are
15 Available.
16
17 Selection of values for n. In the absence of data to derive a value for n, a value for n of 1
18 is initially selected when extrapolating from shorter to longer exposure durations and a value for
19 n of 3 is initially selected when extrapolating from longer to shorter exposure durations. The
20 values of n are used with the equation C" x t = k to extrapolate from the empirically reported
21 exposure concentrations and exposure durations to the AEGL-specified exposure durations.
22 AEGL values in accord with the supporting data are then selected.
23
24 THE RATIONALE FOR THE SELECTION OF THE TIME SCALING APPROACH SHOULD
25 INCLUDE:
26
27 1. A presentation of the rationale in the TSD text as follows: The relationship between
28 concentration and duration of exposure as related to lethality was examined by ten
29 Berge et al. (1986) for approximately 20 irritant or systemically-acting vapors and
30 gases. The authors subjected the individual animal data sets to probit analysis
31 with exposure duration and exposure concentration as independent variables. An
32 exponential function (C'x t = k), where the value of n ranged from 0.8 to 3.5 for
33 different chemicals was found to be an accurate quantitative descriptor for the
34 chemicals evaluated. Approximately 90 percent of the values of n range between
35 n=l and n=3. Consequently, these values were selected as the reasonable lower
36 and upper bounds of n. A value of n=l is used initially when extrapolating from
37 shorter to longer time periods because the extrapolated values represent the most
38 conservative approach in the absence of other data. Conversely, a value of n=3 is
39 used when extrapolating from longer to shorter time periods because the
40 extrapolated values are more conservative in the absence of other data. If
41 supporting data are available (description and references for data should be
42 included) indicating that the AEGL value initially extrapolated is (too high/too
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1 low), the AEGL value has been adjusted to reflect these (data, effects, etc.).
2 2. Presentation of the AEGL values or exposure concentrations extrapolated from data
3 using a value of n=l or n=3 and the adjustments made as a result of supporting
4 data..
5 3. Discussion of the adjustment(s) made and the rationale for making them.
6
7 2.7.8.4 Determining Concentration-Exposure Relationships when Data are
8 not Available to Derive a Value for n and no Supporting Data are Available.
9
10 In the absence of data to derive a value(s) of n and the absence of supporting data to
11 validate a value of n, the value of n=l will be selected for extrapolating from shorter to longer
12 exposure durations, and the value n=3 will be selected for extrapolating from longer to shorter
13 expoosure durations.
14
15 THE RATIONALE FOR THE SELECTION OF THIS TIME SCALING APPROACH SHOULD
16 INCLUDE-
17
18 1. A presentation of the rationale in the TSD text as follows: The relationship between
19 concentration and duration of exposure as related to lethality was examined by ten
20 Berge et al. (1986) for approximately 20 irritant or systemically-actmg vapors and
21 gases. The authors subjected the individual animal data sets to probit analysis
22 with exposure duration and exposure concentration as independent variables. An
23 exponential function (C1 x t = k), where the value of n ranged from 0.8 to 3.5 for
24 different chemicals was found to be an accurate quantitative descriptor for the
25 chemicals evaluated. Approximately 90 percent of the values of n range between
26 n=l and n=3. Consequently, these values were selected as the reasonable lower
27 and upper bounds of n to use when data are not available to derive a value of n. A
28 value of n=l is used when extrapolating from shorter to longer time periods
29 because the extrapolated values are conservative and therefore, reasonable in the
30 absence of any data to the contrary. Conversely, a value of n=3 is used when
31 extrapolating from longer to shorter time penods because the extrapolated values
32 are conservative and therefore reasonable in the absence of any data to the
33 contrary.
34
35 2.7.8.5 AEGL Exposure Values are Constant Across Time.
36
37 THE RATIONALE FOR THE SELECTION OF THE TIME SCALING APPROACH SHOULD
38 INCLUDE.
39
40 1. The data and mode or mechanism of action of the chemical and its effect on humans
41 that supports the assignment of constant AEGL values across exposure durations.
42
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1 2.8 GUIDELINES/CRITERIA FOR ADDRESSING SHORT TERM
2 EXPOSURE KNOWN AND SUSPECT CARCINOGENS
3
4 Cancer represents a serious adverse health effect. Historically, the concerns for
5 chemically-induced cancers were based on long-term, continuous exposure in controlled animal
6 studies or information derived from clinical or epidemiological studies of continuous or
7 long-term exposures in humans. To conduct quantitative risk assessments for cancer in humans,
8 mathematical (probit-log-dose) models were developed to utilize primarily animal bioassay data
9 and extrapolate from the higher experimental levels to assess the carcinogenic risk to humans at
10 low levels of chemical exposure. The evolution and usefulness of mathematical models to
11 accommodate new understanding or new concepts regarding the mechanisms of carcmogenesis
12 have been summarized in two publications by the National Research Council (NRC), National
13 Academy of Sciences (NAS): Developing Spacecraft Maximum Allowable Concentrations for
14 Space Station Contaminants (NRC, 1992a), and Guidelines for Developing Community
15 Emergency Exposure Levels for Hazardous Substances (NRC, 1993a).
16
17 In the United States, some state and federal regulatory agencies conduct quantitative risk
18 assessments on known or suspect carcinogens for continuous or long-term human exposure by
19 extrapolating downward in linear fashion from an upper confidence limit on theoretical excess
20 nsk (FDA, 1985; U. S. EPA, 1986). The values derived for a specified "acceptable" theoretical
21 excess risk to the U.S. human population, based on a lifetime of exposure to a carcinogenic
22 substance, have been used extensively for regulatory purposes.
23
24 There are no adopted state or federal regulatory methods for deriving such short-term
25 standards on the basis of carcinogenic risk because nearly all carcinogemcity studies in animals
26 and retrospective epidemiologic studies have entailed high-dose, long-term exposures. As a
27 result, there is uncertainty regarding the extrapolation from such studies in animals to the case of
28 brief human exposures. This is particularly problematical because the specific biological
29 mechanisms at the molecular, cell and tissue levels leading to cancer are often not known. It is
30 also possible that the mechanisms of injury that follow brief, high-dose exposures will often
31 differ from those following long-term exposures. To date U.S. federal regulatory agencies have
32 not established regulatory standards based on, or applicable to, less than lifetime exposures to
33 carcinogenic substances.
34
35
36 2.8.1 NRC/NAS Guidance
37
38 Guidance on the development of short-term exposure limits, published by the U. S.
39 National Research Council, National Academy of Sciences identified cancer as one of the
40 potential adverse health effects that may be associated with short-term inhalation exposures to
41 certain chemical substances (NRC, 1993a). This guidance document discusses and recommends
42 specific risk assessment methodologies for known genotoxic carcinogens and for carcinogens
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1 whose mechanisms are not well understood. As a first approximation the general approach
2 involves linear low-dose extrapolation from an upper confidence limit on theoretical excess nsk.
3 Further, the NRC/NAS guidance states that the determination of short-term exposure limits will
4 require the translation of risks estimated from long-term, continuous exposures to risks
5 associated with short-term exposures. Conceptually, the approach recommended for genotoxic
6 carcinogens is the method developed by Crump and Howe (1984) for applying the multistage
7 model to assessing carcinogenic risks based on exposures of short duration. In the case of non-
8 genotoxic chemical carcinogens, the NRC/NAS guidance acknowledges that the approach is less
9 clear because of the many different modes of action and the complexities of non-genotoxic
10 carcinogenic mechanisms and the paucity of data on chemical-specific mode of action. It is
11 acknowledged also that dose thresholds may exist for certain non-genotoxic, carcinogens. The
12 NRC guidance suggests that, in lieu of linear, low-dose extrapolation, approaches involving non-
13 carcinogen nsk assessment techniques or the pure-promoter model from the class of
14 initiation-promotion-progression models be used, provided a known mechanism of action can
15 justify the specific approach. The guidance emphasizes the importance of knowing the
16 underlying biological processes when using any such models.
17
18
19 2.8.2 Precedents for Developing Short-Term Exposure Limits Based on
20 Carcinogenicity
21
22 The NRC/NAS guidance (1993a) for assessing the excess risks of genotoxic carcinogens
23 is based on an adaptation of the work of Crump and Howe (1984) by the NAS1 Committee on
24 Toxicology (COT). The COT's adaptation of the methodology was made for developing
25 Emergency Exposure Guidance Levels (EEGLs) and Short-Term Public Exposure Guidance
26 Levels (SPEGLs) for the Department of Defense (NRC, 1986). EEGLs represent exposure levels
27 intended to be acceptable for the performance of specific tasks by military personnel during
28 emergency conditions lasting 1 to 24 hours. The SPEGLs represent acceptable ceiling
29 concentrations for a single, unpredicted short-term exposure to the public. The exposure periods
30 range from 1 hour or less to 24 hours and the SPEGLs are generally set at 0.1 to 0.5 times the
31 corresponding EEGL value.
32
33 The criteria and methods document prepared by the COT for the development of EEGLs
34 and SPEGLs indicates that theoretical excess carcinogenic risk levels in the range of 10"" to 10"6
35 are acceptable nsk levels (NRC, 1986). However, the document states that "The role of
36 short-term exposures in producing cancer is not clear .... any exposure to a carcinogen has the
37 potential to add to the probability of carcinogenic effects .... (but).... the effects of long or
38 repeated exposures could greatly overshadow brief exposures (up to 24h)." Additionally, the
39 COT states "The assumption that the carcinogenic response is directly proportional to total dose
40 is likely not to hold for all materials and all tissues that these matenals affect." However, these
41 concerns not withstanding, the COT set SPEGL values based on the carcinogenic nsk assessment
42 methodology previously mentioned for hydrazine, methyl hydrazine, and 1,1 -dimethyl hydrazme.
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1 In each case, the excess cancer nsk level used was 10"4 and the derived values were determined to
2 be lower than corresponding airborne concentration levels that were estimated to cause acute
3 toxicity. SPEGL values for exposure periods of less than 24 hours of other known or suspect
4 human carcinogens were not based on carcinogenicity. These chemicals included benzene,
5 tnchloroethylene, ethylene oxide, and lithium chromate.
6
7 The National Aeronautics and Space Administration (NASA) requested that the COT
8 develop spacecraft maximum allowable concentrations (SMACs) for space-station contaminants.
9 The COT published guidelines for the development of short-term and long-term SMACs (NRC,
10 1992a). Short-term SMACs refer to concentrations of airborne substances that will not
11 compromise the performance of specific tasks during emergency conditions lasting up to 24
12 hours. Because of NASA's concern for the health, safety, and functional abilities of space crews,
13 SMACs for exposure from 1 to 24 hours should not cause serious or permanent effects but may
14 cause reversible effects that do not impair judgement or interfere with proper responses to
15 emergencies. The long-term SMACs are designed to prevent deterioration in space crew
16 performance with continuous exposure for up to 180 days.
17
18 The guidelines for determining SMACs for carcinogens recommend the methods
19 proposed by Kodell, et. al., (1987) based on the linear multistage model. The level of excess nsk
20 used in the computation is 10"4. The guidelines suggest extrapolations of long-term (often
21 lifetime) exposures to shorter durations such as 1, 30, or 180 days and refer to a single-day
22 exposure as "the case of near instantaneous exposure." Further, the guidance states "It must be
23 remembered that extrapolation from a daily lifetime exposure level and conversion to an
24 instantaneous exposure level using.... (equations presented).... is an extreme case and is valid
25 only under the assumptions underlying the multistage theory of carcinogenesis." A review of the
26 first three volumes of published SMACs (35 chemicals) including ten (10) known or suspect
27 carcinogens, indicated that an assessment of excess risk for less than a 24 hour exposure period
28 was conducted on only one of the 10 carcinogenic substances. Carcinogenic assessments for
29 excess nsk were conducted on all 10 chemicals for 24 hours, as well as 7, 30, and 180 days. The
30 reasons provided in the COT technical support documents for not undertaking a risk assessment
31 on carcinogenic substances for exposure periods of less than 24 hours included: (1) "Data not
32 considered applicable to the exposure time (1 hr.)", (2) "Extrapolation to one hour exposure
33 duration produces unacceptable uncertainty in the values", and (3) "The COT model was not
34 used to calculate acceptable concentrations for exposures shorter than 24 hours" (NRC, 1992a).
35
36 As stated previously, to date no U.S. federal or state regulatory agency has promulgated
37 or established regulatory limits for single short-term (less than 24 hours) exposures based on
38 carcinogenic properties.
39
40
41 2.8.3 Scientific Basis for Credible Theoretical Excess Carcinogenic Risk
42 Assessments for Single Exposures of 8 Hours or Less
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1
2 The NRC/NAS guidance (NRC, 1993a) suggests that AEGLs can be developed using
3 carcinogenic risk assessment methodologies for exposure durations of 1 to 8 hours provided
4 adequate data are available. However, the guidance states that risk assessments on chemical
5 carcmogenicity in humans should be based on all relevant data and embody sound biological and
6 statistical principles. While some of the substances may be considered known human
7 carcinogens, most of the information is based on animal testing information. Additionally, since
8 the mode of action for animal carcinogens are not always the same with respect to biological
9 properties among animal species or strains and humans, a weight-of-evidence evaluation must be
10 carried out on a case-by-case basis. The weight of evidence evaluation considers comparative
11 metabolic disposition, pharmacokinetics parameters, routes of exposure, mechanisms of action,
12 and organ or species differences in response in animals and humans.
13
14
15 Uncertainties regarding lifetime theoretical excess carcinogenic risk assessments increase
16 as shorter durations of a single exposure are considered. Most of these concerns stem from the
17 reliance of both conclusions of carcmogenicity and quantitative assessments on long-term
18 exposures in humans in occupational settings or in test animals. Thus, calculations for
19 short-term risks require substantial extrapolation. At the same time, there are special concerns
20 and unresolved issues regarding short exposures that will require more relevant data before they
21 can be resolved. As evidenced from the actual application of these guidelines, the COT was
22 reluctant in most cases to develop quantitative carcinogenic risk assessments for less than 24
23 hours exposure in the development of SMACs.
24
25 To better understand the empirical data base for single exposures, the U.S. EPA funded a
26 study for the AEGL Program by Dr. Edward Calabrese of the University of Massachusetts to
27 review the published literature and assess the circumstances during which a single exposure of
28 short duration may cause cancer. This effort, referred to as the Single Exposure Carcinogen
29 Database, has been completed and represents a computerized summary that will enable the
30 evaluation of toxicological studies to assist in the NAC/AEGL Committee's assessment as to
31 whether a single exposure to a chemical under consideration for AEGL development could cause
32 tumor development. The data base will contain numerous parameters important to tumor
33 outcome and/or quality of the studies conducted. The database will contain approximately 5,500
34 "studies" or data sets involving approximately 500 chemicals from nearly 2000 references.
35
36 Although a brief overview of the Single Exposure Carcinogen Database has been
37 presented to the NAC/AEGL Committee, at the present time it is not known whether the data
38 available on single exposure of carcinogenic substances will be sufficient to justify their use in
39 the development of AEGL values. First, less than 20 of the 5,500 studies or data sets are based
40 on inhalation exposure. An initial review of the database indicates that only a limited number of
41 short-term cancer studies conducted by the inhalation route are available. Hence, route to route
42 extrapolations would need to be conducted in a manner that would not substantially weaken the
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1 conclusions. This could be done for certain substances using standard U. S. EPA or U. S. NAS
2 procedures if the toxicant is likely to cause tumors at a site other than the port of entry. If the
3 substance causes tumors at the site of application or port of entry in oral or parenteral protocols,
4 extrapolation to the inhalation route of exposure becomes problematic. For this reason the
5 NAC/AEGL Committee in most cases will likely continue to rely on data from long-term human
6 and animal studies as the basis for the quantitative cancer risk assessments it conducts for short-
7 term exposures of 8 hours or less.
8
9 The Single Carcinogen Database may prove to be useful in obtaining some important
10 information for AEGL development. The database shows that single exposure to various
11 chemical classes, using various species and strains of animals, can result in tumor formation.
12 Furthermore, chemicals can be selected from the database for which there is dose-response
13 information. Data and information from positive responses of the chemical in the database could
14 be compared between the single dose study and the long-term study.
15
16
17 2.8.4 Practical Issues of Using Quantitative, Carcinogenic Risk Assessments
18 for Developing AEGLs
19
20 In addition to the important scientific issues regarding carcinogenic risk assessments in
21 the development of AEGL values, there are important practical issues to be considered by
22 emergency planners and responders regarding AEGL values that would be based on possible
23 carcinogenic effects. The acceptable cancer risk for a lifetime exposure to known or suspect
24 human carcinogens ranges from 10"4 to 10"6 for the U.S. EPA and most other U.S. federal
25 regulatory agencies (U. S. EPA, 1991). The AEGL values, however, are designed for emergency
26 planning, response, and prevention to accidental releases from chemical accidents. Thus,
27 theoretical excess cancer risk may be accumulated in 30 minutes or in a few hours. In addition to
28 the individual risk of 10"4 to 10"6 one should also consider a measure of population based nsk.
29 Experts in the chemical accident field indicate that the typical U.S. population at risk during most
30 accidental chemical releases is in the range of 1,000 to 5,000. The actual number of individuals
31 exposed depends on many factors, such as population density, quantity released, release rate,
32 prevailing wind direction and velocity, terrain and ambient temperature to name a few.
33 Therefore, a population-based risk range of 10"4 to 10"6, assuming a credible carcinogenic
34 assessment can be made, appears to be approaching zero for a population of 1,000 to 5,000 or
35 higher. The consideration of population-based risks by using assessment methods designed for
36 individual risks has precedent in U.S. EPA assessments of new industrial chemicals under TSCA
37 (Toxic Substance Control Act) Section 5 and pesticide chemicals under FIFRA (Federal
38 Insecticide Fungicide and Rodenticide Act).
39
40 Implementation of emergency response procedures based on theoretical excess risk values
41 of 10"4 to 10 •* values may be problematical. For example, if such values were used, they would
42 be based on an anticipated increased cancer risk of 10"* to 10"6, a level consistent with the EPA's
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1 acceptable cancer nsk for lifetime exposures to known or suspect human carcinogens. However,
2 the nsks associated with evacuation and other response measures might possibly pose greater
3 risks of injury or perhaps death. Thus, setting AEGL values based on a cancer nsk may lead to
4 response measures that increase actual or total risk for the exposed population.
5
6 2.8.5 Current Approach of the NAC/AEGL Committee to Assessing Potential
7 Single Exposure Carcinogenic Risks
8
9 Based on the discussions and considerations presented in the earlier sections of m this
10 chapter on cancer risk assessment, the NAC/AEGL Committee has developed no AEGL values
11 based on carcinogenicity to date. In view of the great uncertainty of the assumptions used in
12 extrapolating from lifetime exposures to 8 hours or less, the paucity of single, inhalation
13 exposure data, the relatively small populations involved, and the potential risks associated with
14 evacuations and other response measures, the Committee does not believe their use in setting
15 AEGL values is justifiable at the present time.
16
17 However, the NAC/AEGL Committee will continue to identify and evaluate carcinogenic
18 data during the development of AEGLs on a chemical-by-chemical basis. The scientific
19 parameters which are used in this analysis are presented later in this section. In those cases
20 where, in the judgement of the Committee, it is appropriate, risk assessments for 10"4, 10"5, and
21 10"6 levels of cancer risk will be conducted. It is believed that information on known or suspect
22 human carcinogens should be provided to emergency planners and responders and made
23 available to the public at large even when such information is not used to set AEGL values.
24 Therefore, the Committee will continue to provide data and information on the carcinogenic
25 properties of chemicals in the Technical Support Documents, and in instances where the
26 appropriate data are available, develop quantitative cancer risk assessments at risk levels of 10"4,
27 10'5, and 10"6 in accordance with the NAS guidance (NAS, 1993a). The NAC/AEGL Committee
28 will attempt to limit potential cancer risk to 10"" or less where there is scientifically credible data
29 to support the risk based on a single exposure. If at some future date, substantial and convincing
30 scientific data become available that clearly establishes a relationship between a single, short-
31 term inhalation exposure to a chemical and the onset of tumors that are likely to occur in humans,
32 the carcinogenic risk in the development of the appropriate AEGL values will be considered.
33
34 2.8.5.1 Evaluation of Carcinogenicity Data
35
36 The evaluation of the carcinogenicity of a chemical in humans should be based on the
37 analysis of all relevant data, both positive and negative responses. Human epidemiologic and
38 clinical studies, as well as accidental exposure reports are considered and used to evaluate the
39 carcinogenic potential of a substance. In the absence of human data, long-term bioassay data
40 from controlled animal studies are used to derive theoretical excess carcinogenic nsk estimates
41 for exposed humans. The selection of data for estimating risk is based on the species and strain
42 considered most closely resembling the human response to provide the most accurate estimates.
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1 Data suggestive of a single exposure inducing a carcinogenic response, including related
2 mechanistic data that support such a possibility, will be considered. If highly convincing data
3 become available the Committee will consider the merits of the information in the development
4 of AEGL values. Weight should be given to those studies most relevant to estimating effects in
5 humans on a case-by-case basis. Data for assessing the strength of conclusions drawn from
6 controlled animal studies should include information on comparative metabolic pathways,
7 pharmacokinetics, routes of exposure, mechanisms of action, and organ or species differences in
8 response. In general, the NAC/AEGL Committee will follow a weight-of-evidence approach in
9 the evaluation of carcinogenicity that is consistent with the availability and biological variability
10 of the data and its relationship to the likelihood of effects in humans.
11
12 2.8.5.2 Methodology Used for Assessing the Carcinogenic Risk of a Single
13 Exposure
14
15 Guidance published in 1993a by the Committee on Toxicology, National Research
16 Council, National Academy of Sciences (NAS) states that the setting of AEGLs (CEELs) should
17 involve linear low-dose extrapolation from an upper confidence limit on excess risk for
18 genotoxic carcinogens and for carcinogens with mechanisms of action that are not well
19 understood. More specifically, the NAS guidance suggests an approach utilizing the methods
20 proposed by Kodell et al. (1987) based on multistage models. Although the NAS guidance states
21 that multistage models could be useful for setting AEGL values, the guidance acknowledges that
22 sufficient information may not be available to postulate the total number of stages in the cancer
23 process and the stage(s) that are dose-related. In these instances, the NAS guidance recommends
24 the use of the time-weighted-average dose where the instantaneous dose D at time t,, is assumed
25 to be the equivalent of the lifetime excess carcinogenic risk as daily dose D up to time t. This
26 equivalence is expressed by the equation D = d x t. As shown by Kodell et al. (1987), the actual
27 risk will not exceed the number of stages in the model (k). In instances where multistage models
28 can be used and prudence dictates conservatism, the NAS guidance suggests reducing the
29 approximation of D by an adjustment factor of 2 to 6, depending on the number of assumed
30 stages in the multistage model employed.
31
32 To date the NAC/AEGL Committee has evaluated excess theoretical risk at levels of 10"4,
33 10"5, and 10"* for a one-time exposure to known or suspect human carcinogens by determining the
34 total cumulative lifetime dose and applying Haber's law (concentration required to produce an
35 effect x time of exposure = constant) for exposure periods ranging from 8 hours to 30 minutes.
36 The resultant doses are then divided by an adjustment factor to account for the multistage nature
37 of carcinogens. See the example below.
38
39
40 2.8.5.2.1 The Determination of an Adjustment Factor Dealing with the Dose-
41 Dependent Stage of Carcinogenesis
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1
2 There is an extensive body of literature which deals with the concept of malignant tumor
3 development, progression of an initiated cell through successive stages and quantitative nsk
4 assessment. Two references, Crump and Howe 1984 and Kodell et al. 1987, are cited in the
5 NRC (1993a), publication. The concept has been further discussed in a number of publications
6 (Goddard et al, 1995; Murdoch et al., 1992; Murdoch and Krewski, 1988). This process is
7 referred to as a cell kinetic multistage model. There are several published variations of the basic
8 tenants in the model. If only one or more stages are dose-dependent and exposure is concentrated
9 m the dose-dependent stage, it is possible to underestimate nsk when the risk is based upon
10 lifetime exposure. For example, if the first stage is dose-dependent, and there is a single
11 exposure to an infant, the probability of cancer induction is maximized because the entire
12 lifetime of the individual is available for progression through the remaining stages in the
13 development of the cancer. If the same dose were given to an elderly person, the probability of
14 inducing cancer approaches 0 because there is insufficient time remaining in the life of that
15 individual for the initiated cell to progress through the subsequent stages to a malignant cancer.
16 Kodell et al. (1987) demonstrated that the underestimation of risk which is based upon a lifetime
17 of exposure will not exceed the number of stages in the multistage model. For this reason the
18 NRC (1986) recommends dividing the risk assessment based upon the lifetime exposure by a
19 factor between 2 and 6 to account for the number of stages in the multistage model applicable to
20 the particular chemical of concern.
21
22 In addition to the multistage model there have been a number of publications
23 investigating the two stage birth-death-mutation model (Morrison, 1987; Chen et al., 1988;
24 Murdoch and Krewski, 1988; Moolgavkar and Luebeck, 1990; Murdoch et al., 1992; Goddard et
25 al. 1995). This model is similar to the multistage model in which there are two stages. However,
26 the impact of the number of stem cells at the time of chemical exposure is considered as well as
27 the net growth rate of cells which have undergone the first stage of initiation. If the first stage
28 initiating event creates a cell which has a net growth rate greater than that of the stem cell, then
29 the risk of that initiating event will be greater than if the initiated cell grew at the same relative
30 rate as the stem cell. In this case, exposure early in life will cause a greater nsk than exposure
31 late in life. Conversely, exposure to a completer (effects only the second stage) late in life will
32 be more effective than early exposure because relatively more initiated cells are present. If this is
33 the only stage effected by the chemical, this situation is the same as 2 stages in the multistage
34 model. However, if the net growth of the initiated cells is 10 times the stem cell rate the relative
35 effectiveness of exposure late in life could be 10 fold (Murcoch and Krewski, 1988) Exposure
36 to promoters between the first and second stage event can have an impact by increasing the net
37 growth rate of initiated cells over that of stem cells. However, for maximum effectiveness the
38 exposure to promoters (generally considered to be non-genotoxic exposure) must encompass
39 multiple events (Chen et al., 1988; Murdoch and Krewski, 1988). Thus, the cancer risk
40 associated with a single exposure to a promoter should not be greater than predicted from
41 multiple exposures and no correction to the estimated risk need be made in this case.
42
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1 A major impact upon the risk assessment of the two stage model comes from carcinogen
2 exposure in the first stage in which the initiation event creates a cell with a greater net growth
3 rate than the stem cells. Modelers have considered a number of scenarios in which the net
4 growth rate of initiated cells varies from -10 to +10. The greatest increase in risk in the two stage
5 model comes about when the first stage is dose-dependent and the initiating event creates a cell
6 with a net growth rate of+10. In this case the increased risk is 10 fold (Murdoch and Krewski,
7 1988; Murdoch et al., 1992; Goddard et al., 1995)
8
9 Unfortunately, data on the biological plausibility of the maximum value for the net
10 growth rate of initiated cells is lacking (Murdoch et al, 1992). Major data needs for the two stage
11 birth-death-mutation model include the number of stem cells at different times of the life cycle,
12 how fast they divide and differentiate and how they respond to chemical exposure in terms of cell
13 division and mutation rate. This information is also needed for the initiated cell populations
14 (Moolgavkar and Luebeck, 1990). Because of this major uncertainty, the projections made for
15 the two stage model remain more speculative than for the multistage model in which there is
16 general agreement that the number of stages should not exceed 6.
17
18 For the above reasons, unless there is evidence to the contrary, the multistage model is
19 used when estimating risks for short-term exposures from lifetime exposure studies. In all of the
20 above referenced publications on the multistage model, the maximum number of stages modeled
21 is 6.
22
23 AEGL values are applicable to humans in all stages of life so the maximum risk to an
24 infant must be considered. In this case, the concentration based upon a lifetime exposure study is
25 divided by 6 unless there is evidence that the chemical is a later stage carcinogen or operates by a
26 mechanism different from the multistage model. The NAC/AEGL Committee will use the
27 divisor of 6 in agreement with the 1993a NAS guidance on the development of short-term
28 exposure limits which states that a factor of 6 represents a conservative adjustment factor for a
29 near-instantaneous exposure.
30
31 2.8.5.3 Summary of Cancer Assessment Methodology used by the
32 NAC/AEGL Committee
33
34 The U.S. EPA ql * values that are listed on the Integrated Risk Information System (IRIS)
35 or the GLOBAL86 generated slope factor values (Howe et al., 1986) are used to compute lifetime
36 risk levels. These values are based upon the guidance in U. S. EPA 1986. The U.S. EPA
37 (1996a) proposed methodology will be considered in the future. These values are used to
38 compute the concentration for a single exposure to the time penods of interest. As discussed in
39 the beginning of this section, these values are typically divided by 6 to account for early exposure
40 to a carcinogen in which the first stage is dose-dependent or late exposure to a carcinogen in
41 which the last stage is dose-dependent. If there is information about the number of stages
42 required for development of the cancer or the stage which is dose-dependent, the divisor will be
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1 modified accordingly. An example of a Carcinogenicity Assessment is given in Appendix I.
2
3 The cancer evaluation includes a weight of evidence discussion which considers the
4 following factors:
5
6 • Less evidence of carcmogenicity from a short-term exposure
7 -No evidence for human carcmogenicity (may or may not lend
8 support of cancer induction from a single exposure but an
9 important consideration)
10 • Lifetime or long-term exposure necessary to elicit cancer
11 • Positive response only at very high doses
12 • Neoplasia appears reversible (when treatment is discontinued)
13 • Appears to be a "threshold" carcinogen
14
15 • Greater evidence of carcinogenicity from a short-term exposure
16 • Proven human carcinogen (may or may not lend support of cancer
17 induction from a single exposure but an important consideration)
18 • Short time-to-tumor
19 • Evidence for cancer from one to a few exposures
20 • Positive response at low doses
21 • Complete carcinogen
22 • Irreversible (when treatment is discontinued)
23 • Strongly mutagenic
24
25
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1 2.9 GUIDELINES/CRITERIA FOR MISCELLANEOUS PROCEDURES
2 AND METHODS
3
4 2.9.1 Mathematical Rounding of AEGL Values
5
6 Given the uncertainties involved in generating AEGL values it could be argued that only
7 one significant figure should be used. However, because of a number of considerations
8 discussed below, numbers will be rounded to 2 significant figures. For example, 1.5, or 23, or
9 0.35. The value 7.35 would be rounded to 7.4.
10
11 Trivial differences in numbers can give large differences if only one significant figure is
12 used. For example, values of 14.9 and 15.1 would yield AEGL values of 10 and 20 respectively.
13 This is a two fold difference for a very small difference in computed AEGL values. Values of
14 18,14, 11, and 6 ppm for 30 minute, 1,4, and 8 hours would give values of 10, 10,10, and 20
15 ppm for the time points. It would not give the appearance of a logical progression. These
16 numbers will be used in exposure models to make decisions. The use of 2 significant figures will
17 allow for a more reasonable progression when different exposure scenarios are considered.
18
19 Two significant figures may seem overly precise when values less than 1 ppm are
20 presented since those levels may be difficult to measure. However, the AEGL-2 values will
21 often be used to compare with ambient air dispersion modeling projections for planning
22 purposes. In this case the use of 2 vs 1 significant figure could have an impact. Other rounding
23 off schemes may be used on a case by case basis with a justification.
24
25
26 2.9.2 Multiplication of Uncertainty Factors
27
28 When uncertainty factors are multiplied together the NAC/AEGL Committee often
29 multiplies two uncertainty factors of 3. Since the value 3 represents the geometric mean of 10
30 and 1, the actual number is 3.16. Therefore, the product of two different uncertainty factors is
31 not 3 times 3 but 3.16 times 3.16, which equals 10. For simplicities sake 3 times 10 is
32 represented by 30.
33
34
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i 3. FORMAT AND CONTENT OF TECHNICAL
2 SUPPORT DOCUMENTS
3
4 The Technical Support Document (TSD) is the compilation of all relevant data and
5 information from all key studies/references and the most important supporting studies/references
6 for both human exposures and laboratory animals. Additionally, this support document
7 addresses all methodologies employed in the derivation of the AEGL values in question and the
8 rationale and justifications for why certain data were used in the derivation and why certain
9 studies or data were not selected, why specific methodologies and adjustment factors were or
10 were not used, the scientific evidence supporting the rationale and justification, and the
11 appropnate references to the published scientific literature or sources of unpublished data and
12 information.
13
14 Major components to the TSD include 1) the Preface which includes definitions of the
15 AEGL tiers; 2) an Executive Summary which includes a concise summary of toxicity
16 information on the chemical, rationales used for time scaling and selection of uncertainty factors,
17 and a table of AEGL values for the three tiers as well as key references; 3) the main body of the
18 TSD which includes a detailed discussion of the items in listed in 2) and; 4) a Denvation
19 Summary Table which includes a list and discussion of the key data elements and rationale used
20 to derive the AEGL values.
21
22 EDITORIAL CONVENTIONS
23
24 • Concentrations will be expressed in the units used in the publication. If the data in the
25 publication or other data sources, were expressed in ppm, enter only ppm values. If data,
26 were expressed in mg/m3 or other units, then state the concentration as expressed in the
27 data source and add ppm in parentheses.
28
29 • References to footnotes should be superscript and lower case.
30
31 3.1 FORMAT AND CONTENT OF THE TECHNICAL SUPPORT
32 DOCUMENT (TSD)
33
34 PREFACE
35
36 The AEGL tiers are defined in the Preface of each TSD. See Chapter 2.1 for definitions
37 of AEGL-1, 2, and 3.
38
39 TABLE OF CONTENTS
40 Major headings in the text, tables and figures should be marked with the word processor
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1 indexing tool so that the Table of Contents can be generated by the computer. A sample Table of
2 Contents is presented in Appendix E.
3
4 EXECUTIVE SUMMARY
5
6 The Executive Summary should include:
7
8 The name and CAS number of the chemical being reviewed.
9
10 A brief description of the substance, its physical properties, and uses.
11
12 A brief statement or overview of the toxicology, including the extent of the
13 data/information retrieved and reviewed, highlights of the most important research and strengths
14 and weaknesses of the database. Discuss data on human exposures and data on laboratory
15 animals.
16
17 A brief summary (1 paragraph for each AEGL tier) of the key study (with references), the
18 data used, and the denvation of the AEGL values. Each summary will include:
19
20 Information on the toxic endpoints and exposure levels used as the basis for
21 deriving the AEGL values.
22 Exposure level (If the data m the publication are expressed in ppm enter only ppm
23 values. If data were expressed in mg/m3 or other units then state the
24 concentration as expressed in the publication and add ppm in parentheses).
25 Exposure period.
26 Why this time-concentration point was selected (include effects observed or not
27 observed, relate to the AEGL level, etc.).
28 The species and number of animals used.
29 Consistency with human data if appropnate.
30 The reference to the key study.
31 A statement of uncertainty factors and modifying factors used or not used and why
32 a specific value was chosen.
33 A statement of the time scaling method used and why it was selected (include the
34 rationale for the value of n in the time scaling equation).
35
36 A brief statement regarding carcinogenicity, if appropnate.
37
38 A brief statement on the adequacy of the data (see Section 2.3.3 of this SOP Manual).
39
40 A summary table of draft/proposed AEGL values with:
41 Values presented in ppm with mg/m in parentheses.
42 A rationale and reference for AEGL-1, -2, and -3.
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1 Reasons for no AEGL value.
2
3 References
4
5 A sample Executive Summary is presented in Appendix F.
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1 OUTLINE OF THE MAIN BODY OF THE TECHNICAL SUPPORT
2 DOCUMENT
3
4 1. INTRODUCTION
5 • General information regarding occurrence, production/use, physical/chemical data
6 (table for physical chemical data)
7
8 2. HUMAN TOXICITY DATA
9 2.1 Acute Lethality - include anecdotal case reports if pertinent
10 2.2 Nonlethal Toxicity
11 2.2.1 Acute Studies - include anecdotal case reports if pertinent
12 2.2.2 Epidemiologic Studies
13 2.3 Developmental/Reproductive Toxicity
14 2.4 Genotoxicity
15 2.5 Carcinogemcity - include EPA and IARC classifications
16 2.6 Summary - weight-of-evidence approach
17
18 As appropriate, data are tabulated within sections and/or in summary
19
20 3. ANIMAL TOXICITY DATA
21 3.1 Acute Lethality - include species/strain, number of animals, exposure
22 concentrations/durations, mortality rates/ratios, time to death. (The order of
23 animals shown should be used. If no data are available for a species, the number
24 should be used for the next species discussed.)
25 3.1.1 Nonhuman Primates
26 3.1.2 Dogs
27 3.1.3 Rats
28 3.1.4 Mice
29 3.1.5 Guinea Pigs
30 3.1.6 Rabbits
31 3.1.7 Other Species
32
33 • Sections to include relevant studies (potential key studies and supporting data) or
34 provide overall picture of toxicity data as appropriate
35 • Third-level headers to vary dependent upon available data; exclusion of header to
36 imply no data
37
38 3.2 Nonlethal Toxicity - include species/strain, no. of animals, exposure
39 concentrations/durations, critical effects, time course data, etc. (The order of
40 animals shown should be used. If no data are available for a species, the number
41 should be used for the next species discussed.)
42 3.2.1 Nonhuman Primates
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1 3.2.2 Dogs
2 3.2.3 Rats
3 3.2.4 Mice
4 3.2.5 Guinea Pigs
5 3.2.6 Rabbits
6 3.2.7 Other Species
7
8 • Sections to include relevant studies (potential key studies and supporting data) or
9 provide overall picture of toxicity data as appropriate
10 • Third-level headers to vary dependent upon available data; exclusion of header to
11 imply no data
12
13 3.3 Developmental/Reproductive Toxicity
14 3.4 Genotoxicity
15 3.5 Carcinogenicity
16 3.6 Summary - weight-of-evidence approach
17
18 Tabulation of data as appropriate within sections and/or in summary
19
20 4. SPECIAL CONSIDERATIONS
21 4.1 Metabolism and Disposition - general background; interspecies and
22 individual variabilities especially as they pertain to AEGL derivation
23 4.2 Mechanism of Toxicity - general background; interspecies and individual
24 variabilities especially as they pertain to AEGL derivation
25 4.3 Structure-Activity Relationships - data relevant to filling data gaps on the
26 chemical
27 4.4 Other Relevant Information
28 4.4.1 Species Variability
29 4.4.2 Concurrent Exposure Issues (potentiation, etc)
30
31 • Third-level headers to vary dependent upon available data; exclusion of header
32 implies no data
33
34
35 5. DATA ANALYSIS FOR PROPOSED AEGL-1
36 5.1 Summary of Human Data Relevant to AEGL-1 - general summary
37 description of selected key and supporting study(ies) if available
38 5.2 Summary of Animal Data Relevant to AEGL-1 - general summary
39 description of selected key and supporting study(ies) if available
40 5.3 Derivation of AEGL-1 - key study, critical effect, dose/exposure, uncertainty
41 factor application/justification, temporal extrapolation, assumptions, confidence,
42 consistency with human data if appropriate
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1 6. DATA ANALYSIS FOR PROPOSED AEGL-2
2 6.1 Summary of Human Data Relevant to AEGL-2 - general summary
3 description of selected key and supporting study(ies) if available
4 6.2 Summary of Animal Data Relevant to AEGL-2-general summary description of
5 selected key and supporting study(ies) if available
6 6.3 Derivation of AEGL-2 - key study, critical effect, dose/exposure, uncertainty
7 factor application/justification, temporal extrapolation, assumptions, confidence,
8 consistency with human data if appropriate
9
10 7. DATA ANALYSIS FOR PROPOSED AEGL-3
11 7.1 Summary of Human Data Relevant to AEGL-3 - general summary
12 description of selected key and supporting study(ies) if available
13 7.2 Summary of Animal Data Relevant to AEGL-3 - general summary
14 description of selected key and supporting study(ies) if available
15 7.3 Derivation of AEGL-3 - key study, critical effect, dose/exposure,
16 uncertainty factor application/justification, temporal extrapolation,
17 assumptions, confidence, consistency with human data if appropriate
18
19 8. SUMMARY OF PROPOSED AEGLS
20 8.1 AEGL Values and Toxicity Endpoints
21 8.2 Comparison with Other Standards and Criteria (summarized in text and presented
22 in a table - see SOP Appendix K for an example)
23 8.3 Data Adequacy and Research Needs (for content see Section 2.3.3 of this
24 SOP Manual)
25
26 9. REFERENCES CITED
27
28 10. APPENDICES
29
30 APPENDDC A (Derivation of AEGL Values) See SOP Appendix G for an example
31 APPENDDC B (Time Scaling Calculations) See SOP Appendix H for an example
32 APPENDDC C (Carcinogenicity Assessment) See SOP Appendix I for an example
33 APPENDDC D (Derivation Summary) See SOP Appendix J for specific format and an example
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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APPENDIX D: Format for Derivation Summary
DERIVATION SUMMARY
(CAS NUMBER; CHEMICAL NAME)
10 minutes
ppm
AEGL-1(OR 2 OR 3) VALUES
30 minutes
ppm
1 hour
ppm
4 hours
ppm
8 hours
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 Adequacy3:
a Elements that should be included in the Data Adequacy Section 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.
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1 3.2 Potential Inclusion of Graphic Descriptions of Data
2
3 Graphic descriptions of important and relevant data can be helpful in identifying,
4 understanding and comparing data in terms of similarities and differences, degree of variation,
5 and trends among the values cited. Well prepared graphs provide the reader with a rapid
6 overview of dose-response relationships in terms of both airborne concentrations and exposure
7 periods among vanous studies and various species. The graphs should supplement the data
8 tables but not replace them. They can be placed in the body of the document or in an appendix.
9 Below are examples of presentations of graphic data.
10
11 It is very difficult to keep different times and the toxicity values for those times in one's
12 head when reading the Technical Support Document. Comparisons are difficult to make between
13 times because the values vary according to the time. The old adage "A picture is worth a
14 thousand words" is especially appropriate when analyzing inhalation data. A particularly useful
15 way to present the data is presented in Table 3.2-1 and Figure 3.2-1. It is based upon the concept
16 of placing the toxic response into severity categories (Hertzberg and Miller, 1985; Hertzberg and
17 Wymer, 1991; and Guth et al., 1991). In Table 3.2-1 the seventy categories are chosen to fit into
18 definitions of the AEGL level health effects. In the table the category severity definitions for the
19 column headings are 0 = No effect; 1 = Discomfort; 2 = Disabling; 3 = Lethal; NL = Did not die
20 at a lethal cone (at an experimental concentration in which some of the animals died and some
21 did not, the NL label refers to the animals which did not die); AEGL or C = AEGL or censored
22 (severity category could not be established). The effects which will place an experimental result
23 into a particular category will vary according to the spectrum of data available on a specific
24 chemical and the effects from exposure to that chemical. When the exposure concentration is
25 placed into the appropriate column, the graph in Figure 3.2-1 is generated. The doses often span
26 a number of orders of magnitude, especially when human data exist. Therefore the concentration
27 is placed on a log scale. Note that the AEGL values are designated as a triangle without an
28 indication to their level. The AEGL-3 is higher than the AEGL-2, which is higher than the
29 AEGL-1.
30
31 This type of plot is useful for a number of reasons and can be used to address the
32 following questions:
33
34 • Are the AEGL levels protective?
35
36 • Are the AEGL-3 levels below the concentration causing death in experimental
37 animals? If the answer is no then the question should be raised about the
38 appropriateness of the AEGL-3 value. Is the AEGL-3 level appropriate and the data
39 point anomalous, or should the AEGL-3 value be lowered?
40
41 • Similar questions should be asked about the AEGL-1 and AEGL-2 values.
42
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 • Are there data points which appear to be outliers? Why are they outliers? Should they be
2 considered in the development of AEGL values or discarded because of faulty
3 experimental technique.
4
5 • Does the spread of data points for a particular seventy category indicate major differences
6 between species or are the results from different species congruent.
7
8 • Is the time scaling algorithm reasonable consistent with the data? For example, does the
9 plot of the AEGL-3 values using the derived or chosen value of n in the equation Cn x t =
10 k parallel the slope of the lethality data. Similar questions can be asked about the AEGL-
11 1 and AEGL-2 plots.
12
13 • Is there evidence that a different time scaling factor should be used for the AEGL-2?
14
15 • What are the most appropnate data points to use for the time scaling?
16
17
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
TABLE 3.2-1 GROUPING DATA INTO CATEGORIES FOR PLOTTING
Reference
chemical
NAC/AEGL-i
NAC/AEGL-1
NAC/AEGL-1
NAC/AEGL-1
NAC/AEGL-2
NAC/AEGL-2
NAC/AEGL-2
NAC/AEGl-2
NAC/AEGL-3
NAC/AEGL-3
NAC/AEGL-3
NAC/AEGL-3
Baelurn et a).. 1965
: Wilson 1943
Wilson 1943
Wilson 1943
Ukalelal., 1993
Lee at al.. 1988
Gamberale and Huttengren, 1972
Gamberale and Hultengren, 1972
von Oettingen etal., 1942
von Oettingen el at., 1942
yon Oettlngen el al., 1942
. Baetum et al.. 1990
: Echeverriaelel.. 1991
Andersen et al., 1963
RahiH et at.. 1996
Dfcketal., 1984
Cherry el al., 1983
: Carpenter etal., 1976
Piyoretal.. 1978
Pryor etal., 1978
Cameron et al.. 1938
Cameron el al.. 1938
Kojima and Kobayashl. 1973
Kpjirna and Kobayashl, 1973
Cameron el al.. 1938
Carpenter el al.. 1976
Carpenter el al., 1976
Smyth etal., 1969
' Smyth et a!.. 1969
Bonnet et at.. 1979
Bonnet et el.. 1979
Svirbely etal.. 1943
Svkbely etal., 1943
Moser and Batster, 1985
Moser and Balster, 1985
Moser and Balster. 1985
Moser and Batster. 1985
. Moser and Balster. 1985
, Moser and Balster, 1985
Exp : Grp Species Sex
hu
,hu
4rat
mouse
' mouse
\ mouse
mouse
mouse
1 mouse
, mouse
mouse
; mouse
897
634
317
224
100
200
200
500
500
100
100
300
700
200
200
600
800
100
150
40
100
100
100
80
220
26700
26700
24400
24400
15000
15000
12200
8800
8800
4000
4000
6940
6940
5320
5320
38465
38465
21872
21872
19018
19018
GpSize
sensory Imtatton, steeplness, Intoxication, manual dexterity, color discrimin
headache, lassitude, anorexia '
headache, nausea, (ncoordination, reaction lime
headache, nausea, Incoodination, reaction time
headache, nausea. incoordinaUon. reaction time and palpitation, extreme wi
weight toss, dizziness, headache, tightness In chest dimmed vision
weight toss, dizziness, headache.
reaction time :
perceptual speed !
muscular weakness, confusion. Impaired coordination, end dilated pupils
severe incoodination, confusion, dilated pupils, nausea, and extreme fatigue
severe (ncoordination, confusion, dilated pupils, nausea, and extrerne fatigue
loss of self-control, rnuscuiar weakness, extreme fatigue, nausea, and bone i
sensory irritation, altered temp, perception, headache, dizziness, and score:
performance on spatial and neurobehavtoral tasks, headache, eye Irritation.
no effect/sensory Irritation, odor [
no effect/sensory Irritation, odor :
latency on a neurobehavioral task [not a btotoglcalr/ relevant neufobehavioi
accuracy on visual-vigilance test (not a biologically
no impairment on neurobehavioral tasks
, sensory threshold
LC50
ILC50
60% mortality
, 6O% mortality
80% mortality
80% mortality
100% mortality
iLCSO
UC50
, 16% mortality
16% mortality
: LCSO
iLCSO
LCSO
jLCSO
LCSO
LCSO
; LCSO
LC50
ILC50
,LC50
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Q.
Q.
100.0 -
10.0
Chemical Toxicity - TSD All Data
Toluene
60 120 180 240
Minutes
300 360 420
480
o
no or minimal effect
discomfort
disabling
did not die @ lethal cone
AEGL or censored
1 FIGURE 3.2-1 PLOT OF CATEGORIES OF DATA
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i 4. CURRENT ADMINISTRATIVE PROCESSES AND
2 PROCEDURES FOR THE DEVELOPMENT OF AEGL
3 VALUES
4
5 The primary purpose of the AEGL Program and the NAC/AEGL Committee is to develop
6 guideline levels for short-term exposures to airborne concentrations of acutely toxic, high priority
7 chemicals. These Acute Exposure Guideline Levels (AEGLs) are needed for a wide range of
8 planning, response, and prevention applications. These applications may include many U. S.
9 initiatives such as the EPA's SARA Title ni Section 302-304 emergency planning program, the
10 CAAA Section 112(r) accident prevention program, and the remediation of Superfund sites
11 program; the DOE environmental restoration, waste management, waste transport, and fixed
12 facility programs; the DOT emergency waste response program; the DOD environmental
13 restoration, waste management, and fixed facility programs; ATSDR health consultation and nsk
14 assessment programs; NIOSH/OSHA regulations and guidelines for workplace exposure; State
15 CAA Section 112(b) programs and other state programs; the U. S. Chemical Manufacturer's
16 Association (CMA) Chemtrec program; and other chemical emergency programs in the U. S.
17 private sector. From an international perspective, it is anticipated that the AEGLs will find a
18 wide range of applications in chemical emergency planning, response, and prevention programs
19 in both the public and private sectors of member-countries of the Organization for Economic and
20 Cooperation Development (OECD). It is hoped that the AEGLs also will be used by other
21 countries in the international community
22
23 A principal objective of the NAC/AEGL Committee is to develop the most scientifically
24 credible, acute (short-term) exposure guideline levels possible within the constraints of data
25 availability, resources and time. This includes highly effective and efficient efforts in data
26 gathering, data evaluation and data summarization, fostering the participation of a large cross-
27 section of the relevant scientific community, both nationally and internationally, and the adoption
28 of procedures and methods that facilitate consensus-building for AEGL values within the
29 NAC/AEGL Committee.
30
31 Another principal objective of the NAC/AEGL Committee is to develop AEGL values for
32 approximately 400 to 500 acutely hazardous substances within the next ten (10) years.
33 Therefore, the near-term objective is to increase the level of production of AEGL development to
34 approximately forty (40) to fifty (50) chemicals per year without exceeding budgetary limitations
35 or compromising the scientific credibility of the values developed.
36
37 To reach these objectives, the NAC/AEGL Committee must adopt and adhere to specific
38 processes and procedures both scientifically and administratively. This is accomplished through
39 the development and maintenance of a comprehensive "Standing Operating Procedures" Manual
40 (SOP Manual) that addresses both the scientific and administrative procedures required to
41 achieve the objectives of the NAC/AEGL Committee previously mentioned. This section is
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1 devoted to those administrative processes and procedures deemed necessary to achieve the
2 AEGL Program objectives.
3
4 4.1 COMMITTEE MEMBERSHIP AND ORGANIZATIONAL
5 STRUCTURE
6
7 The NAC/AEGL Committee is comprised of representatives of U. S. federal, state and
8 local agencies, and organizations in the pnvate sector that derive programmatic or operational
9 benefits from the AEGL values. This includes federal representatives from the Environmental
10 Protection Agency (EPA), the Department of Energy (DOE), the Agency for Toxic Substances
11 and Disease Registry (ATSDR), the National Institute for Occupational Safety and Health
12 (NIOSH), Occupational Safety and Health Administration (OSHA), the Department of
13 Transportation (DOT), the Department of Defense (DOD), the Center for Disease Control
14 (CDC), the Food and Drug Administration (FDA), and the Federal Emergency Management
15 Agency (FEMA). States providing committee representatives include New York, New Jersey,
16 Texas, California, Minnesota, Illinois, Connecticut, and Vermont. Private companies with
17 representatives include Allied Signal Corporation, Exxon Corporation, and Olm Chemical
18 Company. Other organizations with representatives include the American Industrial Hygiene
19 Association (AIHA), American College of Occupational and Environmental Medicine
20 (ACOEM), American Association of Poison Control Centers (AAPCC), and the American
21 Federation of Labor - Congress of Industrial Organizations (AFL-CIO). In addition, the
22 committee membership includes individuals from academia, a representative of environmental
23 justice, and other organizations in the private sector. A current list of the NAC/AEGL
24 Committee members and their affiliations is shown in Appendix A of this SOP manual. At
25 present, the Committee is comprised of 32 members.
26
27 Recently, the Organization of Economic and Cooperation Development (OECD) and
28 various OECD member countries have expressed an interest in the AEGL Program. Several
29 OECD member countries such as Germany and the Netherlands have been participating in the
30 Committee's activities and actively pursuing formal membership on the NAC/AEGL Committee.
31 It is envisioned that the Committee and the AEGL Program in general will progressively expand
32 its scope and participation to include the international community.
33
34 The Director of the AEGL Program has the overall responsibility for the entire AEGL
35 Program and the NAC/AEGL Committee and its activities. A Designated Federal Officer (DFO)
36 is responsible for all administrative matters related to the Committee to insure that it functions
37 properly and efficiently. These individuals are not voting members of the Committee. The
38 NAC/AEGL Committee Chair is appointed by EPA and is selected from among the committee
39 members. In concert with the Program Director and the DFO, the Chair coordinates the activities
40 of the Committee and also directs all formal meetings of the Committee. From time to time, the
41 members of the Committee serve as Chemical Managers and Chemical Reviewers in a
42 collaborative effort with assigned scientist-authors (non-Committee members) to develop AEGLs
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1 for a specific chemical. These groups of individuals are referred to as the AEGL Development
2 Teams and their function is discussed in Section 4.8 of this manual..
3
4 4.2 THE AEGL DEVELOPMENT AND PEER REVIEW PROCESS
5
6 The process that has been established for the development of the AEGL values is the
7 most comprehensive ever employed for the determination of short-term exposure limits for
8 acutely toxic chemicals. A summary of the overall process is presented in diagram form in
9 Figure 4.2-1. The process consists of four basic stages in the development and status of the
10 AEGLs and they are identified according to the review level and concurrent status of the AEGL
11 values. They include (1) "Draft" AEGLs, (2) "Proposed" AEGLs, (3) "Interim" AEGLs and (4)
12 "Final" AEGLs. The entire development process can be descnbed by individually describing the
13 four basic stages in the development of AEGL values.
14
15
16 Stage 1: "Draft" AEGLs
17
18 This first stage begins with a comprehensive search of the published scientific literature.
19 Attempts are made to mobilize all relevant, non-published data through industry trade
20 associations and from individual companies in the private sector. A more detailed description of
21 the published and unpublished sources of data and information utilized is provided in Section 2.3
22 of this document which addresses search strategies. The data are evaluated following the
23 guidelines published in the NRC/NAS guidance document and this SOP manual and selected
24 data are used as the basis for the derivation of the AEGL values and the supporting scientific
25 rationale. Data evaluation, data selection, and the development of a technical support document
26 are all performed as a collaborative effort among the Staff Scientist at the organization which
27 drafts Technical Support Documents, the Chemical Manager, and two Chemical Reviewers.
28 This group is referred to as an "AEGL Development Team". NAC/AEGL Committee members
29 are specifically assigned this responsibility for each chemical under review. Hence, a separate
30 team comprised of different Committee members is formed for each chemical under review. The
31 product of this effort is a technical support document (TSD) that contains "Draft" AEGLs. The
32 Draft TSD is subsequently circulated to all other NAC/AEGL Committee members for review
33 and comment prior to a formal meeting of the Committee. Revisions to the initial TSD and the
34 "Draft" AEGLs are made up to the time of the NAC/AEGL Committee meeting scheduled for
35 formal presentation and discussion of the AEGL values and the documents. Following
36 deliberations during the committee meeting, an attempt is made to reach consensus, or the
37 minimum of a two-thirds majority of a quorum present, to elevate the AEGLs to "Proposed"
38 status. If agreement cannot be reached, the Committee conveys its issues and concerns to the
39 AEGL Development Team and further work is conducted by this group. After completion of
40 additional work, the chemical is resubmitted for consideration at a future meeting. If a consensus
41 or two-thirds majority vote of the Committee cannot be achieved because of inadequate data
42 unrelated to the completeness of the data search, the chemical becomes a candidate for
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1 appropriate toxicity studies.
2
3
4 Stage 2: "Proposed" AEGLs
5
6 Once the NAC/AEGL Committee has reached a consensus, or the minimum two-thirds
7 majority vote, on the AEGL values and supporting rationale, they are referred to as "Proposed"
8 AEGLs and are published in the Federal Register for a thirty (30) day review and comment
9 penod. Following publication of the "Proposed" AEGLs in the Federal Register, the Committee
10 reviews the public comments, addresses and resolves relevant issues and seeks a consensus or
11 minimum two-thirds majority of those present on the Committee on the original or modified
12 AEGL values and the accompanying scientific rationale.
13
14
15 Stage 3: "Interim" AEGLs
16
17 Following resolution of relevant issues raised through public review and comment and
18 subsequent approval of the Committee, the AEGL values are classified as "Interim". The
19 "Interim" AEGL status represents the best efforts of the NAC/AEGL Committee to establish
20 exposure limits and the values are available for use as deemed appropnate on an interim basis by
21 federal and state regulatory agencies and the private sector. The "Interim" AEGLs, the supporting
22 scientific rationale, and the TSD are subsequently presented to the U. S. National Academy of
23 Sciences (NAS/AEGL Subcommittee) for review and concurrence. If concurrence cannot be
24 achieved, the NAS/AEGL Subcommittee will submit its issues and concerns to the NAC/AEGL
25 Committee for further work and resolution.
26
27
28 Stage 4: "Final" AEGLs
29
30 When concurrence by the NAS/AEGL Subcommittee is achieved, the AEGL values are
31 considered "Final" and published by the U. S. NAS. Final AEGLs may be used on a permanent
32 basis by all federal, state and local agencies and private sector organizations. It is possible that
33 from time to time new data will become available that challenges the scientific credibility of
34 "Final" AEGLs. If this occurs, the chemical will be resubmitted to the NAC/AEGL Committee
35 and recycled through the review process.
36
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1
2
Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
FIGURE 4.2-1 THE AEGL DEVELOPMENT PROCESS
AEGL Development Process
Non-published.
Non-peer Reviewed
Industry Data
Published
Literature
Search
Other
Data / Information
Sources
Special
Toxiaty
Studies
AEGL Dei
Team-
Saentist.
Manager.
Revie
/elopment
ORNL
Chemical
Chemical
iwers
Technical
Support
Documents
(TSDs)
Distribute Draft or
Proposed TSDs /
AEGLs to
Committee
Members
4-
NAC/AEGL
Committee Meeting to Discuss
Draft or Proposed AEGLs
-NO-
NAC/AEGL
Committee
Consensus on
Proposed
AEGLs
Major Changes
FR Publication I
NAS-NRC AEGL
Subcommittee
NAS-NRC
Publication of
Final AEGLs
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1 4.3 OPERATION OF THE COMMITTEE
2
3 The NAC/AEGL Committee meets formally four (4) times each year for two and one-half
4 (2-1/2) days. The meetings are scheduled for each quarter of the calendar year and are generally
5 held in the months of March, June, September, and December. Based on overall cost
6 considerations, the meetings are generally held in Washington, D.C. However, from time to
7 time, committee meetings may be held at other locations for justifiable reasons.
8
9 At least 15 days prior to the committee meetings, a notice of the meeting is published in
10 the Federal Register together with a list of chemicals and other matters to be addressed by the
11 Committee and provides dates, times and location of the meetings. The agenda is finalized and
12 distributed to committee members approximately one week prior to the meeting. The agenda
13 also is available to other interested parties at that time, upon request, through the Designated
14 Federal Officer (DFO).
15
16 All NAC/AEGL Committee meetings are open to the public and interested parties may
17 schedule individual presentations of relevant data and information by contacting the DFO to
18 establish a date and time. Relevant data and information from interested parties also may be
19 provided to the Committee through the DFO during the period of development of the Draft
20 AEGLs so that it can be considered during the early stage of development. Data and information
21 also may be submitted during the Proposed and Interim stages of AEGL development as well.
22
23 The NAC/AEGL Committee meetings are conducted by the Chair who is appointed by
24 the U.S. Environmental Protection Agency in accordance with the Federal Advisory Committee
25 Act (FACA). At the time of the meeting, both the Chair and all other committee members will
26 have received the initial draft and one or more revisions of the Technical Support Document
27 (TSD) and "Draft", "Proposed", or "Interim" AEGL values for each chemical on the agenda.
28 Reviews, comments, and revisions are continuous up to the time of the meeting and committee
29 members are expected to be familiar with the "Draft", "Proposed", or "Interim" AEGLs,
30 supporting rationale, and other data and information in each TSD and to participate in the
31 resolution of residual issues at the meeting. Procedures for the AEGL Development Teams and
32 the other Committee members regarding work on AEGLs in the Proposed or Interim status are
3 3 similar to those for Draft AEGLs.
34
35 All decisions of the NAC/AEGL Committee related to the development of Draft,
36 Proposed, Interim, and Final AEGLs and their supporting rationale are made by consensus or a
37 minimum of two-thirds (2/3) majority of a quorum of committee members. A quorum of the
38 NAC/AEGL Committee is defined as fifty-one percent (51%) or more of the total NAC/AEGL
39 Committee membership m attendance.
40
41 The highlights of each meeting are recorded by the scientists who draft the Technical
42 Support Documents and written minutes are prepared, ratified and maintained in the
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1 Committee's permanent records. Deliberations of each meeting also are tape-recorded and stored
2 in the Committee's permanent records by the Designated Federal Officer (DFO) for future
3 reference as necessary.
4
5 All Proposed AEGL values and supporting scientific rationale are published in the
6 Federal Register. Review and comment by interested parties and the general public are requested
7 and encouraged. The Committee's response to official comments on Federal Register notices on
8 Proposed AEGL values consists of the discussions and deliberations that take place during the
9 Committee meetings for elevating the AEGLs from "Proposed" to "Interim" status. This
10 information is reflected on the tapes and in the minutes of the meetings and will be maintained
11 for future reference. Changes in the Proposed AEGL values and the supporting rationale that are
12 considered appropriate by the NAC/AEGL Committee based on Federal Register Comments will
13 be made prior to elevating the AEGLs to Interim status.
14
15 As previously mentioned a "Standing Operating Procedures" Workgroup (SOP
16 Workgroup) was established in March, 1997 to document, summarize, and evaluate the various
17 procedures, methodologies, and guidelines employed by the Committee in the gathering and
18 evaluation of scientific data and information and the development of the AEGL values. The SOP
19 Workgroup performs a critical function by continually providing the Committee with detailed
20 information on the Committee's interpretation of the NAS guidelines and the approaches the
21 Committee has taken in the derivation of each AEGL value for each chemical addressed. This
22 documentation enables the Committee to continually assess the basis for its decision-making,
23 insure consistency with the NAS guidelines, and maintain the scientific credibility of the AEGL
24 values and accompanying scientific rationale. This ongoing effort is continuously documented
25 and is identified as the "SOP Manual".
26
27 4.4 ROLE OF THE DIRECTOR OF THE AEGL PROGRAM
28
29 The Director has the overall responsibility for the AEGL Program, including the
30 NAC/AEGL Committee and its interface with other programs and organizations in the public and
31 private sectors nationally and internationally. More specifically he is responsible for the overall
32 management of the AEGL Program as it relates to:
33
34 • NAC/AEGL Committee and AEGL Program objectives of scientific credibility, quality,
35 productivity and cost effectiveness.
36
37 • AEGL Program resource needs.
38
39 • Fostering a collaborative spirit among Committee members, Staff Scientists of the
40 organization which drafts Technical Support Documents, and interested parties from all
41 participating organizations in the public and private sectors.
42
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1 • Matters related to the U. S National Academy of Sciences.
2
3 • Expanding the scope of the AEGL Program, including international participation.
4
5 4.5 ROLE OF THE DESIGNATED FEDERAL OFFICER
6
7 The Designated Federal Officer (DFO) serves as the administrative officer of the
8 Committee to insure that all operations, processes, and general precedures function properly and
9 efficiently. The DFO serves as an executive secretariat to the NAC/AEGL Committee and has
10 the responsibility for:
11
12 • Effective communication/coordination with NAC/AEGL Committee members, the
13 Committee Chair, the organization which drafts Technical Support Documents, and
14 interested parties in the public and private sector.
15
16 • Day-to-day administrative management of the NAC/AEGL Committee with respect to the
17 agenda for future meetings, distribution of Technical Support Documents and other
18 correspondence with Committee members, maintenance of meeting minutes, tapes of
19 meetings and other important Committee records, funding and other financial matters and
20 Committee membership matters.
21
22 • Administrative management of quarterly meetings including responsibility for all Federal
23 Register Notices related to NAC/AEGL Committee activities, minutes and decision
24 making records, meeting venues, facilities, and equipment, as well as the assurance that
25 the meetings are held in compliance of the Federal Advisory Committee Act (FACA).
26
27 • Ensuring compliance with the FACA on all matters that extend beyond the quarterly
28 meetings such as the submission of appropriate reports to the U.S. Office of Management
29 and Budget (OMB) and the Library of Congress.
30
31 4.6 ROLE OF THE NAC/AEGL COMMITTEE CHAIR
32
33 The NAC/AEGL Committee Chair is appointed by EPA as specified in the Federal
34 Advisory Committee Act (FACA) and is selected from the Committee membership. The Chair's
35 responsibilities include conducting and directing specific activities to insure the effective and
36 efficient conduct of business by the Committee:
37
38 • Support in the planning and preparation of upcoming meetings by collaborating with the
39 AEGL Program Director, the DFO and the organization which drafts Technical Support
40 Documents, including the review of the meeting agenda.
41
42 • Manage the NAC/AEGL Committee meetings in an effective and efficient manner to
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1 insure completion of the agenda for each meeting.
2
3 • Attempt to reach a consensus of the Committee by msunng adequate time for
4 presentation of differing opinions and focusing on the major issues to break deadlocks or
5 stalemates.
6
7 • Participation in scientific matters on AEGLs as related to the U. S. National Academy of
8 Sciences.
9
10 • Participate with the AEGL Progam Director and the DFO in evaluating and improving
11 Committee activities and expanding the scope of the AEGL Program.
12
13 4.7 CLASSIFICATION OF THE STATUS OF AEGL VALUES
14
15 Draft AEGL Values are AEGL values proposed by the AEGL Development Team (see
16 section 4.8) prior to the full NAC/AEGL Committee discussion and approval.
17
18 Proposed AEGL Values are AEGL values which have been formally approved and
19 elevated to "Proposed" status by a consensus or two-thirds majority of a quorum of the
20 NAC/AEGL Committee.
21
22 Interim AEGL Values are AEGL values formally approved by the NAC/AEGL
23 Committee and elevated to "Interim" status after publication in the Federal Register, response to
24 comments, and appropriate adjustments made by the Committee. These "Interim" AEGLs are
25 forwarded to the Committee on Toxicology, National Research Council, National Academy of
26 Sciences for review and comment by the Subcommittee on Acute Exposure Guideline Levels
27 (NAS/AEGL Subcommittee).
28
29 Final AEGL Values are AEGL values which have been reviewed and finalized by the U.
30 S. National Academy of Sciences (NRC NAS) and are published inder the auspices of the NAS.
31
32
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1 4.8 ROLE OF AEGL DEVELOPMENT TEAMS
2
3 Each AEGL Development Team consists of a Staff Scientist from the organization which
4 drafts Technical Support Documents and a Chemical Manager and two Chemical Reviewers,
5 who are members of the NAC/AEGL Committee. The primary function of the NAC/AEGL
6 Development Team is to provide the NAC/AEGL Committee with Draft AEGL values and a
7 Technical Support Document (TSD) containing relevant data and information on the chemical
8 and the derivation of the Draft AEGLs. The Staff Scientist provides the initial effort by
9 identifying and preliminarily evaluating available data from varied resources including on-line
10 literature databases, other databases, journal reviews, secondary source reviews, unpublished
11 data, federal and state documents and other sources, including accounts of accidents in the
12 workplace or in the community (see Section 2.3). Interaction takes place among the Chemical
13 Manager, the Chemical Reviewers, and the Staff Scientist during the development of the TSD
14 and the Draft AEGL values. The resulting document is then distributed and reviewed by
15 Committee Members prior to a formal meeting and attempts are made to resolve issues of
16 concern expressed by Committee Members prior to distribution of the TSD to the NAC/AEGL
17 Committee and formal presentation and discussion at a Committee meeting.
18
19 4.8.1 Role of a Chemical Manager
20
21 The Chemical Manager has the overall responsibility for the development of the "Draft",
22 "Proposed", and "Interim" AEGL values and their presentation to the rest of the NAC/AEGL
23 Committee and to the NAS Committee for evaluation of "Final" AEGLs. The Chemical Mangers
24 serve on a rotating basis as the Committee's principal representative on the AEGL Development
25 Team for a specific chemical. The Chemical Manager in turn selects two Committee members to
26 serve as Chemical Reviewers.
27
28 The Chemical Manager collaborates with the Staff Scientist and the Chemical Reviewers
29 on the development of the AEGLs, the supporting rationale, and the Technical Support
30 Documents. In instances where the Chemical Manager has accepted the responsibilities, taken
31 ownership for the AEGL values, resolved scientific issues, and led the discussions with
32 Committee members, the Committee has moved rapidly toward the development of a consensus.
33 Where the Chemical Manager's role has been less decisive, the Committee's deliberations have
34 been more protracted, less focused, and highly inefficient. Implicit in the description of the
35 Chemical Manager's role is the expectation that he/she will work with the Staff Scientist, the
36 Chemical Reviewers, and the rest of the Committee members to develop exposure guidance
37 levels that are appropriate and scientifically credible. It is expected that the Chemical Manager
38 will achieve a consensus within the AEGL Development Team on the issues related to the
39 development of the AEGL values prior to the meeting of the full Committee. Further, as time
40 permits, the Chemical Manager will attempt to resolve issues raised by individual Committee
41 Members prior to the scheduled Committee meeting.
42
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1 The following is a summary outline of specific activities and responsibilities of the
2 Chemical Manager within the NAC/AEGL Committee:
3
4 • To participate as the leader of the ad hoc AEGL Development Team.
5
6 • To select and utilize two Chemical Reviewers as technical support.
7
8 • To provide direct support to the Staff Scientist assigned to the chemical in the
9 development of the Technical Support Documents (TSD), the "Draft" AEGL values,
10 and the supporting rationale.
11
12 • To serve as liaison among Committee members and the Staff Scientist during the
13 development of draft AEGL values and the Technical Support Document.
14
15 • To resolve scientific issues prior to the Committee meetings such as:
16 Completeness of data gathering (published/unpublished).
17 Selection of key and supporting data (following guidelines).
18 Interpretation of data.
19 Credibility of AEGL values (use of appropriate methodology).
20 Validity of scientific rationale for AEGLs.
21 Other (as necessary for development of scientifically credible AEGL values).
22
23 • To seek consensus of Committee members by resolving issues with individual Committee
24 members prior to the Committee meeting.
25
26 • To frame important scientific issues related to the chemical and the AEGLs for
27 presentation at the Committee meeting (i.e. significant issues that cannot be resolved
2 8 before the meeting).
29
30 • To participate in the presentation of AEGL values, supporting rationale and important
31 issues at the Committee meeting in collaboration with the Staff Scientist.
32
33 • To oversee appropriate follow-up activities:
34 Revisions as appropriate (AEGL values, TSD, rationales).
35 Toxicity testing.
36 FR Notice comments (conversion of "Proposed" to "Interim" values).
37 Preparation of AEGL proposal to NAS.
38
39 4.8.2 Role of a Chemical Reviewer
40
41
42 • To participate as a member of the ad hoc AEGL Development Team
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1
2 • To conduct a detailed review of the assigned document and key references.
3
4 • To assist the Chemical Manager and Staff Scientist in evaluating the data, the candidate
5 AEGLs, and the scientific rationale for their support.
6
7 • To participate actively in discussions of the document during AEGL Committee
8 meetings.
9
10 • To stand in for the Chemical Manager if and when he/she is unable to perform his/her
11 duties.
12
13 4.8.3 Role of an Staff Scientist at the Organization which Drafts Technical
14 Support Documents
15
16 The Staff Scientist has the primary responsibility for data gathering, data evaluation,
17 identification of potential key data and supporting data, identification of potential methodologies,
18 calculations, and extrapolations, and the preparation of the Technical Support Document. This
19 includes the following tasks:
20
21 • To participate as a member of the ad hoc AEGL Development Team
22
23 • To participate with the others on the AEGL Development Team in the development of
24 "Draft" AEGL values and their presentation at the NAC/AEGL Committee meetings
25
26 • To prepare Technical Support Documents (TSD) in a timely manner and make
27 appropriate revisions based upon discussions and decisions of the AEGL
28 Development Team and later based upon the discussions and decisions of the
29 NAC/AEGL Committee.
30
31 • To develop and maintain a data file on the chemical substance.
32
33 • To present a summary of the data and information on the substance in collaboration with
34 the Chemical Manager at the AEGL Committee meetings.
35
36 • To provide continuing support to an assigned chemical through the "Draft," "Proposed,"
37 "Interim," and "Final" stages of AEGL development, including preparation for, and
38 response to, Federal Register Notice review and comment.
39
40 4.9 ROLE OF NAC/AEGL COMMITTEE MEMBERS
41
42
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1 • To review all Technical Support Documents in advance of meetings and to work out
2 issues with the Chemical Manager at the earliest possible date. The importance of
3 resolving issues before Committee meetings is greatly emphasized to increase the
4 efficiency and productivity of the meetings.
5
6 • To circulate Technical Support Documents to other qualified scientists within their
7 respective organizations or other organizations as appropriate to broaden the
8 evaluation by the scientific community.
9
10 • To serve as experts in specific areas or on specific scientific issues (e.g. sensitive human
11 sub-populations, etc.) as a member of an ad hoc task force under the SOP Workgroup
12 chair.
13
14 • To volunteer as a Chemical Manager at least once a year and to select chemicals where a
15 significant contribution to the development of credible AEGL values can be made
16 based on special knowledge, expertise, or past experience.
17
18 • To assist in the application of AEGLs in appropriate programs within the organization the
19 Committee member represents.
20
21 • To make suggestions for modification or expansion of the Chemical Priority List by
22 providing lists of chemicals and supporting rationale for their priority to the
23 Designated Federal Officer (DFO).
24
25 • To attend all scheduled NAC/AEGL Committee meetings and to participate in the
26 discussions and decision making of all AEGL values. AEGL values are approved or
27 disapproved by a vote of 2/3 majority of a quorum, with a quorum defined as the
28 presence of more than 50 percent of the total NAC/AEGL Committee membership..
29
30 4.10 ROLE OF THE ORGANIZATION THAT DRAFTS TECHNICAL
31 SUPPORT DOCUMENTS
32
33 The role of the organization that drafts the TSDs is to provide the principal technical
34 support in gathering and evaluating the relevant scientific data and information from all sources,
35 including preparation and/or revision of the Technical Support Documents (TSDs) following the
36 guidance provided in this SOP Guidance Manual. As a member of the AEGL Development
37 Team, to collaborate with the Chemical Manager and Chemical Reviewers in the preparation and
38 distribution of "Draft" AEGLs, the supporting rationale, and the TSDs for the NAC/AEGL
39 Committee members. Provide continuing technical and administrative support to assigned
40 chemicals through the "Draft," "Proposed," "Interim," and "Final" stages of AEGL development,
41 with revisions based upon the consensus or majority opinion of the NAC/AEGL Committee and
42 the NAS/AEGL Subcommittee.
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1 To provide the Staff Scientists, the administrative personnel, and the facilities and
2 equipment necessary for data gathering, maintenance of databases, dissemination of relevant
3 information to Committee members, presentations or co-presentations (with Chemical Managers)
4 at the NAC/AEGL Committee meetings, development and revisions of TSDs, preparation of
5 submissions to the Federal Register, summarization of Federal Register (F.R.) comments and
6 identification of important scientific issues, presentations to the Committee on F.R. comments,
7 and preparation of technical information to be entered on the Internet.
8
9 To distribute the TSDs to companies and other interested parties as directed by the DFO
10 after review and comment by the NAC/AEGL Committee. This distribution to interested parties
11 will be only by request through the Designated Federal Officer (DFO). This initial distributed
12 version will be without the AEGL values and the rationale used to derive them and will occur
13 between 1-14 days prior to the Committee meeting.
14
15
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i 5. REFERENCES
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1 Leisenring, W. Ryan, L. 1992. Statistical properties of the NOAEL. Regulatory Toxicol. and
2 Pharmacol. 15:161-171.
3
4 Lerman, J., Robinson, S., Willis, M.M., Gregory, G.A. 1983. Anesthetic requirements for
5 halothane in young children 0-1 months and 1-6 months of age. Anesthesiology. 59:
6 421-424.
7
8 Linn.W.S., Avol E.L., Peng R. C., Shamoo, D.A., Hackney, J.D. 1987. Replicated dose-response
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12 Litchfield Jr., J.T., Wilcoxon, F. 1948. A simplified method of evaluating dose-effect
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14
15 Lu, F.C. 1979. Assessments at an international level of health hazards to man of chemicals
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18
19 Lu, F.C. 1988. Acceptable daily intake: Inception, evolution, and application. Regul. Toxicol.
20 Pharmacol. 8:45-60.
21
22 Lu, F.C., Sielken, R.L. 1991. Assessment of safety/nsk of chemicals: Inception and evolution of
23 the ADI and dose-response modeling procedures. Toxicol. Lett. 59:5-40.
24
25 Marsoni, S., Ungerleider, R.S., Hurson, S.B., Simon, R.M., Hammershaimb, L.D. 1985.
26 Tolerance to antineoplastic agents in children and adults. Cancer Treat. Rep. 69:
27 1263-1269.
28
29 Matthew, M.T.V., Mainland, P., Gin, T. 1996. Minimum alveolar concentration of halothane
30 and enflurane are decreased in early pregnancy. 85: 782-786.
31
32 McLellan, R.K., Becker, C.E., Borak, J.B., Coplein, C., Ducatman, A.M., Favata, E.A., Green,
33 J.F., Herzstein, J., Holly, A.T., Kalnas, J., Kulig, K., Kipen, H.M., Logan, D.C., Mitchell,
34 F.L., McKinnon, H.W., Roberts, M.A., Russi, M., Sawyer, H.J., Sepulveda, M.J., Upfal,
35 M.J., Zepeda, M.C. 1999. ACOEM Position statement. Multiple chemical sensitivities:
36 Idiopathic environmental intolerance. J. Occup. Environ. Med. 41(11):940-942.
37
38 Meek, M.E., Newhook, R., Liteplo, R.G., Armstrong, V.C. 1994 Approach to assessment of
39 risk to human health for priority substances under the Canadian Environmental Protection
40 Act. Environ. Carcinogen. Ecotoxicol. Rev. C12 (2). 105-134.
41
42 Melton, C.E. 1982. Effect of long-term exposure to low levels of ozone: a review. Aviat. Space
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1 Environ. Med. 53: 105-111.
2
3 Moolgavkar,S.H., Luebeck.G. 1990. Two-event model for carcmogenesis: Biological,
4 mathematical, and statistical considerations. Risk Analysis. 10:323-341
5
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7 Health Perspect. 76-133-140.
8
9 Murdoch, D.J., Krewski, D. 1988. Carcinogenic risk assessment with time-dependent exposure
10 patterns. Risk Analysis. 8. 521-530.
11
12 Murdoch, D.J., Krewski, D., Wargo, J. 1992. Cancer risk assessment with intermittent
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14
15 NAS (National Academy of Sciences). 1977. Drinking Water and Health. Washington, D.C.,
16 National Academy Press.
17
18 NRC (National Research Council). 1983. Risk Assessment in the Federal Government.
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20
21 NRC (National Research Council). 1986. Criteria and Methods for Preparing Emergency
22 Exposure Guidance Level (EEGL), Short-Term Public Emergency Guidance Level
23 (SPEGL), and Continuous Exposure Guidance Level (CEGL) Documents. Washington,
24 D.C., National Academy Press. Appendix F.
25
26 NRC (National Research Council). 1992a. Guidelines for Developing Spacecraft, Maximum
27 Allowable Concentrations for Space Station Contaminants. Washington, D.C., National
28 Academy Press.
29
30 NRC (National Research Council). 1992b. Multiple Chemical Sensitivities: A Workshop.
31 Washington, D.C., National Academy Press.
32
33 NRC (National Research Council). 1992c. Biologic Markers in Immunotoxicology.
34 Washington, D.C., National Academy Press.
35
36 NRC (National Research Council), Committee on Toxicology. 1993a. Guidelines for
37 Developing Community Emergency Exposure Levels for Hazardous Substances.
38 Washington, DC., National Academy Press.
39
40 NRC (National Research Council). 1993b. Pesticides in the Diets of Infants and Children.
41 Washington, D.C., National Academy Press.
42
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1 NRC (National Research Council). 1994. Science and Judgement in risk Assessment.
2 Washington, D.C., National Academy Press.
3
4 NTP (National Toxicology Program). 1987. Toxicology and carcinogenesis studies of ethylene
5 oxide (CAS No. 75-21-8) in B6C3F, Mice (Inhalation Studies). NTP TR 326, NIH Publ.
6 No. 88-2582, U.S. Department of Health and Human Services, Research Triangle Park,
7 NC.
8
9 OECD. OECD's Guidelines for the Testing of Chemicals.
10 http://www.oecd.org/ehs/test/testlist.htm
11
12 P/CC (President/Congressional Commission on Risk Management). 1997. Final Report. Vol 2.
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14
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18
19 Plummer, J.L., Hall, P., de la Ilsey, A.H., Jenner, M.A., Cousins, M J. 1990. Influence of
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22
23 Pohl, H.R., Abdin, H.G. 1995. Utilizing uncertainty factors in minimal risk levels derivation.
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25
26 Rail, D.P. 1969. Difficulties in extrapolating the results of toxicity studies in laboratory animals
27 to man. Environ. Res. 2:360-367.
28
29 Renwick, A.G. 1993. Data derived safety factors for the evaluation of food additives and
30 environmental contaminants. Food Additives and Contaminants. 10(3):275-305.
31
32 Rhomberg, L.R., Wolff, S.K. 1998. Empirical scaling of single oral lethal doses across
33 mammalian species based on a large database. Risk Analysis. 18: 741-753.
34
35 Rinehart, W.E., Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in
36 sublethal exposures to phosgene. Ind. Hyg. J. 25: 545-553.
37
38 Rondinelli, R.C.A., Koemg, J.Q., Marshall.S.G. 1987. The effects of sulfur dioxide on
39 pulmonary function in healthy nonsmoking male subjects aged 55 years and older. Am.
40 Ind. Hyg. Assoc. J. 48:299-303.
41
42 Roger, L. J., Kehrl H.R., Hazucha M., Horstman, D.H. 1985. Bronchoconstriction in asthmatics
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1 exposed to sulfur dioxide during repeated exercise. J. Appl. Physiol. 59: 784-791
2
3 Savolamen, H., Kurppa, K., Pfaffli, P., Kivisto, H. 1981. Dose-related effects of dichloromethane
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5
6 Sheenan, D.M., Gaylor, D.W. 1990. Divisions of reproductive & developmental toxicology and
7 biometry. Teratology 41:590-591 (abstract).
8
9 Simon, R.A. 1986. Sulfite sensitivity. Ann. Allergy 56:281-288.
10
11 Spiegel, M.R. 1996. Schaum's Outline of Theory and Problems of Statistics. Second Edition.
12 McGraw-Hill:519 pages.
13
14 Stevens, W.C., Dolan, W.M., Gibbons, R.T., White, A., Eger, E.I., Miller, R., deJong, R.H.,
15 Elashoff, R.M. 1975. Minimum alveolar concentration (MAC) of isoflurane with and
16 without nitrons oxide in patients of various ages. Anesthesiology. 42: 196-200
17
18 ten Berge, W.F. Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response
19 relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials.
20 13:301-309.
21
22 Truhaut, R. 1991. The concept of the acceptable daily intake: an historical review Food
23 Additives and Contaminants. 8:151-162.
24
25 U.S. DHHS (Department of Health and Human Services). 1995. Multiple Chemical Sensitivity-
26 A Scientific Overview. ATSDR (Agency for Toxic Substances and Disease Registry). F.
27 Mitchell, Ed. National Academy Press.
28
29 U. S. EPA (Environmental Protection Agency). Health Effects Test Guidelines.
30 http://www.epa.gov/docs/OPPTS_HarmonizeoV
31
32 U. S. EPA (Environmental Protection Agency). 1980. Guidelines and methodology used in the
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35
36 U. S. EPA (Environmental Protection Agency). 1986. Guidelines for carcinogen nsk
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38
39 U. S. EPA (Environmental Protection Agency). 1987. Technical Guidance for Hazards
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41 Environmental Protection Agency in conjunction with the Federal Emergency
42 Management Agency and the Department of Transportation.
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 U. S. EPA (Environmental Protection Agency). 1991. National primary drinking water
2 regulations; Final rule. 40 CFR Parts 141,142, and 143. Federal Register 56(20) January
3 30, 1991:3526-3597.
4
5 US. EPA (Environmental Protection Agency). 1992. Draft report: A cross-species scaling
6 factor for carcinogen risk assessment based on equivalence of mg/kg^Vday. Federal
7 Register 57(109): 24152-24173.
8
9 U. S. EPA (Environmental Protection Agency). 1993. Styrene. The Integrated Risk Information
10 System (IRIS), http://epa.gov/iris/.
11
12 U. S. EPA (Environmental Protection Agency). 1994a. Glossary of Risk Assessment Related
13 Terms, February 1, 1994. Integrated Risk Information System (IRIS).
14 http://www.epa.gov/ngispgm3/iris/glossary.htm
15
16 U.S. EPA (Environmental Protection Agency). 1994b. Methods for Derivation of Inhalation
17 Reference Concentrations and Application of Inhalation Dosimetry. EPA/600/8-90/066F.
18 October 1994.
19
20 U. S. EPA (Environmental Protection Agency). 1995a. The Use of the Benchmark Dose
21 Approach in Health Risk Assessment. Risk Assessment Forum. EPA/630/R-94/007. February
22 1995.
23
24 U. S. EPA (Environmental Protection Agency). 1995b. Methyl mercury. The Integrated Risk
25 Information System (IRIS), http://epa.gov/iris/.
26
27 U. S. EPA (Environmental Protection Agency). 1996a. Proposed Guidelines for Carcinogen
28 Risk Assessment. EPA/600/P-92/003C. April 1996.
29
30 U. S. EPA (Environmental Protection Agency). 1996b. Aroclor 1016. The Integrated Risk
31 Information System (IRIS), http://epa.gov/ins/.
32
33 U. S. EPA (Environmental Protection Agency). 2000. National Center for Environmental
34 Assessment. Benchmark Dose Software Draft Beta Version 1.2.
35 http://www.epa.gov/ncea/bmds.htm.
36
37 U S. PHS (Public Health Service). 1998. A report on multiple chemical sensitivity (MCS). A
38 predecisional draft. The Environmental Health Policy Committee. (The Interagency
39 Workgroup on Multiple Chemical Sensitivity). U.S. Public Health Service. August 24.
40
41 van Stee, E.W., Boorman, G. A., Moorman, M.P., Sloane, R.A. 1982. Time varying
42 concentration profile as a determinant of the inhalation toxicity of carbon tetrachlonde.
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1 J.Toxicol. Environ. Health 10: 785-795.
2
3 Vettorazzi, G. 1976. Safety factors and their application in the lexicological evaluation. In the
4 evaluation of Toxicological Data for the Protection of Public Health. Pergamon,
5 Oxford:pp. 207-223.
6
7 Vettorazzi, G. (1980) Handbook of International Food Regulatory Toxicology. Evaluations,
8 Spectrum, New York, Vol. I:pp. 66-68.
9
10 Vocci, F., Farber, T. 1988. Extrapolation of animal toxicity data toman. Regulatory Toxicol.
11 and Pharmacol. 8: 389-198.
12
13 Weil, C. 1972. Statistics vs safety factors and scientific judgment in the evaluation of safety for
14 man. Toxicol. Appl. Pharmacol. 21:454-463.
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i APPENDIX A. NAC/AEGL PROGRAM PERSONNEL.
2
3 ADMINISTRATIVE MANAGEMENT:
4 Roger Garrett Director, AEGL Program, U.S. Environmental Protection Agency
5 Paul S. Tobin Designated Federal Officer, NAC/AEGL Committee,
6 U.S. Environmental Protection Agency
7
8 NAC/AEGL COMMITTEE MEMBERS AND THEIR AFFILIATIONS
9 George Rusch Chair, Honeywell, Inc.
10 Ernest Falke Chair, SOP Workgroup, U S. Environmental Protection Agency
11
12 George AlexeefF Air Toxicology & Epidemiology California EPA
13 Steven Barbee Olin Corporation
14 Lynn Beasley U.S. Environmental Protection Agency (5204G)
15 David Belluck Minnesota Pollution Control Agency
16 Robert Benson U.S. Environmental Protection Agency Region VIE
17 Jonathan Borak American College of Occupational and Environmental Medicine
18 (ACOEM)
19 William Bress Vermont Department of Health
20 George Cushmac Department of Transportation
21 Larry Gephart Exxon Mobil Biomedical Sciences, Inc.
22 Doan Hanson Brookhaven National Laboratory (DOE Alternate)
23 John P. Hinz Armstrong Laboratory/Occupational and Environmental Health Directorate (AF)
24 Jim Holler Agency for Toxic Substances Disease Registry
25 Thomas C. Homshaw Illinois Environmental Protection Agency
26 Nancy K. Kim New York State Department of Health
27 Loren Koller College of Veterinary Medicine, Oregon State University
28 Dr. Glenn Leach U.S. Army Center for Health Promotion & Preventive Medicine
29 Mark A. McClanahan Centers for Disease Control & Prevention
30 John Morawetz International Chemical Workers Union
31 Richard Niemeier National Institute for Occupational Safety and Health
32 Marinelle Payton Harvard Medical School
33 Zarena Post Texas Natural Resource Conservation Commission
34 George Rodgers American Association of Poison Control Centers (AAPCC)
35 Michelle Schaper Mine Safety and Health Administration
36 Robert Snyder Environmental and Occupational Health Sciences Institute
37 Thomas J. Sobotka Food and Drug Administration HFS-507
38 Kenneth Still Medical Service Corp/U.S. Navy
39 Judy Strickland U.S. Environmental Protection Agency (Pending)
40 Richard Thomas International Ctr for Environmental Hlth
41 Thomas Tuccinardi U.S. Department of Energy
42
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30,2000
1 PAST COMMITTEE MEMBERS
2 Kyle Blackman Federal Emergency Management Agency
3 Luz Claudio Mt. Sinai Medical Center
4 Benjamin Jackson Consultant
5 William Pepelko U.S. Environmental Protection Agency
6 Patricia Talcott University of Idaho, Dept of Food Science & Toxicology
7
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i APPENDIX B. PRIORITY LISTS OF CHEMICALS
2
3 A master list of approximately 1,000 acutely toxic chemicals was initially compiled
4 through the integration of individual priority lists of chemicals submitted by each U. S. federal
5 agency placing a representative on the Committee. The master list was subsequently reviewed by
6 individuals from certain state agencies and representatives from organizations in the private
7 sector and modified as a result of comments and suggestions received. The various priority
8 chemical lists were compiled separately by each federal agency based on their individual
9 assessments of the hazards, potential exposure, risk, and relevance of a chemical to their
10 programmatic needs.
11
12 On May 21, 1997, a list of 85 chemicals was published in the Federal Register. This list
13 identified those chemicals to be of highest priority across all U. S. federal agencies and
14 represented the selection of chemicals for AEGL development by the NAC/AEGL Committee for
15 the first two to three years of the program. The Committee has now addressed these chemicals
16 and they are presently in the Proposed, Interim, or Final stages of development. Certain
17 chemicals did not contain an adequate database for AEGL development and, consequently, are on
18 hold pending decisions regarding further toxicity testing. This initial "highest" priority list of 85
19 chemicals is shown below.
20
21 A second "working list" of approximately 100 priority chemicals is being selected from
22 the original master list, or from new, high priority candidate chemicals submitted by U. S.
23 Agencies and organizations and by OECD member countries that are planning to participate in
24 the AEGL Program. Although "working lists" will be published in the U. S. Federal Register
25 and elsewhere from time-to-time to indicate the NAC/AEGL Committee's agenda, the priority of
26 chemicals addressed, and , hence, the "working list" is subject to modification if priorities of the
27 NAC/AEGL Committee or individual stakeholder organizations, including international
28 members, change during that period.
29
30
31 Initial List of 85 Priority Chemicals for Acute Exposure Guideline Level
32 (AEGL) Development*
33
34
35 ORGANIZATION LISTS USED TO COMPILE THE MASTER LIST AND THE INITIAL
36 LIST OF 85 PRIORITY CHEMICALS
37
38 'ATSDR Medical Managment Agency for Toxic Substances and Disease Registry
39 M = Chemicals with an ATSDR Medical
40 Management Guideline
41 T = Chemicals with an ATSDR Toxicology Profile
42
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
2DOD
3DOE SCAPA
"DOT ERP
5EPACAA112b
6EPACAA112r
7EPA Superfund
8OSHA PSM
9OSHA STEL
IONIOSH IDLH
"Seveso Annex in
Department of Defense
A = Army Toxicity Summary Chemical
C = Chemical Weapons Convention Schedule 3.A
Toxic Chemical
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 Subcommittee for Consequence Assessment and
Protective Action Chemical
Department of Transportation Emergency Response
Guidebook
P = Priority DOT ERG Chemical
O = Other ERG Chemical
Environmental Protection Agency Clean Air Act 112b
Chemical
Environmental Protection Agency Clean Air Act 112b
Chemical (+ = SARA s.302 also)
Environmental Protection Agency Superfund Chemical
OSHA Process Safety Management Chemical
OSHA Short-term Exposure Limit Chemical
NIOSH Immediately Dangerous to Life or Health Chemical
International Seveso Convention List
* The initial list of 85 priority chemicals shown below 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
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1 high priority for AEGL development, changes to the list could occur. The NAC/AEGL hopes to
2 select 30 to 40 chemicals per year to address in the AEGL development process. Consequently,
3 the initial list will expand as the NAC/AEGL continues to address chemicals of interest to its
4 member organizations.
5
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1
2
Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
TABLE B-l. PRIORITY LIST OF CHEMICALS
CAS NO.
56-23-5
57-14-7
60-34-4
62-53-3
67-66-3
68-12-2
71-43-2
71-55-6
74-90-8
74-93-1
75-09-2
75-21-8
75-44-5
75-55-8
75-56-9
CHEMICAL
Carbon tetrachloride
1,1-Dimethyl hydrazine
Methyl hydrazine
Aniline
Chloroform
Dimethylformamide
Benzene
1,1,1 -Trichloroethane
Hydrogen cyanide
Methyl mercaptan
Methylene chloride
Ethylene oxide
Phosgene
Propyleneimine
Propylene oxide
'ATSDR
T
M
T
X
T
M
T
MT
MT
M
2DOD:
AIS
AIS
AIS
X
c
AIS
C
3DOE
SCAPA'
X
X
X
X
4DOT
ERG
P
P
P
P
P
P
P
5EPA
CAA
112b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6EPA
CAA
112r
X+
x+
+
x+
x+
x+
x+
x+
x+
x+
7EPA
Super
fund
X
X
X
X
X
X
X
•OSHA
,PSM
X
X
X
X
X
X
Seves
0
Annex
III
X
X
X
X
X
'OSHA
STEL
"N10SH
IDLH
X
X
X
X
X
X
X
X
X
X
X
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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B4
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30. 2000
CAS NO.
75-74-1
75-77-4
75-78-5
75-79-6
78-82-0
79-01-6
79-21-0
79-22-1
91-08-7
106-89-8
107-02-8
107-11-9
107-12-0
107-15-3
107-18-6
107-30-2
CHEMICAL
Tetramethyllead
Trimethychlorosilane
Dimethyldichlorosilane
Methyltrichlorosilane
Isobutyronitrile
Trichloroethylene
Peracetic acid
Methy chloroformate
Toluene 2,6-diisocyanate
Epichlorohydrin
Acrolein
Allyl amine
Propionitrile
Ethylenediamine
Allyl alcohol
Chloromcthyl methyl ether
'ATSDR
MT
M
T
2DOD
AIS
3E»OE
SCAPA
X
X
4DOT
ERG
P
P
P
O
5EPA
CAA
112b
X
X
X
X
X
6EP-A
CAA
112r
X+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
7EPA
Super
fund •
X
X
'OSHA
PSM
X
X
X
X
X
X
X
Seves
0
Annex
HI
X
X
X
X
X
X
'OSHA
STEL
X
X
"NIOSH
IDLH
X
X
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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B5
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
CAS NO.
108-23-6
108-88-3
108-91-8
109-61-5
110-00-9
1 10-89-4
123-73-9
126-98-7
127-18-4
151-56-4
302-01-2
353-42-4
506-77-7
509-14-8
540-59-0
540-73-8
CHEMICAL
Isopropyl chloroformatc
Toluene
Cyclohexylamine
Propyl chloroformate
Furan
Piperidine
Crotonaldehyde, (E)
Methacrylonitrile
Tetrachloroethylene
Ethyleneimine
Hydrazine
Boron triflounde compound
with methyl ether (1 I)
Cyanogen chloride
Tetranitromethane
1 ,2-Dichloroethylene
1 ,2-Dimethylhydrazine
'ATSDR
MT
T
T
T
2DOD
AINS
AIS
I
'3DOE
SCAPA
X
X
X
"DOT
ERG
P
O
O
P
P
5EPA
CAA
112b
X
X
X
X
X
6EPA
CAA
112r-
X+
X+
x+
x+
x+
x+
x+
x+
x+
x+
.x+
x+
x+
7EPA
Super
fund
X
X
X
'OSHA
PSM
X
X
X
X
Seves
0
Annex
III
X
'OSHA
STEL
X
"NIOSH
IDLH
X
X
X
X
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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B6
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
CAS NO.
584-84-9
594-42-3
624-83-9
811-97-2
814-68-6
1330-20-7
1717-00-6
4170-30-3
6423-43-4
7446-09-5
7446-11-9
7647-01-0
7647-01-0
7664-39-3
CHEMICAL
Toluene 2,4-diisocyanate
Perchloromcthylmcrcaptan
Methyl isocyanate
HFC 134A (1,1,1,2-
Tetrafluoroethane)
Acrylyl chloride
Xylenes (mixed)
HCFC 141b(l,l-
Dichloro- 1 -fluoroethane)
Crotonaldehyde cis &
trans mixture
Propylene glycol dinitrate
(Otto Fuel II)
Sulfur dioxide
Sulfur trioxide
Hydrogen chloride
Hydrochloric acid
Hydrogen fluoride
'ATSDR
M
X
T
M
2DOD
N
AIN
N
Navy
3DOE
SCAPA
"DOT
ERG
P
P
P
P
P
P
P
5EPA
CAA
112b
X
X
X
X
X
X
6EPA
CAA
112r
X+
X+
x+
x+
x+
x+
x+
x+
x+
x+
7EPA
Super
fund
X
X
X
X
'OSHA
PSM
X
X
X
X
X
X
X
X
Seves
0
Annex
III
X
X
X
X
X
X
'OSHA
STEL
X
X
X
X
X
"NIOSH
IDLH
X
X
X
X
X
X
X
X
1
2
3
4
5
6
7
10
11
12
13
14
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
CAS NO.
7664-41-7
7664-93-9
7697-37-2
7719-12-2
7726-95-6
7782-41-4
7782-50-5
7783-06-4
7783-60-0
7783-81-5
7784-34-1
7784-42-1
7790-91-2
7803-51-2
8014-95-7
10025-87-3
CHEMICAL
Ammonia
Sulfuric acid
Nitric acid
Phosphorus trichloride
Bromine
Fluorine
Chlorine
Hydrogen sulfide
Sulfur tetrafluoride
Uranium hexafluoride
Arsenous trichloride
Arsine
Chlorine trifluoride
Phosphine
Oleum
Phosphorus oxychlonde
'ATSDR
MT
M
M
M
M
2DOD
3DOE
SCAPA
X
X
X
X
X
4DOT
ERG
P
P
P
P
P
P
P
P
P
0
P
P
o
SEPA
CAA
112b
X
X
X
X
6EPA
CAA
I12r
X+
+
X+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
x+
7EPA
Super
fund
X
X
X
X
'OSHA
PSM
X
X
X
X
X
X
X
X
X
X
X
X
Seves
0
Annex
III
X
X
X
X
X
'OSHA
STEL
X
X
X
X
X
IONIOSH
IDLH
X
X
X
X
X
X
X
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
CAS NO.
10049-04-4
10102-43-9
10102-44-0
10294-34-5
13463-39-3
13463-40-6
19287-45-7
25323-89-1
70892-10-3
163702-07-6
163702-08-7
CHEMICAL
Chlorine dioxide
Nitric oxide
Nitrogen dioxide
Boron trichloride
Nickel carbonyl
Iron, pentacarbonyl-
Diborane
Trichloroethane
Jet fuels (JP-5 and JP-8)
Methyl nonafluorobutyl
ether (HFE 7 100
component)
Methyl nonafluorobutyl
ether (HFE 7 100
component)
'ATSDR
T
,2DOD
AS
N
N
N
3DOR
SCAPA
X
X
X
'DOT
ERG
P
X
P
P
P
P
5EPA
CAA
112b
X
X
6EPA
CAA
112r
X
X+
X
x+
x+
x+
x+
7EPA
Super
fund
X
'OSHA
PSM
X
X
X
X
X
X
X
Seves
o
Annex
III
X
'OSHA
STEL
X
X
X
'•NIOSH
IDLH
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
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6
Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
APPENDIX C. DIAGRAM OF THE AEGL
DEVELOPMENT PROCESS
FIGURE C-l THE AEGL DEVELOPMENT PROCESS
AEGL Development Process
Non-published.
NoTHpeer Reviewed
IndusdyData
Published
Literature
Search
Older
Data / Information
Sources
Speoal
Toxraty
Studies
AEGL Dm
Team-
Saentis,
Manager.
Rene
Blopni6nt
ORNL
•herncal
rfherracel
were
Technical
Support
Documents
(TSDs)
Oistnbute Draft or
Proposed TSDs/
AEGLs to
COCTTlttOG
Members
+
NAC/AEGL
Draft or Proposed AEGLs
!S
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
1
AAPCC
ACGIH
ACOEM
ADI
AEGL
AFL-CIO
AIHA
ATSDR
BMC
BMC05
BMC.o
CAAA
CAER
CAS
CDC
CEEL
CEL
CMA
CORR
COT
Ct or Cxt
CURE
DFO
DOD
DOE
DOT
DTIC
ECETOC
EEGL
EEL
Einsatztoleranzwert
EPA
ERP
ERPG
APPENDIX D. GLOSSARY - ACRONYMS,
ABBREVIATIONS, AND SYMBOLS
American Association of Poison Control Centers
American Conference of Government Industrial Hygienist
American College of Occupational and Environmental Medicine
Acceptable Daily Intake
National Advisory Committee for Acute Exposure Guidelines
Levels for Hazardous Substances (AEGL Committee)
American Federation of Labor - Congress of Industrial
Organizations
American Industrial Hygienist Association
Agency for Toxic Substances and Disease Registry (U. S.)
Benchmark Concentration
Benchmark Concentration, 5% response
Benchmark Concentration, 10% response
Clean Air Act Amendments (U. S. EPA)
Community Awareness and Emergency Response
Chemical Abstract Service (U. S.)
Centers for Disease Control and Prevention (U. S. HHS)
Community Emergency Exposure Levels (U. S. NAS)
Emergency Exposure Limits (U. S. NAS)
Chemical Manufacturers Association (U. S.)
Chemicals on Reporting Rules
Committee on Toxicology (U. S. NAS)
Measure of cumulative exposure
Chemical Unit Record Estimates
Designated Federal Official
Department of Defense (U. S.)
Department of Energy (U. S.)
Department of Transportation (U. S.)
Defense Technical Information Center (U. S.)
European Chemical Industry Ecology and Toxicology Centre
Emergency Exposure Guideline Levels (U. S NAS)
Emergency Exposure Limits (U. S. NAS)
[Action Tolerance Levels] Federation for the Advancement of
German Fire Prevention (Germany)
Environmental Protection Agency (U. S.)
Emergency Response Planning, (U. S.) American Industrial
Hygiene Association (AIHA)
Emergency Response and Planning Guidelines, (U. S.) American
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
FACA
FDA
FEDRIP
FEMA
FEV,
FR
FYI
GLP
GSA
HEAST
HSDB
HUD
IARC
IDLH
IPCS
IRIS
LC01
LCSO
LCL
LOAEL
MAC
MAC
MAK
MAKS.
MCS
MF
MLE
MLEOI
MTD
N/A
NAAQS
NAC
NAC/AEGL
NAS
NAS/AEGL
NASA
Industrial Hygiene Association (AIHA)
Federal Advisory Committee Act (U. S.)
Food and Drug Administration (U. S.)
Federal Research in Progress
Federal Emergency Management Agency (U. S.)
Forced Expiratory Volume
Federal Register (U. S.)
For Your Information
Good Laboratory Practice Standards
General Services Administration (U. S.)
Health Effects Assessment Tables
Hazardous Substances Data Base
Department of Housing and Urban Development (U. S.)
International Agency for Research on Cancer
Immediately Dangerous to Life and Health (U. S. NIOSH)
International Programme for Chemical Safety
Integrated Risk Information System
Lethal Concentration, 1 % kill
Lethal Concentration, 50 % kill
Lower Confidence Limit
Lowest-observe-adverse effect level
Mean Alveolar Concentration
Maximum Acceptable Concentration (The Netherlands)
[Maximale Arbeitsplatzkonzentration] Maximum Workplace
Concentration, 8 hour time weighted average German Research
Association (Germany)
Spitzenbegrenzung (Kategorie 11,2) [Peak Limit 11,2] 30 minute x 2
per day (Germany)
Multiple Chemical Sensitivity
Modifying Factor
Maximum Likelihood Estimate
Maximum Likelihood Estimate, 1% response
Maximum Tolerated Dose
Not Applicable
National Ambient Air Quality Standards, U.S.
National Advisory Committee
National Advisory Committee for Acute Exposure Guideline
Levels for Hazardous Substances (NAC/AEGL Committee)
National Academy of Sciences (U. S.)
National Academy of Sciences Subcommittee on Acute Exposure
Guideline Levels (NAS/AEGL Subcommittee) (U. S.)
National Aeronautical and Space Administration (U. S.)
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
NCI
NIOSH
NOAEL
NRC
NSF
NTIS
NTP
OECD
ORNL
OSHA
OSWER
PEL-TWA
PEL-STEL
QA
QC
QSARs
REL-STEL
REL-TWA
RfC
RfD
RTECS
SARA
SMAC
SOP
SPEGL
STPL
TARA
TLV-STEL
TLV-TWA
TSD
UF
WEELS
>
>
<
National Cancer Institute (U. S.)
National Institute for Occupational Safety and Health (U. S.)
No Observed-Adverse-Effect Level
National Resource Council (U. S.)
National Science Foundation (U. S.)
National Technical Information Services (U. S.)
National Toxicology Program (U. S.)
Organization for Economic Cooperation and Development
Oak Ridge National Laboratories (U. S.)
Occupational Safety and Health Administration (U. S.)
Office of Solid Waste and Emergency Response
Permissible Exposure Limits - Time Weighted Average (U. S.
OSHA)
Permissible Exposure Limits - Short Term Exposure Limit (U. S.
OSHA)
Quality Assurance
Quality Control
Quantitative Structure Activity Relationships
Recommended Exposure Limits-Short Term Exposure Limit (U. S.
NIOSH)
Recommended Exposure Limits-Time Weighted Average (U. S.
NIOSH)
Reference Concentration (U. S. EPA)
Reference Dose (U. S. EPA)
Registry of Toxic Effects of Chemical Substances
Superfund Amendments and Reauthorization Act (CERCLA)
Spacecraft Maximum Allowable Concentrations
Standing Operating Procedures Manual
Short-term Public Exposure Guideline Levels (U. S. NRC, NAS)
Short Term Public Limits (U. S. NAS)
Toxicology And Risk Assessment Document List (ORNL)
Threshold Limit Value - Short Term Exposure Limit (U. S.
ACGIH)
Threshold Limit Value - Time Weighted Average (U. S. ACGIH)
Technical Support Document
Uncertainty Factor
Workplace Environmental Exposure Levels (AIHA)
Greater than
Greater than or equal to
Less than
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30,2000
1 < Less than or equal to
2 % Percent
3
4 dl - Deciliter
5 gorgm -- Gram
6 hr. — Hour
7 urn — Micrometer
8 ug — Microgram
9 mg ~ Milligram
10 min — Minute
11 mL - Milliliter
12 mm — Millimeter
13 ppb — Parts per billion
14 ppm — Parts per million
15 ppt — Parts per trillion
16
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
i APPENDIX E. EXAMPLE OF A TABLE OF CONTENTS
2 IN A TECHNICAL SUPPORT DOCUMENT
3
4 TABLE OF CONTENTS
5
6 PREFACE 2
7
8 LIST OF TABLES 5
9
10 EXECUTIVE SUMMARY 6
11
12 1. INTRODUCTION 9
13
14 2. HUMAN TOXICITY DATA 10
15 2.1. Acute Lethality 10
16 2.2. Nonlethal Toxicity 10
17 2.2.1. Acute Studies 10
18 2.2.2. Epidemiologic Studies 11
19 2.3. Developmental/Reproductive Toxicity 11
20 2.4. Genotoxicity 11
21 2.5. Carcinogenicity 11
22 2.6. Summary 11
23
24 3. ANIMAL TOXICITY DATA 11
25 3.1. Acute Lethality 12
26 3.1.1. Nonhuman Primates 12
27 3.1.2. Dogs 12
28 3.1.3. Rats 12
29 3.1.4. Mice 13
30 3.1.5. Hamsters 14
31 3.2. Nonlethal Toxicity 14
32 3.2.1. Nonhuman Primates 14
33 3.2.2. Dogs 14
34 3.2.3. Rats 15
35 3.2.4. Mice 15
36 3.3. Developmental/Reproductive Toxicity 15
37 3.4. Genotoxicity 18
38 3.5. Carcinogenicity 19
39 3.6. Summary 19
40
41 4. SPECIAL CONSIDERATIONS 20
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 4.1. Metabolism and Disposition 20
2 4.2. Mechanism of Toxicity 20
3 4.3. Structure-Activity Relationships 21
4 4.4. Other Relevant Information 21
5 4.4.1. Species Variability 21
6 4.4.2. Unique Physicochemical Properties 22
7 4.4.3. Concurrent Exposure Issues 22
8
9 5. DATA ANALYSIS FOR AEGL-1 22
10 5.1. Summary of Human Data Relevant to AEGL-1 22
11 5.2. Summary of Animal Data Relevant to AEGL-1 22
12 5.3. Derivation of AEGL-1 22
13
14 6. DATA ANALYSIS FOR AEGL-2 23
15 6.1. Summary of Human Data Relevant to AEGL-2 23
16 6.2. Summary of Animal Data Relevant to AEGL-2 23
17 6.3. Derivation of AEGL-2 23
18
19 7. DATA ANALYSIS FOR AEGL-3 24
20 7.1. Summary of Human Data Relevant to AEGL-3 24
21 7.2. Summary of Animal Data Relevant to AEGL-3 24
22 7.3. Derivation of AEGL-3 24
23
24 8. SUMMARY OF AEGLS 25
25 8.1. AEGL Values and Toxicity Endpoints 25
26 8.2. Comparison with Other Standards and Criteria 26
27 8.3. Data Adequacy and Research Needs 27
28
29 9. REFERENCES CITED 29
30
31 Appendix A (Derivation of AEGL Values) 32
32 Appendix B (Time Scaling Calculations for Dimethylhydrazme AEGLs) 36
33 Appendix C (Carcinogenicity Assessment for Dimethylhydrazme) 39
34 Appendix D (Derivation Summary for Dimethylhydrazme AEGLs) 41
35
36
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
i APPENDIX F. EXAMPLE OF AN EXECUTIVE
2 SUMMARY IN A TECHNICAL SUPPORT DOCUMENT
3
4 EXECUTIVE SUMMARY
5
6 Dimethylhydrazine occurs as a symmetrical (1,2-dimethylhydrazine) and unsymmetrical
7 (1,1-dimethylhydrazine) isomer. Unless otherwise specified, dimethylhydrazine refers to
8 unsymmetrical dimethylhydrazine in this document. Both compounds are clear, colorless liquids.
9 Unsymmetrical dimethylhydrazine (1,1-dimethylhydrazine) is a component of rocket fuels and is
10 also used as an absorbent for acid gas, as a plant growth control agent, and in chemical synthesis.
11 Although it has been evaluated as a high-energy rocket fuel, commercial use of the symmetrical
12 isomer (1,2-dimethylhydrazine) is limited to small quantities and it is usually considered to be a
13 research chemical. Because data are limited for 1,2-dimethylhydrazine (symmetrical
14 dimethylhydrazine), the AEGL values for both isomers are based upon 1,1-dimethylhydrazine
15 (unsymmetrical). Limited data suggest that 1,1-dimethylhydrazine may be somewhat more toxic
16 than 1,2-dimethylhydrazine.
17
18 Data on acute exposures of humans to both isomers of dimethylhydrazine are limited to
19 case reports of accidental exposures. Signs and symptoms of exposure include respiratory
20 irritation, pulmonary edema, nausea, vomiting, and neurological effects. However, definitive
21 exposure data (concentration and duration) were unavailable for these exposures. The limited
22 data in humans suggest that the nonlethal toxic response to acute inhalation of dimethylhydrazine
23 is qualitatively similar to that observed in animals. No information was available regarding
24 lethal responses in humans. In the absence of quantitative data in humans, the use of animal data
25 is considered a credible approach for developing AEGL values.
26
27 Toxicity data of varying degrees of completeness are available for several laboratory
28 species, including, rhesus monkeys, dogs, rats, mice, and hamsters (Weeks et al., 1963). Most of
29 the animal studies were conducted using 1,1-dimethylhydrazine, although limited data suggest
30 that 1,2-dimethylhydrazine exerts similar toxic effects. Minor nonlethal effects such as
31 respiratory tract irritation appear to occur at cumulative exposures of < 100 ppm-hrs. At
32 cumulative exposures of 100 ppm-hrs, or slightly greater than this level more notable effects
33 have been reported, including, muscle fasciculation, behavioral changes, tremors, and
34 convulsions. Lethality has been demonstrated when cumulative exposures exceed these levels
35 only slightly. The available data suggest that there is a very narrow margin between exposures
36 resulting in no significant toxicity and those causing substantial lethality (LC50 = 900-2,000 ppm-
37 hrs).
38
39 Developmental toxicity of dimethylhydrazmes has been demonstrated in rats following
40 parenteral administration of maternally toxic doses.
41
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
1 Both isomers of dimethylhydrazine have been shown to be carcinogenic in rodents
2 following oral exposure and 6-month inhalation exposure to 1,1-dimethylhydrazine. Increased
3 tumor incidence was observed in mice, although these findings are compromised by the
4 contaminant exposure to dimethylmtrosarnine. An increased incidence of lung rumors and
5 hepatocellular carcinomas was also seen in rats but not in similarly exposed hamsters. Inhalation
6 slope factors are currently unavailable.
7
8 AEGL-1 values for dimethylhydrazine are not recommended. This is due to inadequate
9 data to develop health-based criteria, and because the concentration-response relationship for
10 dimethylhydrazine indicated a very narrow margin exists between exposures producing no toxic
11 response and those resulting in significant toxicity.
12
13 Behavioral changes and muscle fasciculations in dogs exposed for 15 minutes to 360 ppm
14 1,1-dimethylhydrazine (Weeks et al., 1963) served as the basis for deriving AEGL-2 values.
15 Available lethality data in dogs and rats indicated a near linear temporal relationship (n=0.84 and
16 0.80 for dogs and rats, respectively). For temporal scaling (C1 x t = K) to derive values for
17 AEGL-specific exposure durations a linear concentration-response relationship; n=l was used.
18 This value was adjusted by an uncertainty factor of 30. An uncertainty factor of 3 for
19 interspecies variability was applied because the toxic response to dimethylhydrazine was similar
20 across the species tested. This was especially true for lethality responses among rats, mice, dogs,
21 and hamsters with LCSO values for time periods ranging from 5 minutes to 4 hours. A
22 comparison of LC50 values for the same exposure durations in these species did not vary more
23 than 3-fold. An uncertainty factor of 10 was used for mtraspecies variability. This was based
24 primarily on the variability in the toxic response observed in dogs where responses varied from
25 one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects.
26 Additionally, experiments by Weeks et al. (1963) indicated that dogs previously stressed by
27 auditory stimuli may have potentiated their response to dimethylhydrazine. Based on these data,
28 it was assumed that humans may be equally divergent in their response to dimethylhydrazine as a
29 result of similar stresses.
30
31 The AEGL-3 values were derived from the 1 -hr LC50 (981 ppm) for 1,1 -
32 dimethylhydrazine in dogs (Weeks et al., 1963). Because of the steep slope of the dose-response
33 curve of 1,1-dimethyl hydrazine, the 1 hour LC50 of 981 ppm was adjusted downward to estimate
34 the lethality threshold of 327 ppm. An uncertainty factor of 3-fold for interspecies variability
35 was applied for several reasons. The 4-hr LC50 values for mouse, rat, and hamster differ by a
36 factor of approximately 2 and were consistent with the dog data when extrapolated from 1 hr
37 using n=l. The more sensitive species, the dog, was used to derive the AEGL-3 values. An
38 uncertainty factor of 10 for intraspecies variability was used since a broad spectrum of effects
39 were seen including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and
40 vomiting. The mechanism of toxicity is uncertain and sensitivity among individuals may vary.
41 Following identical exposures, the responses of the dogs varied from one of extreme seventy
42 (vomiting, tremors, convulsions, and death) to no observable effects. Temporal scaling as
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3
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7
8
9
10
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19
20
21
22
23
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Standing Operating Procedures of the NAC/AEGL FACA Committee Version 08-02 - June 30, 2000
previously described was applied to obtain exposure values for AEGL-specific exposure periods.
Verified inhalation and oral slope factors were unavailable for dimethylhydrazine. A
cancer assessment based upon the carcinogenic potential (withdrawn cancer slope factors) of
dimethylhydrazine revealed that AEGL values for a 10"4 carcinogenic risk exceeded the AEGL- 2
values that were based on noncancer endpoints. Because the cancer risk for dimethylhydrazine
was estimated from nonverified cancer estimates, 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-DIMETHYLHYDRAZINES
Classification
AEGL-1
(Nondisablmg)
AEGL-2
(Disabling)
AEGL-3
(Lethal)
30-mm
NR
6 pptn
14.7 mg/m3
22ppm
54 mg/m3
1-hour
NR
3ppm
7 4 mg/m3
11 ppm
27 mg/m3
4-hour
MR
0 75 ppm
2 mg/m1
2 7 ppm
6 6 mg/m3
8-hour
MR
0 38 ppm
1 mg/m3
1 4 ppm
3 4 mg/m3
Endpomt(Reference)
Not recommended due to insufficient data,
concentration-response relationships suggest little
margin between exposures causing minor effects and
those resulting in senous toxicity *
Behavioral changes and muscle fasciculations in dogs
exposed to 360 ppm for 1 5 minutes (Weeks ct al ,
1963)
Lethality threshold of 327 ppm for 1 hr estimated from
1 -hr LCM in dogs (Weeks et al . 1 963)
NR: Not Recommended. Analysis of dimethylhydrazine toxicity data in total revealed that significant toxicity may
occur at or below the odor threshold. Furthermore, the available data indicate that there is there an almost
nonexistent margin between exposures resulting in no response and those causing lethality. Therefore,
AEGL-1 values for dimethylhydrazine are not recommended (NR) Absence of an AEGL-1 does not imply that
exposure below the AEGL-2 is without adverse effects
"Refer to AEGL-1 for hydrazine if hydrazme is also present.
References
Weeks, M.H., Maxey, G.C., Sicks, Greene, E.A. 1963. Vapor toxicity of UDMH in rats and dogs
from short exposures. American Industrial Hygiene Association Journal 24: 137-143.
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i APPENDIX G. EXAMPLE OF THE DERIVATION OF
2 AEGL VALUES APPENDIX IN A TECHNICAL
3 SUPPORT DOCUMENT
4
5
6
7 DERIVATION OF AEGL-1 VALUES
8
9
10 Key study None. An AEGL-1 was not recommended due to inadequate data for developing
11 health-based criteria and because exposure-response relationships suggest little
12 margin between exposures resulting in no observable adverse effects and those
13 producing significant toxicity. The absence of an AEGL-l does not imply that
14 exposure below the AEGL-2 is without adverse effects. In situations where
15 hydrazine may also be present, the AEGL-1 values (0.1 ppm for all exposure
16 periods) for hydrazine should be used.
17
18
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8
9
10
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15
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20
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22
23
24
25
26
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DERIVATION OF AEGL-2 VALUES
Key study:
Toxicity endpoint:
Uncertainty factors:
Calculations:
Time scaling:
30-min AEGL-2
1-hr AEGL-2
4-hr AEGL-2
8-hr AEGL-2
Weeks etal., 1963
Dogs exposed to 360 ppm 1,1-dimethylhydrazine for 15 minutes exhibited
behavioral changes and muscle fasciculations
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 minutes to 4 hours) among rats, mice, dogs, and hamsters. A
comparison of LCSO 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 which included
behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and
vomiting. The mechanism of toxiciry is uncertain and sensitivity among
individuals regarding these effects may vary. Following identical exposures, the
responses of the dogs varied from one of extreme seventy (vomiting, tremors,
convulsions, and death) to no observable effects. A factor of 10 was also retained
because experiments by Weeks et al. (1963) indicated that dogs that had been
previously stressed (auditory stimuli) were more sensitive to the adverse effects of
dimethylhydrazine.
12 ppm
360ppm/30 = 12
C1 x t = k
12 ppm x 15 mm = 180 ppm-min
C1 \t = Jt(tenBerge, 1986)
(12 ppm)1 x 15 min =180 ppm-min
LC50 data were available for 5, 15, 30, 60, and 240-minute exposures in rats and
5, 15, and 60 minutes for the dog. 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 of n=l was selected
C1 x 30 min = 180 ppm-min
C = 6 ppm
C1 x 60 min = 180 ppm-min
C = 3 ppm
C1 x 240 min = 180 ppm-min
C = 0.75 ppm
C1 x 480 min =180 ppm-min
C = 0.38 ppm
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DERIVATION OF AEGL-3 VALUES
Key study
Toxicity endpomt
Uncertainty factors:
Calculations:
Time scaling.
30-mm AEGL-2
l-hrAEGL-2
4-hr AEGL-2
8-hr AEGL-2
Weeks etal., 1963
1 -hr LCjo of 98 1 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-minute exposure of dogs to 36-400 ppm produced only minor,
reversible effects (behavioral changes and mild muscle fasciculations)
An uncertainty factor of 3 for mterspecies variability was applied because the toxic
response to dimethylhydrazme was similar across the species tested. This was
especially true for lethality responses (LC50 values for varying time penods ranging
from 5 minutes to 4 hours) among rats, mice, dogs, and hamsters. A companson of
LCjo 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 which included
behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting.
The mechanism of toxicity is uncertain and sensitivity among individuals regarding
these effects may vary. Following identical exposures, the responses of the dogs
vaned from one of extreme seventy (vomiting, tremors, convulsions, and death) to no
observable effects. A factor of 10 was also retained because experiments by Weeks et
al. (1963) indicated that dogs that had been previously stressed (auditory stimuli)
were more sensitive to the adverse effects of dimethylhydrazme.
327ppm/30 = 10.9 ppm
C'xt = k
1 1 .9 ppm x 60 mm = 654 ppm-min
C'x/ = it(tenBerge, 1986)
1 1 .9 ppm' x 60 min = 654 ppm-min
LCj0 data were available for 5, 15, 30, 60, and 240-mmute exposures in rats and 5,
15, and 60 minutes for the dog. 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 of n=l was selected.
C1 x 30 mm = 654 ppm-min
C = 22 ppm
C1 x 60 mm = 654 ppm-min
C = 11 ppm
C1 x 240 mm = 654 ppm-min
C = 2.7 ppm
C1 x 480 mm = 654 ppm-min
C = 1 .4 ppm
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i APPENDIX H. EXAMPLE OF A TIME SCALING
2 CALCULATIONS APPENDIX IN A TECHNICAL
3 SUPPORT DOCUMENT
4
5
6
7 APPENDIX B
8
9 TIME SCALING CALCULATIONS FOR
10 DIMETHYLHYDRAZINE AEGLS
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1 The relationship between dose and time for any given chemical is a function of the
2 physical and chemical properties of the substance and the unique lexicological and
3 pharmacological properties of the individual substance. Historically, the relationship according
4 to Haber (1924), commonly called Haber's Law (NRC, 1993a) or Haber's Rule (i.e., C x t = k,
5 where C = exposure concentration, t = exposure duration, and k = a constant) has been used to
6 relate exposure concentration and duration to effect (Rinehart and Hatch, 1964). This concept
7 states that exposure concentration and exposure duration may be reciprocally adjusted to
8 maintain a cumulative exposure constant (k) and that this cumulative exposure constant will
9 always reflect a specific quantitative and qualitative response. This inverse relationship of
10 concentration and time may be valid when the toxic response to a chemical is equally dependent
11 upon the concentration and the exposure duration. However, an assessment by ten Berge et al.
12 (1986) of LC50 data for certain chemicals revealed chemical-specific relationships between
13 exposure concentration and exposure duration that were often exponential. This relationship can
14 be expressed by the equation C" x t = k, where n represents a chemical specific, and even a toxic
15 endpoint specific, exponent. The relationship described by this equation is basically the form of
16 a linear regression analysis of the log-log transformation of a plot of C vs t. Ten Berge et al.
17 (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship
18 relative to death for approximately 20 chemicals and found that the empirically derived value of
19 n ranged from 0.8 to 3.5 among this group of chemicals. Hence, these workers showed that the
20 value of the exponent («) in the equation C" x t = k quantitatively defines the relationship
21 between exposure concentration and exposure duration for a given chemical and for a specific
22 health effect endpoint. Haber's Rule is the special case where n = 1. As the value of n increases,
23 the plot of concentration vs time yields a progressive decrease in the slope of the curve.
24
25 Two data sets of LC50 values for different time periods of exposure were analyzed using a
26 linear regression analysis of the log-log transformation of a plot of C vs t to derive values of n for
27 dimethylhydrazine.
28
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Dog data from Weeks et al.,1963
The LC50 values for 5, 15,
respectively.
Log
Time Cone. Time
5 22300 0.6990
15 3580 1.1761
60 981 1.7782
n= 0.8
Calculated LC50 values:
Minutes Cone.
30 2036.15
60 860.12
240 153.48
480 64.83
and 60-minute exposures were 22,300, 3580, and 981 ppm,
Log
Cone.
4.3483
3.5539
2.9917
at
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Rat data from Weeks et al., 1963
For the 5, 15, 30, 60, and 240-minute exposure periods, LC50 values of 24,500, 8,230,
4,010, 1,410, and 252 ppm were reported by the study authors.
Time Cone.
5
15
30
60
240
24500
8230
4010
1410
252
Log
Time
0.6990
1.1761
1.4771
1.7782
2.3802
Log
Cone.
4.3892
3.9154
3.6031
3.1492
2.4014
n = 0.84
Calculated LC50 values:
Minutes
30
60
240
480
Cone.
3323.28
1449.93
276.00
120.42
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i APPENDIX I. EXAMPLE OF A CARCINOGENICITY
2 ASSESSMENT APPENDIX IN A TECHNICAL SUPPORT
3 DOCUMENT
4
5 CARCINOGENICITY ASSESSMENT OF DIMETHYLHYDRAZINE
6
7 Slope factors for 1,1 -dimethylhydrazine and 1,2-dimethylhydrazme were available but have been
8 withdrawn from the U.S. EPA Integrated Risk Information System (IRISJ. For a preliminary
9 carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine
10 (cited in ATSDR, 1994) will be used. The assessment follows previously described
11 methodologies (NRC, 1985; Henderson, 1992).
12
13 The withdrawn slope factor for 1,1-dimethylhydrazine was 3.5 (mg/kg-day)"1 which, based upon
14 a human inhalation rate of 20 mVday and a body weight of 70 Kg, is equivalent to 1 (mg/m3)"'.
15
16 To convert to a level of monomethylhydrazine that would cause a theoretical excess cancer risk
17 oflO-":
18
19 Risk of 1 x 10"4 = (1 x lO-4/!) x 1 mg/m3 = 1 x 10"4 mg/m3
20 (virtually safe dose)
21
22 To convert a 70-year exposure to a 24-hour exposure:
23
24 24-hr exposure = d x 25,600
25 = (1 x 10^ mg/m3) x 25,600 days
26 = 2.56 mg/m3
27
28 To account for uncertainty regarding the variability in the stage of the cancer process at which
29 monomethylhydrazine or its metabolites may act, a multistage factor of 6 is applied (Crump and
30 Howe, 1984):
31
32 (2.56mg/m3)/6 = 0.43 mg/m3 (0.18 ppm)
33
34 Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-
35 hr exposure would be 0.9 mg/m3 (0.5 ppm).
36
37 If the exposure is limited to a fraction (f) of a 24-hr period, the fractional exposure becomes 1/f x
38 24 hrs (NRC, 1985).
39
40 24-hr exposure = 0.43 mg/m3 (0.18 ppm)
41 8-hr = 1.3 mg/m3 (0.5 ppm)
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1 4-hr = 2.6mg/m3 (l.lppm)
2 1-hr 10.3mg/m3(4.2ppm)
3 0.5 hr = 20.6 mg/m3 (8.5 ppm)
4
5 Because the AEGL-2 values based upon acute toxicity were equivalent to or lower than the 1O*4
6 risk values derived based on potential carcinogenicity, the acute toxicity data were used for the
7 AEGLs for dimethylhydrazine. For 10's and 10"6 risk levels, the 10"* values are reduced by 10-
8 fold or 100-fold, respectively.
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APPENDIX J. EXAMPLE OF THE DERIVATION
SUMMARY APPENDIX IN A TECHNICAL SUPPORT
DOCUMENT
DERIVATION SUMMARY
(CAS NO. 57-14-7; 1,1-DIMETHYLHYDRAZINE)
(CAS NO. 540-73-8; 1,2-DIMETHYLHYDRAZINE)
AEGL-1 VALUES
30 minutes
Not recommended
1 hour
Not recommended
4 hours
Not recommended
8 hours
Not recommended
Reference:
Not applicable.
Test Species/Strain/Number: Not applicable
Exposure Route/Concentrations/Durations- Not applicable
Effects: Not applicable
Endpomt/Concentration/Rationale: Not applicable
Uncertainty Factors/Rationale: Not applicable
Modifying Factor: Not applicable
Animal to Human Dosimetric Adjustment: Not applicable
Time Scaling: Not applicable
Data Adequacy: Analysis of dimethylhydrazine toxicity data in total revealed that significant
toxicity may occur at or below the odor threshold. Furthermore, the available data indicate
that there is there an almost nonexistent margin between exposures resulting in no response
and those causing lethality. Therefore, AEGL-1 values for dimethylhydrazine are not
recommended (NR). Absence of an AEGL-1 does not imply that exposure below the AEGL-
2 is without adverse effects.
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
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1 AEGL-2 is without adverse effects.
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DERIVATION SUMMARY
(CAS NO. 57-14-7; 1,1-DIMETHYLHYDRAZINE)
(CAS NO. 540-73-8; 1,2-DIMETHYLHYDRAZINE)
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AEGL-2 VALUES
30 minutes
6.0 ppm
1 hour
3.0 ppm
4 hours
0.75 ppm
8 hours
0.38 ppm
Reference: Weeks, M.H., G.C. Maxey, M.E. Sicks, 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
minutes; 360,400 or 1,530 ppm for 15
minutes; 80-250 ppm for 60 minutes
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 to 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.
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Uncertainty Factors/Rationale:
Total uncertainty factor: 30
Interspecies: 3 - The toxic response to dimethylhydrazine (LCSO values) was similar
across species. The 4-hr 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 hr using n=l. The more sensitive
species, the dog, was used to derive the AEGL-2 values.
Intraspecies: 10 - A broad spectrum of effects were seen which included
behavioral effects, hyperactivity, fasciculations, tremors, convulsions,
and vomiting. The mechanism of toxicity is uncertain and sensitivity
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 retained. A
factor of 10 was also retained because experiments by Weeks et al.
(1963) indicated that dogs that 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 divergent in their response to
dimethylhydrazine.
Modifying Factor: None
Animal to Human Dosimetric Adjustment: None applied, insufficient data
Time Scaling: C" x t = k where n = 1 and k = 180 ppm-min; LC50 data were available for 5,
15, 30, 60, and 240-minute exposures in rats and 5,15, and 60 minutes for the
dog. 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=l 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 neurological
effects to lethality. Because the nonlethal effects in humans and annuals 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.
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DERIVATION SUMMARY
(CAS NO. 57-14-7; 1,1-DIMETHYLHYDRAZINE)
(CAS NO. 540-73-8; 1,2-DIMETHYLHYDRAZINE)
AEGL-3
30 minutes 1 hour
22 ppm 1 1 ppm
VALUES
4 hours 8 hours
2.7 ppm 1 .4 ppm
Reference: Weeks, M.H., G.C. Maxey, M.E. Sicks, 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 minutes
Effects:
1-hr LC50 981 PPm (reduction by 1/3 was basis for AEGL-3 derivation)
15-minLC50 3,580 ppm
5-min LC50 22,300 ppm
Endpoint/Concentration/Rationale:
1-hr 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 three
fold reduction in LC50 values results in
exposures which would not be associated
with lethality.
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Uncertainty Factors/Rationale:
Total uncertainty factor: 30
Interspecies: 3 -The toxic response to dimethylhydrazine (LC50 values) was similar
across species. The 4-hr 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 hr using n=l. The more sensitive species, the
dog, was used to derive the AEGL-3 values.
Intraspecies: 10 - A broad spectrum of effects were seen which included behavioral
effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting.
The mechanism of toxicity is uncertain and sensitivity among individuals
regarding these effects may vary. This variability was especially
demonstrated in dogs wherein responses varied from one of extreme
seventy (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 divergent in their response to dimethylhydrazine
subsequent to similar stresses.
Modifying Factor: None
Animal to Human Dosimetnc Adjustment: None applied, insufficient data
Time Scaling: Cn x t = k where n = 1 and k = 654 ppm-min; LC50 data were available for 5,
15, 30,60, and 240-minute exposures in rats and 5, 15, and 60 minutes for
the dog. 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=l
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.
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i APPENDIX K. LIST OF EXTANT STANDARDS AND
2 GUIDELINES IN A TECHNICAL SUPPORT
3 DOCUMENT
4
5 Section 8.2 of the Technical Support Document compares the AEGL values for a chemical
6 with other standards and guidelines previously published for exposure durations ranging from 10
7 minutes to 8 hours. A summary discussion of important comparisons should be presented in the
8 text and the values for recognized standards and guidelines, if available, should be presented on
9 the table. The statement "All currently available standards and guidelines are shown in Table ..."
10 should be included in the text to affirm completeness of the table. Only those standards or
11 guidelines with published values for a given chemical should be included in the table. In cases
12 where the exposure duration of a published standard or guideline differs from those designated
13 for AEGLs (e.g., 15 minute PEL-STEL), the value should be placed in parentheses in the column
14 of the closest AEGL exposure duration category and footnoted to indicate its true exposure
15 duration. A list of recognized standards and guidelines and the order in which they should
16 appear in the table is shown below.
17
18 List and Order of Presentation of Extant Standards and Guidelines in the TSD Table.
19
20 AEGL-1
21 AEGL-2
22 AEGL-3
23 ERPG-1 (AIHA)
24 ERPG-2 (AIHA)
25 ERPG-3 (AIHA)
26 SPEGL(NRC)
27 EEL (NRC)
28 STPL (NRC)
29 GEL (NRC)
30 EEGL (NRC)
31 SMAC(NRC)
32 PEL-STEL (OSHA)
33 PEL-TWA (OSHA)
34 IDLH (NIOSH)
35 REL-STEL (NIOSH)
36 TLV-STEL (ACGffl)
37 TLV-TWA (ACGffl)
38 MAC (THE NETHERLANDS)
39 MAK (GERMANY)
40 MAK S. (GERMANY)
41 BINSATZTOLERANZWERT (ACTION TOLERANCE LEVELS - GERMANY)
42
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