p. 1 United States Office of Research and EPA/600/8-90/066F Environmental Protection Development October 1994 Agency Washington DC 2046 0 EPA Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry p. 2 EPA/600/8-90/066F October 1994 METHODS FOR DERIVATION O F INHALATION REFERENCE CONCENTRATIONS AND APPLICATION OF INHALATION DOSIMETRY Environmental Criteria and Assessment Offic e Office of Health and Environmental Assessment Office of Research and Development U .S . Environmental Protection Agency Research Triangle Park, NC 2771 1 ~* Printed on Recycled Paper p. 3 DISCLAIMER This document has been reviewed in accordance with U . S . Environmental Protection Agency policy and approved for publication . Mention of trade names or commercial products does not constitute endorsement or recommendation for use . 11 p. 4 TABLE OF CONTENTS Page LIST OF TABLES . vi LIST OF FIGURES . viii AUTHORS, CONTRIBUTORS, AND REVIEWERS . xiii LIST OF ACRONYMS AND ABBREVIATIONS . xix GLOSSARY . xxvii 1 . INTRODUCTION AND OVERVIEW . 1-1 1 .1 INHALATION REFERENCE CONCENTRATION: DEVELOPMENT, DEFINITION, AND DERIVATION . 1-1 1 .2 GENERAL PRINCIPLES OF DOSE-RESPONS E ASSESSMENT FOR NONCANCER TOXICITY . 1-8 1 .3 GUIDELINES ON SPECIFIC ENDPOINTS . 1-14 1 .4 USE OF THE INHALATION REFERENCE CONCENTRATION IN THE NATIONAL ACADEMY OF SCIENCES RISK ASSESSMENT AND RISK MANAGEMENT PARADIGM . 1-15 1 .5 OCCUPATIONAL EXPOSURE LIMITS VERSUS INHALATION REFERENCE CONCENTRATIONS . 1-16 1 .6 PRIMARY NATIONAL AMBIENT AIR QUALITY STANDARDS VERSUS INHALATION REFERENC E CONCENTRATIONS . 1-17 1 .7 STATE-OF-THE-ART APPLICATIONS TO THE DEVELOPMENT OF THE INHALATION REFERENC E CONCENTRATION METHODOLOGY . 1-18 2 . QUALITATIVE EVALUATION OF THE DATA BASE . 2-1 2.1 GUIDELINES FOR SELECTIONS OF KEY STUDIES . 2-2 2.1 .1 Human Data . 2-2 2.1 .1 .1 Molecular Epidemiology and Biologic Markers . 2-3 2.1 .1 .2 Epidemiologic Data . 2-16 2.1 .1 .3 Nonepidemiologic Data . 2-20 2.1 .1 .4 Intraspecies Variability and Identifyin g Sensitive Subgroups . 2-22 2.1 .1 .5 Summary . 2-24 2.1 .2 Laboratory Animal Data . 2-26 2 .1 .2.1 Study Design . 2-26 2 .1 .2 .2 Impact of Experimental Protocol . 2-27 2.1 .2 .3 Appropriateness of Laboratory Anima l Species as a Model for Humans . 2-35 2.1 .2.4 Study Validity and Relevance to Extrapolation . 2-43 2 .1 .3 Summarizing the Evidence . 2-44 iii p. 5 TABLE OF CONTENTS (cont'd) Page 3 . CONCEPTUAL BASIS FOR INHALATION DOSE-RESPONSE ASSESSMENT METHODOLOGY . 3-1 3.1 FACTORS CONTROLLING COMPARATIVE INHALED DOSE . 3-1 3.1 .1 Respiratory Anatomy and Physiology . 3-3 3.1 .1 .1 Respiratory Regions and Branching Patterns . 3-3 3.1 .1 .2 Clearance Mechanisms . 3-18 3.1 .2 Physicochemical Characteristics of the Inhale d Toxicant . 3-29 3.1 .2 .1 Particles . 3-30 3.1 .2 .2 Gases and Vapors . 3-30 3.2 MODELING COMPARATIVE DOSIMETRY OF INHALED TOXICANTS . 3-34 3.2 .1 Particle Disposition Model Based on Available Data . 3-35 3 .2 .2 Gas Categorization Scheme Directs Default Gas Modeling . 3-36 3 .2 .3 Summary Considerations for Judging Model Structures . 3-39 4 . QUANTITATIVE PROCEDURES . 4-1 4 .1 MINIMUM DATA BASE CRITERIA . 4-2 4 .1 .1 Evaluation of Comprehensiveness . 4-2 4.1 .2 Route-to-Route Extrapolation . 4-5 4.1 .3 Not-Verifiable Status . 4-1 2 4 .2 DESIGNATION OF EFFECT LEVELS . 4-12 4 .3 CALCULATION OF HUMAN EQUIVALENT CONCENTRATIONS . 4-17 4.3.1 Conversion to Standard Units . 4-19 4.3.2 Temporal Relationships of Toxicity an d Duration Adjustment . 4-20 4.3.3 Use of Pharmacokinetic and Pharmacodynamic Data . 4-22 4.3.4 Default Dosimetric Adjustment and Physiologica l Parameters . 4-25 4 .3 .5 Dosimetric Adjustments for Particle Exposures . 4-29 4 .3 .5 .1 Respiratory Effects . 4-37 4 .3 .5 .2 Remote (Extrarespiratory) Effects . 4-38 4 .3 .5 .3 Additional Issues for Particle Dosimetry . 4-39 4 .3 .6 Dosimetric Adjustments for Gas Exposures . 4-44 4 .3 .6.1 Respiratory Effects . 4-46 4 .3 .6.2 Remote (Extrarespiratory) Effects . 4-57 4 .3 .6.3 Additional Assumptions and Default Values . 4-63 4.3 .7 Derivation and Dosimetric Adjustment Using Human Studies . 4-64 iv p. 6 TABLE OF CONTENTS (cont'd) Pa~e 4 .3 .7.1 Selecting the Threshold Estimate . 4-65 4 .3 .7.2 Defining the Exposure Level . 4-65 4.3 .7.3 Dosimetric Adjustment for Human Data . 4-66 4.3 .7.4 Uncertainty Factors for Human Data . 4-67 4.3 .8 Data Array Evaluation and Choice of Principa l Study/Studies . 4-68 4.3.9 Operational Derivation of the Inhalation Referenc e Concentration . 4-70 4.3 .9.1 Application of Uncertainty Factors . 4-73 4 .3 .9.2 Assignment of Confidence Levels . 4-80 5. REFERENCES . 5-1 APPENDIX A-Alternative Approaches to the Estimation o f No-Observed-Adverse-Effect Levels . A-1 APPENDIX B-Criteria for Assessing the Quality of Individual Epidemiological Studies . B-1 APPENDIX C-Criteria for Causal Significance . C-1 APPENDIX D-Adverse Human Respiratory Health Effects . D-1 APPENDIX E-Guidance on Pulmonary Function Testing . E-1 APPENDIX F-Criteria for Assessing the Quality of Individua l Laboratory Animal Toxicity Studies . F-1 APPENDIX G-The Particle Deposition Dosimetry Model . G-1 APPENDIX H-Particle Sizing Conventions . H-1 APPENDIX I-Derivation of an Approach To Determine Human Equivalen t Concentrations for Effects of Exposures to Gases in Categories 1 and 2 . I-1 APPENDIX J-Derivation of an Approach To Determine Human Equivalent Concentrations for Extrarespiratory Effects of Category 3 Ga s Exposures Based on a Physiologically Based Pharmacokineti c Model Using Selected Parameter Values . J-1 v p. 7 LIST OF TABLES Number Page 2-1 Steps in the Development of a Biomarker . 2-8 2-2 Qualitative Rating for Validity of Biologic Markers . 2-10 2-3 Comparison of the Qualities of Field and Experimental Approaches in the Study of Threshold Limit Value/Biologic Exposur e Indices Relationships . 2-15 2-4 Prevalence of Subgroups Susceptible to Effects of Common Pollutants . 2-23 2-5 Agents Causing Wheezing and Bronchoconstriction . 2-41 2-6 Approach for Summarizing the Evidence from Diverse Data . 2-45 2-7 Human Data for Use in Health Risk Assessment . 2-46 3-1 Respiratory Tract Regions . 3-4 3-2 Comparative Lower Airway Anatomy as Revealed on Casts . 3-8 3-3 Normal Surface Airway Epithelium: Cell Types . 3-23 3-4 Some Specific Lung Cell Types and Their Functions . 3-24 3-5 Main Species Differences in Epithelial Cells and Glands . 3-25 3-6 Hierarchy of Model Structures for Dosimetry and Interspecie s Extrapolation . 3-40 4-1 Minimum Data Base for Both High and Low Confidence in th e Inhalation Reference Concentration . 4-3 4-2 Four Types of Effect Levels Considered in Deriving Inhalation Reference Concentrations for Noncancer Toxicity . 4-14 4-3 Effect Levels Considered in Deriving Inhalation Reference Concentrations in Relationship to Empirical Severity Rating Values . 4-16 4-4 Default Surface Area Values for Respiratory Effects . 4-26 4-5 Body Weight Default Values-Rats . 4-28 vi p. 8 LIST OF TABLES (cont'd) Number Page 4-6 Intercept and Coefficient Values Used in Algorithm To Calculate Default Minute Volumes Based on Body Weight . 4-29 4-7 Comparison of the Highest Individual Species NOAELMEC] and Its LOAEL[HEC] . 4-71 4-8 Guidelines for the Use of Uncertainty Factors in De riving Inhalation Reference Concentration . 4-76 4-9 The Use of Uncertainty Factors in Deriving an Inhalation Reference Concentration . 4-77 E-1 Definition of Various Pulmonary Function Test Volumes and Capacities . E-4 E-2 Change in Spirometric Indices Over Time . E-17 F-1 General Clinical Biochemistry Examinations . F-5 F-2 Organs and Tissues Preserved for Histological Examination . F-6 G-1 Regional Frac tional Deposition . G-4 G-2 Deposition Efficiency Equation Estimated Parameters . G-6 H-1 Particle Diameter Definitions . H-5 H-2 Lognormal Conversion Equations for Common Types of Diameters . H-7 H-3 Percentage of Particles in the Reported Range Associated with the Number of Standard Deviations Used To Calculate the Geometric Standard Deviation . H-10 H-4 General Pa rticle Descriptions and Associated Sizes . H-12 I-1 Definition of Parameter Symbols Used in Appendix I . 1-9 J-1 Definition of Symbols . J-5 vii p. 9 LIST OF FIGURES Number PAge 1-1 National Research Council (1983) framework for risk assessmen t and risk management . 1-2 1-2 Schematic characterization of comprehensive exposure-dose-respons e continuum and the evolution of protective to predictiv e dose-response estimates . 1-11 2-1 Biological marker components in sequential progression between exposure and disease . 2-4 2-2 Schematic representation of possible relationships to researc h using biologic markers . 2-11 2-3 Schematic relationships between threshold limit values in air , biologic exposure indices, and effects . 2-13 3-1 Diagrammatic representation of three respiratory tract regions . 3-5 3-2 Schematic representation of selected parameters influencing regional deposition of particles in the respiratory tract . 3-9 3-3 Regional deposition in humans of monodisperse particles by indicate d particle diameter for mouth breathing and nose breathing . 3-10 3-4 Schematic representation of selected parameters influencin g regional deposition of gases in the respiratory tract . 3-11 3-5 Net dose of ozone versus sequential segments along.