Toxicological Review of Libby Amphibole Asbestos ... · TOXICOLOGICAL REVIEW . OF . LIBBY AMPHIBOLE...

EPA/635/R-11/002F www.epa.gov/iris

TOXICOLOGICAL REVIEW

OF

LIBBY AMPHIBOLE ASBESTOS

In Support of Summary Information on the Integrated Risk Information System (IRIS)

December 2014

(Note: This document is an assessment of the noncancer and cancer health effects

associated with the inhalation route of exposure only)

Integrated Risk Information System National Center for Environmental Assessment

Office of Research and Development U.S. Environmental Protection Agency

Washington, DC

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.

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CONTENTS―TOXICOLOGICAL REVIEW OF LIBBY AMPHIBOLE ASBESTOS

LIST OF TABLES ......................................................................................................................... ix LIST OF FIGURES ..................................................................................................................... xvi FOREWORD .............................................................................................................................. xxii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................. xxiii 1. INTRODUCTION .............................................................................................................. 1-1

1.1. RELATED ASSESSMENTS..................................................................................... 1-2 1.1.1. Integrated Risk Information System (IRIS) Assessment for Asbestos

(U.S. EPA, 1988a) ......................................................................................... 1-2 1.1.2. EPA Health Assessment for Vermiculite (U.S. EPA, 1991b) ....................... 1-4

1.2. LIBBY AMPHIBOLE ASBESTOS-SPECIFIC HUMAN HEALTH ASSESSMENT .......................................................................................................... 1-4

2. LIBBY AMPHIBOLE ASBESTOS: GEOLOGY AND EXPOSURE POTENTIAL ...... 2-1

2.1. INTRODUCTION ..................................................................................................... 2-1 2.2. GEOLOGY AND MINERALOGY OF AMPHIBOLES .......................................... 2-3

2.2.1. Overview ........................................................................................................ 2-3 2.2.2. Mineralogy of Amphibole Asbestos and Related Amphibole Minerals ........ 2-3 2.2.3. Morphology of Amphibole Minerals ............................................................. 2-6

2.3. METHODS FOR ANALYSIS OF ASBESTOS ....................................................... 2-9 2.3.1. Methods for Air Samples ............................................................................... 2-9 2.3.2. Methods for Solid Materials ........................................................................ 2-10

2.4. CHARACTERISTICS OF LIBBY AMPHIBOLE ASBESTOS ............................. 2-11 2.4.1. Mineralogy of Libby Amphibole Asbestos.................................................. 2-11 2.4.2. Morphology of Libby Amphibole Asbestos ................................................ 2-16

2.5. HUMAN EXPOSURE POTENTIAL ...................................................................... 2-20 2.5.1. Exposures Pathways in the Libby Community ............................................ 2-20 2.5.2. Exposure Pathways in Communities with Vermiculite Expansion and

Processing Plants ......................................................................................... 2-21 2.5.3. Libby Amphibole Asbestos Exposure Pathways in Other Communities .... 2-23

3. FIBER TOXICOKINETICS ............................................................................................... 3-1

3.1. DEPOSITION OF FIBERS IN THE RESPIRATORY TRACT ............................... 3-2 3.2. CLEARANCE MECHANISMS ................................................................................ 3-8

3.2.1. Physical and Physicochemical Clearance of Fibers ....................................... 3-9 3.2.1.1. Mechanical Reflex Mechanisms ..................................................... 3-9 3.2.1.2. Mucociliary Clearance .................................................................... 3-9 3.2.1.3. Phagocytosis by Alveolar Macrophages ....................................... 3-10 3.2.1.4. Epithelial Transcytosis .................................................................. 3-11 3.2.1.5. Translocation................................................................................. 3-11 3.2.1.6. Dissolution and Fiber Breakage .................................................... 3-13

3.3. DETERMINANTS OF TOXICITY ........................................................................ 3-13 3.3.1. Dosimetry and Biopersistence ..................................................................... 3-13 3.3.2. Biological Response Mechanisms ............................................................... 3-14

3.3.2.1. Inflammation and Reactive Oxygen Species (ROS) Production ..................................................................................... 3-16

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CONTENTS (continued)

3.3.2.2. Genotoxicity .................................................................................. 3-16 3.3.2.3. Carcinogenicity ............................................................................. 3-16

3.4. FIBER DOSIMETRY MODELS ............................................................................ 3-18 3.5. SUMMARY ............................................................................................................. 3-18

4. HAZARD IDENTIFICATION OF LIBBY AMPHIBOLE ASBESTOS .......................... 4-1

4.1. STUDIES IN HUMANS―EPIDEMIOLOGY ......................................................... 4-1 4.1.1. Overview of Primary Studies ......................................................................... 4-3

4.1.1.1. Studies of Libby, MT Vermiculite Mining and Milling Operations Workers ........................................................................ 4-3

4.1.1.2. Studies of O.M. Scott, Marysville, OH Plant Workers ................... 4-9 4.1.1.3. Community-Based Studies Around Libby, MT Conducted by

Agency for Toxic Substances and Disease Registry (ATSDR) .... 4-12 4.1.2. Respiratory Effects, Noncancer ................................................................... 4-14

4.1.2.1. Asbestosis and Other Nonmalignant Respiratory Disease Mortality ....................................................................................... 4-14

4.1.3. Other Effects, Noncancer ............................................................................. 4-37 4.1.3.1. Cardiovascular Disease ................................................................. 4-37 4.1.3.2. Autoimmune Disease and Autoantibodies .................................... 4-38

4.1.4. Cancer Effects .............................................................................................. 4-41 4.1.4.1. Lung Cancer .................................................................................. 4-41 4.1.4.2. Mesothelioma ................................................................................ 4-46 4.1.4.3. Other Cancers................................................................................ 4-50 4.1.4.4. Summary of Cancer Mortality Risk in Populations Exposed

to Libby Amphibole Asbestos ...................................................... 4-50 4.1.5. Comparison With Other Asbestos Studies―Environmental Exposure

Settings ......................................................................................................... 4-51 4.2. SUBCHRONIC- AND CHONIC-DURATION STUDIES AND CANCER

BIOASSAYS IN ANIMALS―ORAL, INHALATION, AND OTHER ROUTES OF EXPOSURE ...................................................................................... 4-53 4.2.1. Inhalation ..................................................................................................... 4-62 4.2.2. Intratracheal Instillation Studies .................................................................. 4-63 4.2.3. Injection/Implantation Studies ..................................................................... 4-65 4.2.4. Oral .............................................................................................................. 4-66 4.2.5. Summary of Animal Studies for Libby Amphibole and Tremolite

Asbestos ....................................................................................................... 4-67 4.3. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES.............................. 4-69

4.3.1. Immunological ............................................................................................. 4-69 4.4. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE

MODE OF ACTION ............................................................................................... 4-71 4.4.1. Inflammation and Immune Function ........................................................... 4-78 4.4.2. Genotoxicity ................................................................................................. 4-81 4.4.3. Cytotoxicity and Cellular Proliferation ........................................................ 4-83

4.5. SYNTHESIS OF MAJOR NONCANCER EFFECTS ............................................ 4-84 4.5.1. Pulmonary Effects ........................................................................................ 4-85

4.5.1.1. Pulmonary Fibrosis (Asbestosis) .................................................. 4-85

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4.5.1.2. Other Nonmalignant Respiratory Diseases ................................... 4-86 4.5.2. Pleural Effects .............................................................................................. 4-86 4.5.3. Other Noncancer Health Effects (Cardiovascular Toxicity,

Autoimmune Effects) ................................................................................... 4-87 4.5.4. Summary of Noncancer Health Effects of Exposure to Libby

Amphibole Asbestos .................................................................................... 4-88 4.5.5. Mode-of-Action Information (Noncancer) .................................................. 4-88

4.6. EVALUATION OF CARCINOGENICITY............................................................ 4-90 4.6.1. Summary of Overall Weight of Evidence .................................................... 4-90

4.6.1.1. Synthesis of Human, Animal, and Other Supporting Evidence.... 4-90 4.6.2. Mode-of-Action Information (Cancer) ........................................................ 4-92

4.6.2.1. Description of the Mode-of-Action Information .......................... 4-92 4.6.2.2. Evidence Supporting a Mutagenic Mode of Action ..................... 4-92 4.6.2.3. Evidence Supporting Mechanisms of Action of Chronic

Inflammation, Cytotoxicity, and Cellular Proliferation ................ 4-93 4.6.2.4. Conclusions About the Hypothesized Modes of Action ............... 4-96 4.6.2.5. Application of the Age-Dependent Adjustment Factors ............. 4-101

4.7. SUSCEPTIBLE POPULATIONS ......................................................................... 4-102 4.7.1. Influence of Different Life Stages on Susceptibility ................................. 4-102

4.7.1.1. Life-Stage Susceptibility ............................................................. 4-103 4.7.2. Influence of Gender on Susceptibility ....................................................... 4-107 4.7.3. Influence of Race or Ethnicity on Susceptibility ....................................... 4-107 4.7.4. Influence of Genetic Polymorphisms on Susceptibility ............................. 4-108 4.7.5. Influence of Health Status on Susceptibility .............................................. 4-109 4.7.6. Influence of Lifestyle Factors on Susceptibility ........................................ 4-110 4.7.7. Susceptible Populations Summary ............................................................. 4-110

5. EXPOSURE-RESPONSE ASSESSMENT ........................................................................ 5-1

5.1. ORAL REFERENCE DOSE (RfD) ........................................................................... 5-1 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ..................................... 5-1

5.2.1. Choice of Principal Study .............................................................................. 5-3 5.2.1.1. Candidate Studies............................................................................ 5-3 5.2.1.2. Evaluation of Candidate Studies and Selection of Principal

Study ............................................................................................... 5-7 5.2.2. Methods of Analysis .................................................................................... 5-10

5.2.2.1. Exposure Assessment.................................................................... 5-10 5.2.2.2. Data Sets for Modeling Analyses ................................................. 5-11 5.2.2.3. Selection of Critical Effect ............................................................ 5-14 5.2.2.4. Selection of Explanatory Variables to Include in the

Modeling ....................................................................................... 5-19 5.2.2.5. Selection of the Benchmark Response .......................................... 5-21 5.2.2.6. Exposure-Response Modeling ...................................................... 5-22

5.2.3. Derivation of a Reference Concentration (RfC) for the Critical Effect of Localized Pleural Thickening (LPT) in the Marysville Workers Who Underwent Health Evaluations in 2002−2005 and Were Hired in 1972 or Later―Including Application of Uncertainty Factors (UFs) ......... 5-40

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5.2.3.1. Derivation of a Reference Concentration (RfC) for the Alternative Endpoint of Any Pleural Thickening (APT) in the Marysville Workers Who Underwent Health Evaluations in 2002−2005 and Were Hired in 1972 or Later ............................... 5-44

5.2.3.2. Derivation of a Reference Concentration (RfC) for the Alternative Endpoint of Any Radiographic Change (ARC) in the Marysville Workers Who Underwent Health Evaluations in 2002−2005 and Were Hired in 1972 or Later ........................... 5-45

5.2.4. Derivation of a Reference Concentration (RfC) for Localized Pleural Thickening (LPT) in the Marysville Workers Who Underwent Health Evaluations in 2002−2005 and Were Hired in 1972 or Later Based on the Cumulative Exposure Model ................................................................. 5-46

5.2.5. Derivation of a Reference Concentration (RfC) for the Alternative Endpoint of Any Pleural Thickening (APT) in the Marysville Cohort with Combined X-Ray Results from 1980 and 2002−2005 Regardless of Date of Hire ............................................................................................. 5-46

5.2.6. Summary of Reference Concentration Values (RfCs) for the Different Health Endpoints and Different Sets of Workers in the Marysville Cohort .......................................................................................................... 5-48

5.3. UNCERTAINTIES IN THE INHALATION REFERENCE CONCENTRATION (RfC) ..................................................................................... 5-51 5.3.1. Uncertainty in the Exposure Reconstruction ............................................... 5-51 5.3.2. Uncertainty in the Radiographic Assessment of Localized Pleural

Thickening (LPT)......................................................................................... 5-56 5.3.3. Uncertainty Due to Potential Confounding.................................................. 5-57 5.3.4. Uncertainty Due to Time Since First Exposure (TSFE) .............................. 5-61 5.3.5. Uncertainty in the Endpoint Definition........................................................ 5-65 5.3.6. Summary of Sensitivity Analyses ................................................................ 5-69

5.4. CANCER EXPOSURE-RESPONSE ASSESSMENT ............................................ 5-70 5.4.1. Overview of Methodological Approach ...................................................... 5-70 5.4.2. Choice of Study/Data—with Rationale and Justification ............................ 5-72

5.4.2.1. Description of the Libby Worker Cohort ...................................... 5-73 5.4.2.2. Description of Cancer Endpoints .................................................. 5-75 5.4.2.3. Description of Libby Worker Cohort Work Histories .................. 5-77 5.4.2.4. Description of Libby Amphibole Asbestos Exposures ................. 5-78 5.4.2.5. Estimated Exposures Based on Job-Exposure Matrix (JEM)

and Work Histories ....................................................................... 5-85 5.4.3. Exposure-Response Modeling ..................................................................... 5-90

5.4.3.1. Modeling of Mesothelioma Exposure Response in the Libby Worker Cohort .............................................................................. 5-91

5.4.3.2. Results of the Analysis of Mesothelioma Mortality in the Full Libby Worker Cohort.................................................................... 5-93

5.4.3.3. Modeling and Results of Lung Cancer Exposure Response in the Full Libby Worker Cohort ...................................................... 5-96

5.4.3.4. Rationale for Analyzing the Subcohort of Libby Workers After 1959 ................................................................................... 5-101

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5.4.3.5. Results of the Analysis of Mesothelioma Mortality in the Subcohort .................................................................................... 5-103

5.4.3.6. Results of the Analysis of the Lung Cancer Mortality in the Subcohort .................................................................................... 5-113

5.4.3.7. Sensitivity Analysis of the Influence of High Exposures in Early 1960s on the Model Fit in the Subcohort .......................... 5-124

5.4.3.8. Additional Analysis of the Potential for Confounding of Lung Cancer Results by Smoking in the Subcohort ................... 5-126

5.4.4. Exposure Adjustments and Extrapolation Methods ................................... 5-127 5.4.5. Inhalation Unit Risk (IUR) of Cancer Mortality ........................................ 5-128

5.4.5.1. Unit Risk Estimates for Mesothelioma Mortality ....................... 5-128 5.4.5.2. Unit Risk Estimates for Lung Cancer Mortality ......................... 5-131 5.4.5.3. Inhalation Unit Risk (IUR) Derivation for Combined

Mesothelioma and Lung Cancer Mortality ................................. 5-132 5.4.6. Uncertainties in the Cancer Risk Values ................................................... 5-140

5.4.6.1. Sources of Uncertainty ................................................................ 5-140 5.4.6.2. Summary ..................................................................................... 5-154

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND

EXPOSURE RESPONSE ................................................................................................... 6-1 6.1. HUMAN HAZARD POTENTIAL ............................................................................ 6-1

6.1.1. Exposure ........................................................................................................ 6-1 6.1.2. Fiber Toxicokinetics ...................................................................................... 6-2 6.1.3. Noncancer Health Effects in Humans and Laboratory Animals .................... 6-3 6.1.4. Carcinogenicity in Humans and Laboratory Animals ................................... 6-5 6.1.5. Susceptible Populations ................................................................................. 6-6 6.1.6. Mode-of-Action Information ......................................................................... 6-7 6.1.7. Weight-of-Evidence Descriptor for Cancer Hazard ...................................... 6-7

6.2. EXPOSURE-RESPONSE.......................................................................................... 6-8 6.2.1. Noncancer/Inhalation ..................................................................................... 6-8

6.2.1.1. Uncertainty and Sensitivity Analyses for Reference Concentration (RfC) Derivation ................................................... 6-12

6.2.2. Cancer/Inhalation ......................................................................................... 6-13 6.2.2.1. Background and Methods ............................................................. 6-13

6.2.3. Modeling of Mesothelioma Exposure Response ......................................... 6-15 6.2.4. Unit Risk Estimates for Mesothelioma Mortality ........................................ 6-16 6.2.5. Modeling of Lung Cancer Exposure Response ........................................... 6-17

6.2.5.1. Analysis of Potential Confounding of Lung Cancer Results by Smoking in the Subcohort........................................................ 6-18

6.2.6. Unit Risk Estimates for Lung Cancer Mortality .......................................... 6-18 6.2.7. Inhalation Unit Risk (IUR) Derivation Based on Combined

Mesothelioma and Lung Cancer Mortality from Exposure to Libby Amphibole Asbestos .................................................................................... 6-19 6.2.7.1. Comparison with Other Published Studies of Libby, MT

Workers Cohort............................................................................. 6-21 6.2.8. Uncertainty in the Cancer Risk Values ........................................................ 6-21

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7. REFERENCES ........................................................................................................................ 7-1 APPENDIX A: EPA RESPONSE TO MAJOR EXTERNAL PEER-REVIEW AND

PUBLIC COMMENTS.................................................................................... A-1 APPENDIX B: PARTICLE SIZE DISTRIBUTION DATA FOR LIBBY AMPHIBOLE

STRUCTURES OBSERVED IN AIR AT THE LIBBY ASBESTOS SUPERFUND SITE ..........................................................................................B-1

APPENDIX C: CHARACTERIZATION OF AMPHIBOLE FIBERS FROM ORE

ORIGINATING FROM LIBBY, MONTANA, LOUISA COUNTY, VIRGINIA, ENOREE, SOUTH CAROLINA, AND PALABORA, REPUBLIC OF SOUTH AFRICA ...................................................................C-1

APPENDIX D: ANALYSIS OF SUBCHRONIC- AND CHRONIC-DURATION

STUDIES AND CANCER BIOASSAYS IN ANIMALS AND MECHANISTIC STUDIES ............................................................................. D-1

APPENDIX E: EVALUATION OF EXPOSURE-RESPONSE DATA FOR

RADIOGRAPHIC CHANGES IN WORKERS FROM THE MARYSVILLE, OH COHORT COMBINING DATA FROM THE 1980 AND 2002-2005 HEALTH EXAMINATIONS ...................................... E-1

APPENDIX F: WORKER OCCUPATIONAL EXPOSURE RECONSTRUCTION FOR

THE MARYSVILLE COHORT ...................................................................... F-1 APPENDIX G: EXTRA RISK AND UNIT RISK CALCULATION ...................................... G-1 APPENDIX H: GLOSSARY OF ASBESTOS TERMINOLOGY ........................................... H-1 APPENDIX I: EVALUATION OF LOCALIZED PLEURAL THICKENING IN

RELATION TO PULMONARY FUNCTION MEASURES .......................... I-1 APPENDIX J: DOCUMENTATION OF IMPLEMENTATION OF THE 2011

NATIONAL RESEARCH COUNCIL RECOMMENDATIONS .................... J-1

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LIST OF TABLES

1-1. Derivation of the current Integrated Risk Information System (IRIS) inhalation unit risk for asbestos from the lifetime risk tables in the Airborne Asbestos Health Assessment Update (AAHAU) at 0.01 fiber/cc ........................... 1-3

2-1. Optical and crystallographic properties of fibrous amphiboles associated with Libby Amphibole asbestos ........................................................................... 2-14

2-2. Air sampling results for asbestos from Zonolite vermiculite attic insulation (VAI) in three homes ............................................................................................ 2-23

3-1. Factors influencing fiber deposition and clearance in the respiratory system ........ 3-5

3-2. Determinants of fiber toxicity ............................................................................... 3-15

4-1. Population and exposure assessment methodologies used in studies of Libby, MT vermiculite workers .............................................................................. 4-5

4-2. Source of primary samples for fiber measurements at the Libby vermiculite mining and milling operations ................................................................................ 4-6

4-3. Dimensional characteristics of fibers from air samples collected in the vermiculite mill and screening plant, Libby, MT ................................................... 4-9

4-4. Population and methods used in studies of O.M. Scott, Marysville, OH plant workers.................................................................................................................. 4-10

4-5. Summary of methods used in community-based studies of Libby, MT residents conducted by Agency for Toxic Substances and Disease Registry (ATSDR) ............................................................................................................... 4-13

4-6. Nonmalignant respiratory mortality studies of populations exposed to Libby Amphibole asbestos .............................................................................................. 4-15

4-7. Chest radiographic studies of the Libby, MT vermiculite mine workers ............. 4-22

4-8. Pulmonary function and chest radiographic studies of the O.M. Scott, Marysville, OH plant workers .............................................................................. 4-24

4-9. Prevalence of pleural pathological alterations according to quartiles of cumulative fiber exposure in 280 participants ...................................................... 4-25

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LIST OF TABLES (continued)

4-10. Prevalence of pleural thickening in 280 participants according to various cofactors ................................................................................................................ 4-26

4-11. Pathological alterations of lung parenchyma and pleura in community-based studies ................................................................................................................... 4-30

4-12. Pulmonary function and respiratory symptoms and conditions changes in the Libby, MT community .......................................................................................... 4-32

4-13. Analyses of pulmonary changes seen on radiographs in relation to pulmonary function in the Libby, MT community ............................................... 4-34

4-14. Pulmonary function and respiratory system changes in the Libby, MT community: clinic-based study ............................................................................ 4-36

4-15. Autoimmune-related studies in the Libby, MT community ................................. 4-40

4-16. Respiratory (lung) cancer mortality and exposure-response analyses based on related studies of the vermiculite mining and milling workers in Libby, MT ........................................................................................................................ 4-42

4-17. Mesothelioma mortality risk based on studies of the vermiculite mine workers in Libby, MT ........................................................................................... 4-48

4-18. Exposure levels and health effects observed in communities exposed to tremolite, chrysotile, and crocidolite asbestos ...................................................... 4-52

4-19. In vivo data following exposure to Libby Amphibole asbestos ........................... 4-55

4-20. In vivo data following exposure to tremolite asbestos.......................................... 4-61

4-21. In vitro data following exposure to Libby Amphibole asbestos ........................... 4-74

4-22. In vitro data following exposure to tremolite asbestos ......................................... 4-76

4-23. Hypothesized modes of action for carcinogenicity of Libby Amphibole asbestos in specific organs .................................................................................. 4-100

5-1. Summary of candidate principal studies on LAA for reference concentration (RfC) derivation ...................................................................................................... 5-6

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5-2. Summary of rationale for identifying candidate principal studies on LAA for reference concentration (RfC) development ........................................................... 5-8

5-3. Characteristics of workers at the O.M. Scott plant in Marysville, OH ................. 5-12

5-4. Characteristics of workers at the O.M. Scott plant in Marysville, OH, with health evaluations in 2002−2005 who did not report any previous occupational exposure to asbestos ........................................................................ 5-18

5-5. Modelsa considered to develop a point of departure (POD) ................................. 5-24

5-6. Evaluation of association between covariates and exposure, and between covariates and LPT ............................................................................................... 5-27

5-7. Model features considered in exposure-response modeling to develop a point of departure (POD) ...................................................................................... 5-28

5-8. Univariate exposure-response modeling for any LPT in the Marysville workers who underwent health evaluations in 2002−2005 and whose job start date was on or after 1/1/1972 (n = 119), using a benchmark response (BMR) of 10% extra risk of any localized pleural thickening (LPT) ................... 5-31

5-9. Estimated point of departure (POD) combining information from the Marysville workers who underwent health evaluations in 2002−2005 and hired in 1972 or later (Primary), and from all workers who underwent health evaluations in 2002−2005 (regardless of hire date), using a benchmark response (BMR) of 10% extra risk of LPT in the Dichotomous Hill model with plateau fixed at 85% ..................................................................................... 5-38

5-10. (Copy of Table E-11) Reference concentrations (RfCs) for the alternative endpoint of any pleural thickening (APT) in the Marysville cohort with combined x-ray results from 1980 and 2002−2005 regardless of date of hire ..... 5-48

5-11. Multiple derivations of a reference concentration from the Marysville, OH cohort .................................................................................................................... 5-49

5-12. Exposure distribution among workers at the O.M. Scott plant in Marysville, OH ......................................................................................................................... 5-53

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5-13. Effect of truncating exposures after 1980 and of using arithmetic or geometric mean to summarize multiple fiber measurements ............................... 5-55

5-14. Effect of including covariates into the final model ............................................... 5-60

5-15. Effect of different assumptions for the plateau parameter .................................... 5-62

5-16. Exposure-response modeling for any localized pleural thickening (LPT) in the Marysville workers who underwent health evaluations in 2002−2005 and whose job start date was on or after 1/1/1972 (n = 119), using a benchmark response (BMR) of 10% extra risk of any LPT, and RTW exposure ................................................................................................................ 5-64

5-17. Effect of using different case/noncase definitions ................................................ 5-66

5-18. Exposure-response modeling for any localized pleural thickening (LPT) in the Marysville workers who underwent health evaluations in 2002−2005 (n = 252), comparing the multinomial model and logistic model with different outcome group definitions ..................................................................... 5-68

5-19. Summary of sensitivity analyses. Exposure-response modeling performed using mean exposure in the hybrid Dichotomous Hill model with plateau fixed at 85%, Marysville workers who underwent health evaluations in 2002−2005 and whose job start date was on or after 1/1/1972 (n = 119) ............ 5-70

5-20. Demographic, mortality, and exposure characteristics of the Libby worker cohort .................................................................................................................... 5-74

5-21. Exposure intensity (fibers/cc) for each location operation from the beginning of operations through 1982 ................................................................................... 5-79

5-22. Demographic, mortality, and exposure characteristics of the subset of the Libby worker subcohort hired after 1959 ............................................................. 5-83

5-23. Mesothelioma mortality rate shown by duration of exposure (yr) in the full Libby worker cohort including all hires (n = 1,871) ............................................ 5-93

5-24. Mesothelioma mortality rate shown by age at first exposure in the full Libby worker cohort including all hires (n = 1,871) ....................................................... 5-93

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5-25. Mesothelioma mortality rate shown by time since first exposure (TSFE) in the full Libby worker cohort including all hires (n = 1,871) ................................ 5-94

5-26. Comparison of model fit of various univariate exposure metrics for mesothelioma mortality in the full Libby worker cohort including all hires (n = 1,871) ............................................................................................................ 5-95

5-27. Lung cancer mortality rate shown by duration of exposure (yr) in the full Libby worker cohort including all hires (n = 1,871) ............................................ 5-96

5-28. Lung cancer mortality rate shown by age at first exposure in the full Libby worker cohort including all hires (n = 1,871) ....................................................... 5-97

5-29. Lung cancer mortality rate shown by time since first exposure (TSFE) in the full Libby worker cohort including all hires (n = 1,871) ...................................... 5-97

5-30. Mesothelioma mortality rate in the subcohort of employees hired after 1959 shown by duration of exposure (yr) .................................................................... 5-104

5-31. Mesothelioma mortality rate in the subcohort of employees hired after 1959 shown by age at first exposure ............................................................................ 5-104

5-32. Mesothelioma mortality rate in the subcohort of employees hired after 1959 shown by time since first exposure (TSFE) ........................................................ 5-104

5-33. Comparison of model fit of exposure metrics for mesothelioma mortality in the subcohort hired after 1959 ............................................................................ 5-105

5-34. Mesothelioma mortality rate in the subcohort of employees hired after 1959 for the cumulative exposure (CE) with 15-year lag and 5-year half-life ............ 5-107

5-35. Mesothelioma mortality rate in the subcohort of employees hired after 1959 for the cumulative exposure (CE) with 10-year lag and 5-year half-life ............ 5-107

5-36. Mesothelioma mortality rate in the subcohort of employees hired after 1959 for the Peto model ............................................................................................... 5-107

5-37. Mesothelioma mortality rate in the subcohort of employees hired after 1959 for the Peto model with power k = 3.9 and decay λ = 6.8%/yr .......................... 5-107

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5-38. Mesothelioma mortality rate in the subcohort of employees hired after 1959 for the Peto model with power k = 5.4 and decay λ = 15%/yr ............................ 5-108

5-39. Mesothelioma mortality exposure metrics fits, slopes per day, and credible intervals in the subcohort of employees hired after 1959 ................................... 5-112

5-40. Peto model and Peto model with clearance fits, slopes per year, and credible intervals in the subcohort of employees hired after 1959 ................................... 5-113

5-41. Lung cancer mortality rate in the subcohort of employees hired after 1959 shown by duration of exposure (yr) .................................................................... 5-114

5-42. Lung cancer mortality rate in the subcohort of employees hired after 1959 shown by age at first exposure ............................................................................ 5-114

5-43. Lung cancer mortality rate in the subcohort of employees hired after 1959 shown by time since first exposure (TSFE) ........................................................ 5-114

5-44. Model fit comparison for different exposure metrics and lung cancer mortality associated with LAA, controlling for age, gender, race, and date of birth ..................................................................................................................... 5-116

5-45. Lung cancer mortality exposure metrics fits, slopes, and confidence intervals (CI) for all retained metrics from Table 5-44 ..................................................... 5-120

5-46. Sensitivity analysis of model fit comparison for different exposure metrics and mesothelioma mortality associated with LAA ............................................. 5-125

5-47. Sensitivity analysis of model fit comparison for different exposure metrics and lung cancer mortality associated with LAA, controlling for age, gender, race, and date of birth ......................................................................................... 5-126

5-48. Unit risks for the Peto model and Peto model with clearance ............................ 5-128

5-49. Mesothelioma mortality exposure metrics unit risks for the subcohort hired after 1959 ............................................................................................................ 5-129

5-50. Mesothelioma unit risks for the subcohort hired after 1959 adjusted for underascertainment ............................................................................................. 5-130

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5-51. Mesothelioma unit risks for the subcohort hired after 1959 based on the Peto model and the Peto model with clearance adjusted for mesothelioma underascertainment ............................................................................................. 5-130

5-52. Unit risks for subset of lung cancer models with lagged exposures that yielded statistically significant model fit (p < 0.05) and exposure metric fit (p < 0.05) to the epidemiologic data ................................................................... 5-131

5-53. Estimates of the combined central estimate of the unit risk for mesothelioma and lung cancer and the combined upper-bound lifetime unit risks for mesothelioma and lung cancer risks (the Inhalation Unit Risk for LAA) for different combination of mesothelioma and lung cancer models ....................... 5-133

5-54. Lung cancer regression results from different analyses of cumulative exposure in the cohort of workers in Libby, MT ................................................ 5-136

5-55. Mesothelioma analysis results from different analyses of cumulative exposure in the Libby workers cohort ................................................................ 5-140

6-1. Estimates of the combined central estimate of the unit risk for mesothelioma and lung cancer and the combined upper-bound lifetime unit risks for mesothelioma and lung cancer risks (the Inhalation Unit Risk) for different combination of mesothelioma and lung cancer models ........................................ 6-20

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LIST OF FIGURES

2-1. Vermiculite mining operation on Zonolite Mountain, Libby, MT ......................... 2-1

2-2. Unexpanded and expanded vermiculite .................................................................. 2-2

2-3. Structure of the silicate minerals, illustrating silicate subclasses by the linking of the basic silicon tetrahedron (A) into more complex structures (B, C, or D) ................................................................................................................... 2-4

2-4. Cross section of amphibole fibers showing the silicon tetrahedrons (triangles with open circles at apex) that make up each double-chain plate (shown along the fiber axis) ................................................................................................ 2-5

2-5. Comparison of crystalline forms of amphibole minerals ........................................ 2-8

2-6. Mineralogy of LAA structures from samples taken from the Zonolite Mountain site ........................................................................................................ 2-12

2-7. Solution series linking tremolite, winchite, and richterite amphibole fibers ........ 2-13

2-8. Scanning electron microscope image of amphibole mineral structures from the Libby, MT mine .............................................................................................. 2-17

2-9. Fiber morphology of amphibole asbestos from the Libby, MT mine viewed under a scanning electron microscope .................................................................. 2-18

2-10. Particle size (length, width, aspect ratio) of fibers in Libby ore and Libby air .... 2-19

2-11. Nationwide distribution of Libby ore by county (in tons) .................................... 2-22

3-1. General scheme for fiber deposition, clearance, and translocation of fibers from the lung and gastrointestinal tract .................................................................. 3-3

3-2. Architecture of the human respiratory tract and schematic of major mechanisms of fiber deposition .............................................................................. 3-4

4-1. Investigations of populations exposed to LAA ....................................................... 4-2

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LIST OF FIGURES (continued)

4-2. A (left). Gross appearance at autopsy of asbestos-associated pleural plaques overlying the lateral thoracic wall [(ATS, 2004) Figure 12]. Figure 4-2. B (right). Gross appearance of large asbestos-related pleural plaque over the dome of the diaphragm [(ATS, 2004) Figure 13]. ................................................ 4-19

4-3. Lung cancer mortality risk among workers in the Libby, MT vermiculite mine and mill workers .......................................................................................... 4-45

4-4. Proposed mechanistic events for carcinogenicity of asbestos fibers .................... 4-72

5-1. Candidate studies for derivation of the reference concentration (RfC) in three different study populations, with the most recent study of each population circled ................................................................................................... 5-5

5-2. Radiographic outcomes among Marysville, OH workers ..................................... 5-13

5-3. Plot of exposure-response models for probability of localized pleural thickening (LPT) as a function of mean concentration of occupational exposure in the subcohort ..................................................................................... 5-34

5-4. Predicted risk of localized pleural thickening (LPT) at the benchmark concentration (BMC) and the lower limit of the BMC (BMCL), using the hybrid Dichotomous Hill model with plateau fixed at 85% ................................. 5-40

5-5. Plot of the National Institute for Occupational Safety and Health (NIOSH) job-exposure matrix for different job categories over time .................................. 5-84

5-6. Distribution of values of the Peto metric and Peto metric values of mesothelioma deaths (shown as inverted triangles) in the subcohort of employees hired after 1959 ................................................................................. 5-109

5-7. Distribution of observed values of cumulative exposure (CE) with 15-year lag and 5-year half-life and CE with 15-yr lag and 5-yr half-life values of mesothelioma deaths (shown as inverted triangles) in the subcohort of employees hired after 1959 ................................................................................. 5-110

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LIST OF FIGURES (continued)

5-8. Distribution of observed values of cumulative exposure (CE) with 10-year lag and 5-year half-life and CE with 10-yr lag and 5-yr half-life values of mesothelioma deaths (shown as inverted triangles) in the subcohort of employees hired after 1959 ................................................................................. 5-111

5-9. Regression diagnostics showing model fit based on the Schoenfeld residuals with two levels of nonparametric smoothing (using cubic splines) to show any patterns of departures from the model predicted values .............................. 5-122

xviii

LIST OF ABBREVIATIONS AND ACRONYMS

AAHAU Airborne Asbestos Health Assessment Update AIC Akaike Information Criterion ADAF age-dependent adjustment factor ANA antinuclear antibody APC antigen-presenting cells APT any pleural thickening ARC any radiographic change ATS American Thoracic Society ATSDR Agency for Toxic Substances and Disease Registry BALF bronchoalveolar lavage fluid BGL β-glucuronidase BMI body mass index BMC benchmark concentration BMCL lower limit of the BMC BMR benchmark response C mean exposure CAO costophrenic angle obliteration CDF cumulative distribution frequency CE cumulative exposure CHEEC cumulative human equivalent exposure concentration CI confidence interval COPD chronic obstructive pulmonary disease COX-2 cyclooxygenase-2 CVD cardiovascular disease DEF deferoxamine deq aerodynamic equivalent diameter DIC Deviance Information Criterion DLCO single-breath carbon monoxide diffusing capacity DPT diffuse pleural thickening dsDNA double-stranded DNA EcSOD extracellular superoxide dismutase ED El Dorado tremolite EDS energy-dispersive spectroscopy EPA U.S. Environmental Protection Agency EPMA electron probe microanalysis FEV forced expiratory volume FVC forced vital capacity GOF goodness of fit GSH glutathione GST glutathione-S-transferase HAEC human airway epithelial cell HO heme oxygenase HTE hamster tracheal epithelial IARC International Agency for Research on Cancer ICD International Classification of Diseases

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LIST OF ABBREVIATIONS AND ACRONYMS (continued)

IFN interferon Ig immunoglobulin IH industrial hygiene IL interleukin ILO International Labour Organization IQR interquartile range IRIS Integrated Risk Information System IUR inhalation unit risk JEM job-exposure matrix KL lung cancer slope factor KM mesothelioma slope factor LAA Libby Amphibole asbestos LDH lactate dehydrogenase LEC01 95% lower confidence limit of the exposure concentration associated with 1%

increased risk LPT localized pleural thickening MCAA antimesothelial cell antibodies MCMC Monte Carlo Markov Chain MMP matrix metalloproteinase MOA mode of action Mppcf million particles per cubic foot MSHA U.S. Mine Safety and Health Administration NRC National Research Council NDI National Death Index Nf2 neurofibromatosis 2 NIEHS National Institute of Environmental Health Sciences NIOSH National Institute for Occupational Safety and Health ON Ontario ferroactinolite OR odds ratio PBS phosphate-buffered saline PCM phase contrast microscopy PCMe phase contrast microscopy equivalent PG-PS peptidoglycan-polysaccharide PLM polarized light microscopy PM2.5 particulate matter 2.5 μm diameter or less POD point of departure RCF-1 refractory ceramic fibers RfC reference concentration RfD reference dose RNP ribonucleoprotein RNS reactive nitrogen species ROS reactive oxygen species RPM rat pleural mesothelial RR relative risk RTW residence time-weighted SAED selected area electron diffraction

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LIST OF ABBREVIATIONS AND ACRONYMS (continued)

SAID systemic autoimmune disease SD standard deviation SE standard error SH spontaneously hypertensive SHE Syrian hamster embryo SHHF spontaneously hypertensive-heart failure SIR standardized incidence ratio SM Sumas Mountain chrysotile SMR standardized mortality ratio SOD superoxide dismutase SRR standardized rate ratio SSA/Ro52 autoantibody marker for apoptosis SSB/La autoantibody marker SV40 Simian virus 40 TEM transmission electron microscopy TSFE time since first exposure TWA time-weighted average UCL upper confidence limit UF uncertainty factor UICC Union for International Cancer Control USGS United States Geological Survey VAI vermiculite attic insulation WDS wavelength-dispersive x-ray spectroscopy WKY Wistar-Kyoto rat XRCC1 x-ray repair cross-complementing protein 1

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FOREWORD

The purpose of this Toxicological Review is to provide scientific support and rationale for the hazard and dose-response assessment in the Integrated Risk Information System (IRIS) pertaining to chronic inhalation exposure to Libby Amphibole asbestos, a mixture of amphibole fibers identified in the Rainy Creek complex and present in ore from the vermiculite mine near Libby, MT. It is not intended to be an assessment of the toxicity of asbestos generally (nor a comprehensive treatise on the agent or toxicological nature of Libby Amphibole asbestos). The purpose of this document is to establish a Libby Amphibole asbestos-specific reference concentration to address noncancer health effects and to characterize the carcinogenic potential and establish an inhalation unit risk for Libby Amphibole asbestos-related lung cancer and mesothelioma mortality.

The intent of Section 6, Major Conclusions in the Characterization of Hazard and Exposure Response, is to present the significant conclusions reached in the derivation of the reference dose, reference concentration, and cancer assessment where applicable, and to characterize the overall confidence in the quantitative and qualitative aspects of hazard and dose-response by addressing the quality of data and related uncertainties. The discussion is intended to convey the limitations of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk assessment process.

The intent of Appendix J, Documentation of Implementation of the 2011 National Research Council Recommendations, is to present the IRIS Program’s implementation of the NRC recommendations. Implementation is following a phased approach that is consistent with the NRC’s “Roadmap for Revision” as described in Chapter 7 of the formaldehyde review report.

For other general information about this assessment or other questions relating to IRIS, the reader is referred to U.S. Environmental Protection Agency’s (EPA’s) IRIS Hotline at (202) 566-1676 (phone), (202) 566-1749 (fax), or [email protected] (email address).

xxii

AUTHORS, CONTRIBUTORS, AND REVIEWERS

CHEMICAL MANAGERS/AUTHORS Thomas F. Bateson, ScD, MPH National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Robert Benson, PhD Region 8 Office of Partnerships and Regulatory Assistance U.S. Environmental Protection Agency Denver, CO AUTHORS Krista Yorita Christensen, PhD Formerly with the National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Glinda Cooper, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Danielle DeVoney, PhD, DABT, PE Captain in the U.S. Public Health Service Formerly with the National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Maureen R. Gwinn, PhD, DABT, ATS National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Leonid Kopylev, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC

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AUTHORS, CONTRIBUTORS, AND REVIEWERS (continued)

CONTRIBUTING AUTHORS Rebecca Dzubow, MPH, MEM Formerly with the National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC David Berry, PhD Region 8 U.S. Environmental Protection Agency Denver, CO Malcolm Field, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Annie M. Jarabek National Center for Environmental Assessment U.S. Environmental Protection Agency Research Triangle Park, NC Keith Salazar, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Patricia Sullivan, ScD Division of Respiratory Disease Studies National Institute for Occupational Safety and Health Morgantown, WV CONTRIBUTORS David Bussard National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Samantha J. Jones, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC

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CONTRIBUTORS (continued) Babasaheb Sonawane, PhD National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC Paul White National Center for Environmental Assessment U.S. Environmental Protection Agency Washington, DC CONTRACTOR SUPPORT William Brattin, PhD Syracuse Research Corporation Denver, CO Highlight Technologies, LLC, Fairfax, VA

Dan Heing Debbie Kleiser Sandra Moore Ashley Price Kathleen Secor

CACI International, Inc, Arlington, VA

Thomas Schaffner Linda Tackett Lisa Walker

ECFlex, Inc., Fairborn, OH

Heidi Glick Crystal Lewis Carman Parker-Lawler Lana Wood

IntelliTech Systems, Inc., Fairborn, OH

Cris Broyles

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REVIEWERS This document was provided for review to EPA scientists, interagency reviewers from

other federal agencies and the Executive Office of the President, and the public, and peer reviewed by independent scientists external to EPA. A summary and EPA’s disposition of the comments received from the independent external peer reviewers and the public is included in Appendix A.

Science Advisory Board (SAB) Panel for Review of EPA’s Draft Toxicological Review of Libby Amphibole Asbestos CHAIR Dr. Agnes Kane Professor and Chair Department of Pathology and Laboratory Medicine Brown University Providence, RI MEMBERS Dr. John R. Balmes Professor Department of Medicine, Division of Occupational and Environmental Medicine University of California San Francisco, CA Dr. James Bonner Associate Professor Toxicology North Carolina State University Raleigh, NC Dr. Jeffrey Everitt Director Department of Laboratory Animal Science GlaxoSmithKline Pharmaceuticals Research Triangle Park, NC Dr. Scott Ferson Senior Scientist Applied Biomathematics Setauket, NY

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MEMBERS (continued) Dr. George Guthrie Focus Area Leader Geological and Environmental Sciences National Energy Technology Laboratory, U.S. Department of Energy Pittsburgh, PA Mr. John Harris Principal LabCor Portland, Inc. Portland, OR Dr. Tom Hei Professor and Vice-Chairman Radiation Oncology, College of Physicians and Surgeons Columbia University Medical Center New York, NY Dr. David Kriebel Professor and Chair Department of Work Environment School of Health & Environment, University of Massachusetts Lowell, MA Dr. Morton Lippmann Professor Nelson Institute of Environmental Medicine New York University School of Medicine Tuxedo, NY Dr. John Neuberger Professor Preventive Medicine and Public Health, School of Medicine University of Kansas Kansas City, KS Dr. Lee Newman Professor of Medicine Division of Environmental and Occupational Health Sciences School of Public Health, University of Colorado Aurora, CO

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MEMBERS (continued) Dr. Michael Pennell Assistant Professor Division of Biostatistics College of Public Health, Ohio State University Columbus, OH Dr. Julian Peto Professor Department of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London, UK Dr. Carrie Redlich Professor of Medicine Internal Medicine School of Medicine, Yale University New Haven, CT Dr. Andrew G. Salmon Senior Toxicologist Office of Environmental Health Hazard Assessment California Environmental Protection Agency Oakland, CA Dr. Elizabeth A. (Lianne) Sheppard Professor Biostatistics and Environmental & Occupational Health Sciences School of Public Health, University of Washington Seattle, WA Dr. Randal Southard Professor of Soils AES Dean's Office University of California at Davis Davis, CA Dr. Katherine Walker Senior Staff Scientist Health Effects Institute Boston, MA

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MEMBERS (continued) Dr. James Webber Research Scientist Wadsworth Center New York State Department of Health Albany, NY Dr. Susan Woskie Professor Work Environment, Health and Environment University of Massachusetts Lowell Lowell, MA SCIENCE ADVISORY BOARD STAFF Dr. Diana Wong Designated Federal Officer U.S. Environmental Protection Agency Washington, DC

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1. INTRODUCTION

This document presents background information and justification for the Integrated Risk Information System (IRIS) summary of the hazard and exposure-response assessment of Libby Amphibole asbestos (LAA),1 a mixture of amphibole fibers identified in the Rainy Creek complex and present in ore from the vermiculite mine near Libby, MT. IRIS summaries may include oral reference dose (RfD) and inhalation reference concentration (RfC) values for chronic exposure durations, and a carcinogenicity assessment. This assessment reviews the potential hazards, both cancer and noncancer health effects, from exposure to LAA and provides quantitative information for use in risk assessments: an RfC for noncancer health effects and an inhalation unit risk (IUR) addressing cancer risk. LAA-specific data are not available to support RfD or cancer slope factor derivations for oral exposures.

An RfC is defined as “an estimate (with uncertainty spanning perhaps an order of magnitude) of an exposure (including sensitive subgroups) that is likely to be without an appreciable risk of adverse health effects over a lifetime.” (U.S. EPA, 2002). In the case of LAA, the RfC is expressed in terms of the lifetime exposure in units of fibers per cubic centimeter of air (fibers/cc) in units of the fibers as measured by phase contrast microscopy (PCM). The inhalation RfC for LAA considers toxic effects for both the respiratory system (portal of entry) and for effects peripheral to the respiratory system (extrarespiratory or systemic effects) that may arise after inhalation of LAA.

The carcinogenicity assessment provides information on the carcinogenic hazard potential of the substance in question, and quantitative estimates of risk from inhalation exposures are derived. The information includes a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic effects may be expressed. Quantitative risk estimates are derived from the application of a low-dose extrapolation procedure from human data. An inhalation unit risk (IUR) is typically defined as a plausible upper bound on the estimate of cancer risk per μg/m3 air breathed for 70 years. For LAA, the RfC is expressed as a lifetime daily exposure in fibers/cc (in units of the fibers as measured by PCM), and the IUR is expressed as cancer risk per fibers/cc (in units of the fibers as measured by PCM).

Development of these hazard identification and exposure-response assessments for LAA has followed the general guidelines for risk assessment as set forth by the National Research Council (NRC, 1983). U.S. Environmental Protection Agency (EPA) Guidelines and Risk Assessment Forum technical panel reports that may have been used in the development of this assessment include the following: Guidelines for the Health Risk Assessment of Chemical

1The term “Libby Amphibole asbestos” is used in this document to identify the mixture of amphibole mineral fibers of varying elemental composition (e.g., winchite, richterite, tremolite, etc.) that have been identified in the Rainy Creek complex near Libby, MT. It is further described in Section 2.2.

1-1

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Mixtures (U.S. EPA, 1986c), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988b), Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991a), Interim Policy for Particle Size and Limit Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994b), Use of the Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998), Science Policy Council Handbook: Risk Characterization (U.S. EPA, 2000b), Benchmark Dose Technical Guidance Document (U.S. EPA, 2012), Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S. EPA, 2000c), A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002), Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA, 2005b), Science Policy Council Handbook: Peer Review (U.S. EPA, 2006c), and A Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 2006b).

The literature search strategy employed for this assessment is based on EPA’s National Center for Environmental Assessment’s Health and Environmental Research Online database tool (which includes PubMed, MEDLINE, Web of Science, JSTOR, and other literature sources). The key search terms included the following: Libby Amphibole, tremolite, asbestos, richterite, winchite, amphibole, and Libby, MT. The relevant literature was reviewed through July 2011. Any pertinent scientific information submitted by the public to the IRIS Submission Desk was also considered in the development of this document. Note that references have been added to the Toxicological Review after the external peer review SAB (2013) in response to peer reviewers’ comments and for the sake of completeness. 1.1. RELATED ASSESSMENTS 1.1.1. Integrated Risk Information System (IRIS) Assessment for Asbestos (U.S. EPA,

1988a) The IRIS assessment for asbestos was posted online in IRIS in 1988 and includes an IUR

of 0.23 excess cancers per 1 fiber/cc (U.S. EPA, 1988a); this unit risk is given in units of the fibers as measured by PCM. The IRIS IUR2 for general asbestos (CAS Number 1332-21-4) is derived by estimating excess cancers for a continuous lifetime exposure and is based on the central tendency―not the upper bound―of the risk estimates (U.S. EPA, 1988a) and is applicable to exposures across a range of exposure environments and types of asbestos. Although other cancers have been associated with asbestos [e.g., laryngeal, stomach, ovarian

2For purposes of this document, termed “IRIS IUR.”

1-2

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(Straif et al., 2009)], the IRIS IUR for asbestos accounts for only lung cancer and mesothelioma. Additionally, pleural and pulmonary effects from asbestos exposure (e.g., pleural thickening, asbestosis, and reduced lung function) are well documented, although there is no RfC for these noncancer health effects on the IRIS database (U.S. EPA, 1988a).

The derivation of the unit risk for general asbestos is based on the Airborne Asbestos Health Assessment Update [AAHAU (U.S. EPA, 1986a)]. The AAHAU provides various cancer potency factors and mathematical models of lung cancer and mesothelioma mortality based on synthesis of data from occupational studies and presents estimates of lifetime cancer risk for continuous environmental exposures [0.0001 fiber/cc and 0.01 fiber/cc; (see Table 6-3 of (U.S. EPA, 1986a)]. For both lung cancer and mesothelioma, life-table analysis was used to generate risk estimates based on the number of years of exposure and the age at onset of exposure. Although various exposure scenarios were presented, the unit risk is based on a lifetime continuous exposure from birth. The final asbestos IUR is 0.23 excess cancers per 1 fiber/cc continuous exposure3 and was posted on the IRIS database in 1988 [(U.S. EPA, 1988a) see Table 1-1 below].

Table 1-1. Derivation of the current Integrated Risk Information System (IRIS) inhalation unit risk for asbestos from the lifetime risk tables in the Airborne Asbestos Health Assessment Update (AAHAU) at 0.01 fiber/cc

Gender

Excess deaths per 100,000a

Risk Unit risk

(per fiber/cc) Mesothelioma Lung cancer Total

Female 183 35 218.5 2.18 × 10-1

Male 129 114 242.2 2.42 × 10-1

All 156 74 230.3 2.30 × 10-1 0.23

aData are for exposure at 0.01 fiber/cc for a lifetime. Source: U.S. EPA (1988a).

The IRIS database has an IUR for asbestos based on 14 epidemiologic studies that

included occupational exposure to chrysotile, amosite, or mixed-mineral exposures [chrysotile, amosite, crocidolite (U.S. EPA, 1988a, 1986a)]. Some uncertainty remains in applying the resulting IUR for asbestos to exposure environments and minerals different from those analyzed

3An IUR of 0.23 for general asbestos can be interpreted as 0.23 excess risk of death from mesothelioma or lung cancer per person for each 1 fiber/cc increase in continuous lifetime exposure. Thus, as shown in Table 1-1, for 100,000 people exposed at a concentration of 0.01 fiber/cc, 230 excess deaths would be expected [IUR × Concentration × Number of people = (0.23 excess cancer deaths per fiber/cc per person) × (0.01 fiber/cc) × (100,000 people) = 230 excess cancer deaths]. “Fiber/cc” is a commonly used measure; it is equivalent to 1 million fibers per cubic meter of air while 0.01 fiber/cc is 10,000 fibers per cubic meter of air.

1-3

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in the AAHAU (U.S. EPA, 1986a). No RfC, RfD, or oral slope factor are derived for asbestos on the IRIS database (U.S. EPA, 1988a).

1.1.2. EPA Health Assessment for Vermiculite (U.S. EPA, 1991b)

An EPA health assessment for vermiculite reviewed available health data, including studies on workers who mined and processed ore with no significant amphibole fiber content. The cancer and noncancer health effects observed in the Libby, MT worker cohort were not seen in studies of workers exposed to mines with similar exposure to vermiculite but much lower exposures to asbestos fibers. Therefore, it was concluded that the health effects observed from the materials mined from Zonolite Mountain near Libby, MT, were most likely due to amphibole fibers and not the vermiculite itself (U.S. EPA, 1991b). At the time, EPA recommended the application of the IRIS IUR for asbestos fibers (0.23 per fiber/cc) in addressing potential risk of the amphibole fibers entrained in vermiculite mined in Libby, MT.

1.2. LIBBY AMPHIBOLE ASBESTOS-SPECIFIC HUMAN HEALTH ASSESSMENT

LAA is a complex mixture of amphibole fibers―both mineralogically and morphologically (see Section 2.3). The mixture primarily includes winchite, richterite, and tremolite fibers with trace amounts of magnesio-riebeckite, edenite, and magnesio-arfvedsonite. These fibers exhibit a complete range of morphologies from prismatic crystals to asbestiform fibers (Meeker et al., 2003). Epidemiologic studies of workers exposed to LAA fibers indicate increased lung cancer and mesothelioma, as well as asbestosis and other nonmalignant respiratory diseases (Larson et al., 2010b; Larson et al., 2010a; Moolgavkar et al., 2010; Rohs et al., 2008; Sullivan, 2007; McDonald et al., 2004, 2002; Amandus et al., 1988; Amandus et al., 1987b; Amandus and Wheeler, 1987; Amandus et al., 1987a; McDonald et al., 1986a; McDonald et al., 1986b; Lockey et al., 1984).

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2. LIBBY AMPHIBOLE ASBESTOS: GEOLOGY AND EXPOSURE POTENTIAL

2.1. INTRODUCTION Libby is a community in northwestern Montana that is located near a large open-pit

vermiculite mine that operated from the mid 1920s to 1990 (see Figure 2-1). Vermiculite is a silicate mineral that exhibits a sheet-like structure similar to mica (see Figure 2-2, Panel A). When heated to approximately 870°C, water molecules between the sheets change to vapor and cause the vermiculite to expand like popcorn into a light, porous material (see Figure 2-2, Panel B). This process of expanding vermiculite is termed “exfoliation” or “popping.” Both unexpanded and expanded vermiculite have found a range of commercial applications, the most common of which include packing material, attic and wall insulation, various garden and agricultural products, and various cement and building products.

Figure 2-1. Vermiculite mining operation on Zonolite Mountain, Libby, MT.

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Panel A: Vermiculite ore sample. Vermiculite ore sample, Zonolite Mountain, Rainy Creek complex, Libby, MT.

Source: USGS Field Collection, Meeker (2007)

Panel B: Expanded vermiculite

Figure 2-2. Unexpanded and expanded vermiculite.

The primary product from the mine was vermiculite concentrate, which was produced by

milling, screening, and grading the raw ore to enrich for the vermiculite mineral. In general, mining practices sought to exclude nonvermiculite material when harvesting the ore, and subsequent processing steps were designed to eliminate nonvermiculite materials from the

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finished product. Nevertheless, small amounts of other minerals from the ore body tended to remain in the vermiculite (Zonolite) product. This included a form of asbestos referred to as Libby Amphibole asbestos (LAA).

This chapter provides a brief description of the mineralogical characteristics of asbestos (see Section 2.2), an overview of methods used to identify and measure asbestos in air and solid materials (see Section 2.3), a review of the mineralogical characteristics of LAA in particular (see Section 2.4), and an overview of the potential for current human exposures to LAA (see Section 2.5).

2.2. GEOLOGY AND MINERALOGY OF AMPHIBOLES 2.2.1. Overview

Asbestos is the generic name for a group of naturally-occurring silicate minerals that crystallize in long thin fibers. The basic chemical unit of asbestos and other silicate minerals is [SiO4]4−. This basic unit consists of four oxygen atoms at the apices of a regular tetrahedron surrounding and coordinated with one silicon ion (Si4+) at the center (see Figure 2-3, Panel A). The silicate tetrahedra can bond to one another through the oxygen atoms, leading to a variety of crystal structures (see Figure 2-3, Panels B, C, and D).

There are two main classes of asbestos: serpentine and amphibole. The only member of the serpentine class is chrysotile, which is the form of asbestos that was most commonly used in the past in various man-made asbestos-containing materials (insulation, brake linings, floor tiles, etc.). Chrysotile is a phyllosilicate (see Figure 2-3, Panel D), occurring in sheets that curl into a fibrous form.

There are many different types of amphibole asbestos. This includes five types that were previously used in commerce (actinolite, tremolite, amosite, crocidolite, and anthophyllite), and these forms of asbestos are now regulated. Numerous other asbestiform amphiboles exist, even though they were never used as commercial products and are not currently named in regulations (Gunter et al., 2007). All forms of amphibole asbestos are inosilicates (see Figure 2-3, Panel C) in which the long axis of the fiber (crystallographically called the c-axis) is parallel to the direction of the chain of silicon tetrahedra.

2.2.2. Mineralogy of Amphibole Asbestos and Related Amphibole Minerals

Different types of amphiboles differ from each other primarily in the identity and amounts of monovalent and divalent cations that bind to sites (referred to as A, B, or C sites) along the silicate chains (see Figure 2-4). The specific cations between the two double-chain plates define the elemental composition of the mineral, while the ratio of these cations in each location is used to classify amphiboles within a solid-solution series. The general chemical formula for double-chain inosilicate amphiboles is shown below:

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(A) Nesosilicates or single tetrahedron. The single tetrahedron comprises four oxygen molecules covalently bound to the silicon, at the center of the [SiO4]4−-tetrahedron. (B) Inosilicates [ino (gr.) = thread]―Single-chain silicates. Chain silicates are realized by linking [SiO4]4−-tetrahedrons in a way to form continuous chains. They can be represented by a composition of [SiO3]2−. A typical example is diopside CaMg[Si2O6], in which the “endless” chains are also held together by Ca2+ and Mg2+ ions. (C) Inosilicates―Double-chain silicates. Two silicate chains of the inosilicates are linked at the corners, forming double-chains and yielding [Si4O11]6− ions, as realized in the tremolite-ferro-actinolite series Ca2(Mg,Fe)5Si8O22(OH,F,Cl)2. Double-chain silicates are commonly grouped with the single-chain inosilicates. (D) Phyllosilicates [phyllo (gr.) = sheet] or sheet silicates. These are formed if the double-chain inosilicate [Si4O11]6− chains are linked to form continuous sheets with the chemical formula [Si2O5]2−. Examples of sheet silicates include chrysotile Mg3Si2O5(OH)4 and vermiculite [(Mg, Fe,Al)3(Al,Si)4O10(OH)2 ●4H2O].

Figure 2-3. Structure of the silicate minerals, illustrating silicate subclasses by the linking of the basic silicon tetrahedron (A) into more complex structures (B, C, or D).

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Figure 2-4. Cross section of amphibole fibers showing the silicon tetrahedrons (triangles with open circles at apex) that make up each double-chain plate (shown along the fiber axis). Cations (shown as the darkened dots) occur between the plates forming the basic fiber.

Source: Kroschwitz et al. (2007).

A0−1B2C5T8O22(OH, F, Cl)2 (2-1) where:

A = Na, K B = Na, Li, Ca, Mn, Fe2+, Mg C = Mg, Fe2+, Mn, Al, Fe3+, Ti T = Si, Al

The mineral subgroup within amphiboles is determined by the elemental composition.

• Calcic amphiboles (tremolite)

• Sodic-calcic amphiboles (richterite, winchite)

• Sodic amphiboles (riebeckite [also known as “crocidolite”], arfvedsonite)

• Iron-magnesium-manganese-lithium amphiboles (anthophyllite, cummingtonite-grunerite [also known as “amosite”])

Because the stoichiometry of the cations is not fixed, a continuum of compositions may

occur. These are referred to as “solid solution series.” The series are defined by their end

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members. For example, a solid solution series for the cation Site A will have one end member with 100% sodium ions and one end member with 100% potassium ions. This series would include all intervening ratios.

Because each cation site has multiple possibilities, the elemental composition of the amphibole silicates can be quite complex. It is the complexity of the amphiboles that has historically given rise to a proliferation of mineral names with little systematic basis (Hawthorne, 1981). Currently, amphiboles are identified by a clear classification scheme based on crystal chemistry that uses well-established names based on the basic mineralogy, with prefixes and adjective modifiers indicating the presence of substantial substitutions that are not essential constituents of the end members (Leake et al., 1997). As implemented, this mineral classification system does not designate certain amphibole minerals as asbestos. However, some mineral designations have traditionally been considered asbestos (in the asbestiform habit; e.g., tremolite, actinolite). Other commercial forms of asbestos were known by trade names (e.g., Amosite) rather than mineralogical terminology (cummingtonite-grunerite).

2.2.3. Morphology of Amphibole Minerals

Most amphibole minerals occur in a variety of growth habits, depending on the temperature, pressure, local stress field, and solution chemistry conditions during crystallization. The nomenclature used to describe the crystal forms varies between disciplines [field geologist, microscopist; e.g., see Lowers and Meeker (2002)]. Text Box 2-1 provides definitions for common terms used to describe the morphology of asbestos and other related minerals.

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Text Box 2-1: Nomenclature

Acicular: The shape showed by and extremely slender crystal with small cross-sectional dimensions (a special case of prismatic form). Acicular crystals may be blunt-ended or pointed. The term “needlelike” refers to an acicular crystal with pointed termination at one of both ends.

Amphibole: A group of silicate minerals that may occur either in massive or fibrous (asbestiform) habits.

Asbestiform (mineralogical): A specific type of mineral fibrosity in which the fibers and fibrils are long, thin, and possess high tensile strength and flexibility.

Asbestiform (regulatory): A specific type of fibrosity in which the fibers and fibrils possess high tensile strength and flexibility.

Asbestos: A group of highly fibrous silicate minerals that readily separate into long, thin, strong fibers that have sufficient flexibility to be woven, are heat resistant and chemically inert, are electrical insulators, and therefore are suitable for uses where incombustible, nonconducting, or chemically resistant materials are required.

Bundle: A group of fibers occurring side by side with parallel orientations.

Cleavage fragment: A fragment produced by breakage of crystal in directions that are related to the crystal structure and are always parallel to possible crystal faces.

Cluster: A group of overlapping fibers oriented at random.

Fiber (regulatory): A particle that has an aspect ratio (length of the particle divided by its width), and depending on the analytical methods used, a particle is considered a fiber if it has a length greater than or equal to 5 µm and aspect ratio greater than or equal to 3:1 (by PCM) or 5:1 (by transmission electron microscopy [TEM]).

Fiber (mineralogical): The smallest, elongate crystalline unit that can be separated from a bundle or appears to have grown individually in that shape, and that exhibits a resemblance to organic fibers.

Fibril: A single fiber which cannot be separated into smaller components without losing its fibrous properties or appearance. A substructure of a fiber.

Fibrous: The occurrence of a mineral in bundles of fibers, resembling organic fibers in texture, from which the fibers can usually be separated. Crystallized in elongated, thin, needlelike grains or fibers.

Massive: A mineral form that does not contain fibrous crystals.

Matrix: A particle of nonasbestos material that has one or more fibers associated with it.

Prismatic: Having blocky, pencil-like elongated crystals that are thicker than needles.

Structure: A term used mainly in microscopy, usually including asbestos fibers, bundles, clusters, and matrix particles that contain asbestos.

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Asbestiform morphology is present where the conditions of formation allow crystals to form very long individual flexible fibers which are parallel and easily separable and may become visible to the naked eye when crushed (see Figure 2-5). Under the microscope, individual amphibole structures may be described as asbestiform, acicular, prismatic, or fibrous. Typically, a fiber is defined as a highly elongated crystal with parallel sides. The definitions for acicular crystals are “needlelike” in appearance while prismatic crystals may have several parallel faces with a low aspect ratio (ratio of length to width,

2.3. METHODS FOR ANALYSIS OF ASBESTOS Because asbestos is a solid that does not dissolve in water or other solvents, methods for

the analysis of asbestos are somewhat different than for most other chemical substances. This section provides a brief overview of the most common methods for the analysis of asbestos.

2.3.1. Methods for Air Samples

The exposure pathway of primary health concern for humans is inhalation of asbestos. Air is evaluated for the presence of asbestos by drawing a known volume of air through a filter that traps the solid particles in the air on the filter surface, and the

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