Controlled Human Inhalation-Exposure Studies at EPA

Committee on Assessing Toxicologic Risks to Human Subjects Used in
Controlled Exposure Studies of Environmental Pollutants

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

A Report of

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. Controlled Human Inhalation-Exposure Studies at EPA. Washington, DC: The National Academies Press. doi: 10.17226/24618.

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COMMITTEE ON ASSESSING TOXICOLOGIC RISKS TO HUMAN SUBJECTS USED IN CONTROLLED EXPOSURE STUDIES OF ENVIRONMENTAL POLLUTANTS

Members

ROBERT A. HIATT (Chair), University of California, San Francisco, CA

JOHN BAILER, Miami University, Oxford, OH

REBECCA BASCOM, Pennsylvania State University, Hershey, PA

LARRY CHURCHILL, Vanderbilt University Medical Center, Nashville, TN

KENNY CRUMP, Independent Consultant, Ruston, LA

MARGARET FOSTER RILEY, University of Virginia School of Law, Charlottesville, VA

DANIELA B. FRIEDMAN, University of South Carolina, Columbia, SC

DIANE GOLD, Brigham and Women’s Hospital, Harvard Medical School; Harvard School of Public Health, Boston, MA

LEWIS GOLDFRANK, New York University School of Medicine, New York, NY

NANCY LANE, University of California Davis Health System, Sacramento, CA

MORTON LIPPMANN, New York University School of Medicine, New York, NY

MURRAY MITTLEMAN, Harvard Medical School; Harvard School of Public Health, Boston, MA

PHILIP NEEDLEMAN, Washington University School of Medicine, Creve Coeur, MO

ROBERT PHALEN, University of California, Irvine, CA

HWASHIN SHIN, Health Canada, Ottawa, Ontario

Staff

RAYMOND WASSEL, Project Director

JANET MULLIGAN, Associate Program Officer (until December 2015)

MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center

RADIAH ROSE, Manager, Editorial Projects

ORIN LUKE, Senior Program Assistant

Sponsor

US ENVIRONMENTAL PROTECTION AGENCY

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Members

WILLIAM H. FARLAND (Chair), Colorado State University, Fort Collins, CO

RICHARD A. BECKER, American Chemistry Council, Washington, DC

COLGLAZIER, E. WILLIAM, AAAS, Washington, DC

DOMINIC M. DITORO, University of Delaware, Newark, DE

DAVID C. DORMAN, North Carolina State University, Raleigh, NC

CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY

ANNE FAIRBROTHER, Exponent, Inc., Philomath, OR

GEORGE GRAY, The George Washington University, Washington, DC

STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY

ROBERT A. HIATT, University of California, San Francisco, CA

SAMUEL KACEW, University of Ottawa, Ontario

H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA

ROBERT PERCIASEPE, Center for Climate and Energy Solutions, Arlington, VA

R. CRAIG POSTLEWAITE, Department of Defense, Burke, VA

MARK A. RATNER, Northwestern University, Evanston, IL

JOAN B. ROSE, Michigan State University, East Lansing, MI

GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA

ROBERT M. SUSSMAN, Sussman and Associates, Washington, DC

DEBORAH L. SWACKHAMER, University of Minnesota, St. Paul, MN

PETER S. THORNE, University of Iowa, Iowa City, IA

Staff

TERESA A. FRYBERGER, Director

ELLEN K. MANTUS, Scholar and Director of Risk Assessment

RAYMOND A. WASSEL, Scholar and Director of Environmental Studies

SUSAN N.J. MARTEL, Senior Program Officer for Toxicology

ELIZABETH BOYLE, Program Officer

TAMARA DAWSON, Program Associate

IVORY CLARKE, Research Assistant

BERNIDEAN WILLIAMS-SMITH, Financial Assistant

SUZANNE THILENIUS, Administrative Coordinator

OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Using 21st Century Science to Improve Risk-Related Evaluations (2017)

Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense (2015)

Review of California’s Risk-Assessment Process for Pesticides (2015)

Sustainability Concepts in Decision-Making: Tools and Approaches for the US Environmental Protection Agency (2014)

Rethinking the Components, Coordination, and Management of U.S. Environmental Protection Agency Laboratories (2014)

Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)

Review of the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)

Review of EPA’s Integrated Risk Information System (IRIS) Process (2014)

Review of the Environmental Protection Agency’s State-of-the-Science Evaluation of Nonmonotonic Dose-Response Relationships as They Apply to Endocrine Disruptors (2014)

Assessing Risks to Endangered and Threatened Species from Pesticides (2013)

Science for Environmental Protection: The Road Ahead (2012)

Exposure Science in the 21st Century: A Vision and a Strategy (2012)

A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2012)

Macondo Well-Deepwater Horizon Blowout: Lessons for Improving Offshore Drilling Safety (2012)

Feasibility of Using Mycoherbicides for Controlling Illicit Drug Crops (2011)

Improving Health in the United States: The Role of Health Impact Assessment (2011)

A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration (2011)

Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011)

Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary (2010)

The Use of Title 42 Authority at the U.S. Environmental Protection Agency: A Letter Report (2010)

Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene (2010)

Hidden Costs of Energy: Unpriced Consequences of Energy Production and Use (2009)

Contaminated Water Supplies at Camp Lejeune: Assessing Potential Health Effects (2010)

Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (2009)

Science and Decisions: Advancing Risk Assessment (2009)

Phthalates and Cumulative Risk Assessment: The Tasks Ahead (2008)

Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008)

Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health (2008)

Evaluating Research Efficiency in the U.S. Environmental Protection Agency (2008)

Hydrology, Ecology, and Fishes of the Klamath River Basin (2008)

Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007)

Models in Environmental Regulatory Decision Making (2007)

Toxicity Testing in the 21st Century: A Vision and a Strategy (2007)

Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007)

Environmental Impacts of Wind-Energy Projects (2007)

Scientific Review of the Proposed Risk Assessment Bulletin from the Office of

Management and Budget (2007)

Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006)

New Source Review for Stationary Sources of Air Pollution (2006)

Human Biomonitoring for Environmental Chemicals (2006)

Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)

Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006)

State and Federal Standards for Mobile-Source Emissions (2006)

Superfund and Mining Megasites: Lessons from the Coeur d’Alene River Basin (2005)

Health Implications of Perchlorate Ingestion (2005)

Air Quality Management in the United States (2004)

Endangered and Threatened Species of the Platte River (2004)

Atlantic Salmon in Maine (2004)

Endangered and Threatened Fishes in the Klamath River Basin (2004)

Cumulative Environmental Effects of Oil and Gas Activities on Alaska’s North Slope (2003)

Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002)

Biosolids Applied to Land: Advancing Standards and Practices (2002)

The Airliner Cabin Environment and the Health of Passengers and Crew (2002)

Arsenic in Drinking Water: 2001 Update (2001)

Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001)

Compensating for Wetland Losses Under the Clean Water Act (2001)

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

Acute Exposure Guideline Levels for Selected Airborne Chemicals (20 volumes, 2000-2016)

Toxicological Effects of Methylmercury (2000)

Strengthening Science at the U.S. Environmental Protection Agency: Research-Management and Peer-Review Practices (2000)

Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000)

Ecological Indicators for the Nation (2000)

Waste Incineration and Public Health (2000)

Hormonally Active Agents in the Environment (1999)

Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004)

The National Research Council’s Committee on Toxicology: The First 50 Years 1947-1997 (1997)

Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances (1996)

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

Science and the Endangered Species Act (1995)

Wetlands: Characteristics and Boundaries (1995)

Biologic Markers (five volumes, 1989-1995)

Science and Judgment in Risk Assessment (1994)

Pesticides in the Diets of Infants and Children (1993)

Dolphins and the Tuna Industry (1992)

Science and the National Parks (1992)

Human Exposure Assessment for Airborne Pollutants: Advances and Opportunities (1991)

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

Decline of the Sea Turtles: Causes and Prevention (1990)

Copies of these reports may be ordered from the National Academies Press
(800) 624-6242 or (202) 334-3313
www.nap.edu

Preface

The U.S. Environmental Protection Agency (EPA), as part of its efforts to obtain important scientific information for the periodic review of National Ambient Air Quality Standards (NAAQS) for criteria pollutants, conducts studies in which human volunteer participants are intentionally exposed by inhalation to pollutants under controlled experimental conditions. The objective of those studies has been to produce transient and reversible biomarker or physiologic responses that inform about biologic mechanisms of pollutant effects but do not cause clinical effects.

Citing evidence of causal relationships between air-pollutant exposures and human health effects or premature mortality, some members of Congress and others have expressed concern about the risk of those controlled exposures to the subjects who participate in such exposure studies. In 2012 the chairman of the House Subcommittee on Investigations and Oversight asked EPA’s Office of Inspector General (OIG) to assess whether the agency followed applicable laws, regulations, policies, procedures, and guidance when it exposed human subjects to concentrated airborne particles or diesel exhaust particles.¹

The OIG report concluded that EPA followed applicable regulations in conducting controlled human exposure studies of concentrated airborne particles or diesel exhaust particles. The report also made several recommendations to EPA for enhancing the protection of study subjects through the agency’s policies and guidance.² In addition to implementing corrective actions in response to the OIG recommendations, EPA sought independent expert advice from the National Academies of Sciences, Engineering, and Medicine (NASEM) to address scientific issues and provide guidance on the conduct of controlled human exposure studies. In response, NASEM established the Committee on Assessing Toxicologic Risks to Human Subjects Used in Controlled Exposure Studies of Environmental Pollutants. The committee was asked to:

• Assess the utility of controlled inhalation exposure studies to inform and reduce uncertainties in setting air pollution standards to protect public health, and assess whether continuation of such studies is warranted.
• Assess health risks to test subjects who participated in recent studies of air pollutants at EPA’s clinical research facility.
• If the committee supports continued conduct of human exposure studies, provide further guidance on methods for estimating levels of risk in controlled human exposure studies.
• Provide advice on a template for characterizing reasonably foreseeable risks, which could be used in obtaining informed consent from potential study participants. (The committee’s formal statement of task is presented in Chapter 1.)

NASEM assembled a committee of 15 members who had expertise in clinical research trials, pulmonology, cardiology, critical care medicine, emergency medicine and medical toxicology, inhalation toxicology, ethics, exposure assessment, risk assessment, risk perception and communication, epidemiology, biostatistics, and environmental law. The committee included members knowledgeable about the different types of health-related evidence considered by EPA in the review of NAAQS. (Committee members’ biographical information is presented in Appendix A.) I am grateful to the members of the committee for their efforts throughout this study.

__________________

¹ Letter, dated October 18, 2012, from Rep. Paul Broun, Chairman, Subcommittee on Investigations and Oversight, U.S. House of Representatives Committee on Science, Space, and Technology to Arthur A. Elkins, Jr., Inspector General, U.S. EPA.

² EPA. 2014. Improvements to EPA Policies and Guidance Could Enhance Protection of Human Study Subjects. Office of Inspector General. Report No. 14-P-0154. March 31.

In the course of preparing its report, the committee held a public information-gathering session on June 1, 2015, and heard presentations from EPA representatives. The committee also held an information-gathering session on August 24, 2016, and heard presentations from individuals outside of EPA (see Appendix B). The committee considered the information provided in both sessions in preparing its report.

In addition, the committee requested written information to describe various aspects of the controlled human inhalation exposure studies conducted at EPA’s Human Studies Facility, located in Chapel Hill, North Carolina. Also, the committee requested information on how the results of those studies are used to inform agency decisions about the NAAQS. The committee also considered the OIG report, relevant previous NASEM reports, materials submitted by participants in the committee’s August 2016 information-gathering session, applicable government regulations and policies, and other pertinent published and unpublished documents.

This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise. The purposes of the independent review are to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report:

Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by the review coordinator, Joshua Sharfstein, Johns Hopkins Bloomberg School of Public Health, and the review monitor, Mark Cullen, Stanford University. They were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution.

Finally, I wish to express my appreciation to the members of the project staff for the very effective support they provided to the committee.

Abbreviations

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Contents

SUMMARY

1 INTRODUCTION

A Prior National Research Council Report on Controlled Human Exposure Studies

CHIE Studies at EPA

EPA’s Office of Inspector General Report

Committee’s Statement of Task

Terms for Referring to Individuals Exposed in CHIE Studies

Organization of the Report

2 FOUNDATIONAL ASPECTS OF HUMAN-SUBJECTS RESEARCH

Introduction

Air Pollution Health Effects Science for Managing Air Quality

Human-Subjects Research

Risk–Benefit Framework

3 VALUE OF CONTROLLED HUMAN INHALATION EXPOSURE STUDIES

Introduction

A Framework for Evaluating CHIE Studies

Sensitive Groups

CHIE Studies in the Context of Toxicologic and Epidemiologic Studies, and the Larger Research Agenda

Use of Biomarkers in CHIE Studies

Comparing CHIE Study Exposures with Ambient Pollutant Exposures

Considerations of CHIE Study Value for EPA Decision Making

CHIE Ozone Studies

CHIE PM Studies

Conclusions

4 ASSESSMENT OF CONTROLLED HUMAN INHALATION EXPOSURE STUDIES AT EPA AND ASSOCIATED ADVERSE EVENTS

Introduction

The Eight Studies Identified by EPA for Consideration by the Committee

Evaluation of Evidence for Adverse Events Resulting from Participation in a CHIE Study

Adverse Event Reporting

Relationship of Short-Term CHIE Study Exposure to Chronic Disease Risks

Conclusions

5 THE CONTINUED CONDUCT OF CONTROLLED HUMAN INHALATION EXPOSURE STUDIES BY EPA

Scientific Contributions of Past CHIE Studies

Past Benefits to Society

Study Participant Safety

Potential Future Societal Benefits

Additional External Scientific Input

Conclusion and Recommendation

6 CHARACTERIZING RISKS TO SUBJECTS IN CONTROLLED HUMAN INHALATION EXPOSURE STUDIES

Audiences for Risk Characterization Associated with CHIE Studies

Exclusion Criteria for Screening Study Subjects

Factors That Might Trigger an Adverse Outcome

What Adverse Outcomes Might Be Expected and When? Reasonably Foreseeable Risks

Characterization of Risks Associated with CHIE Pollutant Exposures

Use of the Exposure Comparator Approach for Characterizing Risk

Recommendations

7 COMMUNICATION ABOUT INFORMED CONSENT IN CONTROLLED HUMAN INHALATION EXPOSURE STUDIES

Introduction to Informed Consent and the Common Rule

Researcher Communication and Participant Understanding of Informed Consent

Recommendations

REFERENCES

APPENDIXES

A BIOGRAPHICAL INFORMATION ON THE COMMITTEE ON ASSESSING TOXICOLOGIC RISKS TO HUMAN SUBJECTS USED IN CONTROLLED EXPOSURE STUDIES OF ENVIRONMENTAL POLLUTANTS

B PUBLIC INFORMATION-GATHERING SESSIONS

C ASSESSMENT OF EIGHT CONTROLLED HUMAN EXPOSURE STUDIES

BOXES, FIGURES, AND TABLES

BOXES

S-1 Eight Studies Identified by EPA for Consideration by the Committee

1-1 Selected Recommendations from Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues (NRC, 2004)

1-2 Committee’s Statement of Task

5-1 Reasonable Medical Care Necessitated by Participation in a Clinical Trial

FIGURES

3-1 NAAQS review process

3-2 Simplified flow chart of classes of biomarkers

3-3 Pathways for integrating health-effects data

3-4 Systemic oxidative stress and inflammation

TABLES

2-1 National Ambient Air Quality Standards for Six Criteria Pollutants (as of December 2016)

2-2 Selected Laws, Ethical Codes, and Other Milestones Related to the Protection of Human Subjects

2-3 Seven Requirements for Determining Whether a Research Trial Is Ethical

3-1 EPA’s Reviews of Relevant Scientific Information and Revised NAAQS for O₃ and PM from 1996 to 2015

4-1 Descriptive Information on Eight CHIE Studies

4-2 Potential Health Outcomes Described in CHIE Study Protocols

4-3 Events Reported to the UNC IRB for All CHIE Studies from January 2009 to February 2015

6-1 Largest Concentrations in 1-Hour PM_2.5 samples in 2014 and 2015 in EPA Air Data with Corresponding 2- and 4-Hour Average Concentrations

6-2 Exposure Comparisons Used in EPA CHIE Studies

C-1 Controlled Inhalation Exposure Studies in EPA Human Studies Facility

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