Review of EPA’s 2022 Draft
Formaldehyde Assessment
______
Committee on Review of EPA’s 2022 Draft
Formaldehyde Assessment
Board on Environmental Studies and Toxicology
Division on Earth and Life Studies
Consensus Study Report
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2023. Review of EPA’s 2022 Draft Formaldehyde Assessment. Washington, DC: The National Academies Press. https://doi.org/10.17226/27153.
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COMMITTEE TO REVIEW EPA’S 2022 DRAFT FORMALDEHYDE ASSESSMENT
Members
JONATHAN M. SAMET, (Chair), Colorado School of Public Health
AISHA S. DICKERSON, Johns Hopkins Bloomberg School of Public Health
DANA C. DOLINOY, University of Michigan
DAVID C. DORMAN, North Carolina State University
RAKESH GHOSH, University of California, San Francisco
SABINE S. LANGE, Texas Commission on Environmental Quality
ANDREW F. OLSHAN, University of North Carolina at Chapel Hill
IVAN RUSYN, Texas A&M University
LIANNE SHEPPARD, University of Washington School of Public Health
KATYA TSAIOUN, Johns Hopkins Bloomberg School of Public Health
JOSEPH WIEMELS, University of Southern California
LAUREN ZEISE, California Environmental Protection Agency
YILIANG ZHU, University of New Mexico
Staff
KATHRYN GUYTON, Study Director
BRENNA ALBIN, Senior Program Assistant
NATALIE ARMSTRONG, Associate Program Officer
ELIZABETH BOYLE, Senior Program Officer
ANTHONY DEPINTO, Associate Program Officer
DARLENE GROS, Senior Program Assistant
KATHERINE KANE, Senior Program Assistant
Sponsor
U.S. ENVIRONMENTAL PROTECTION AGENCY
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Members
FRANK W. DAVIS (Chair), University of California, Santa Barbara
ANN M. BARTUSKA, U.S. Department of Agriculture
DANA BOYD BARR, Emory University
GERMAINE M. BUCK LOUIS, George Mason University
FRANCESCA DOMINICI, Harvard University
R. J. LEWIS, ExxonMobil Biomedical Sciences Inc
MARIE L. MIRANDA, Children’s Environmental Health Initiative
REZA J. RASOULPOUR, Dow AgroSciences
JOSHUA TEWKSBURY, Smithsonian Tropical Research
SACOBY M. WILSON, University of Maryland
TRACEY J. WOODRUFF, University of California, San Francisco
Staff
CLIFFORD DUKE, Director
NATALIE ARMSTRONG, Associate Program Officer
LESLIE BEAUCHAMP, Senior Program Assistant
ANTHONY DEPINTO, Associate Program Officer
KATHRYN GUYTON, Senior Program Officer
KATHERINE KANE, Senior Program Assistant
LAURA LLANOS, Finance Business Partner
THOMASINA LYLES, Senior Program Assistant
RAYMOND WASSEL, Scholar and Director of Environmental Studies
Reviewers
This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, 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 individuals for their review of this report:
A. JOHN BAILER, Miami University
RICHARD CORLEY, Greek Creek Toxicokinetics Consulting, LLC
SUSAN FELTER, Procter & Gamble
PENNY FENNER-CRISP, Private consultant
JULIE B. HERBSTMAN, Columbia University Mailman School of Public Health
JULEEN LAM, California State University East Bay
MALCOLM MACLEOD, University of Edinburgh
SUE JINKS-ROBERTSON (NAS), Duke University School of Medicine
MOSHE OREN (NAS, NAM), Weizmann Institute of Science
JOE RODRICKS, Ramboll
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by DANNY REIBLE, Texas Tech University (Monitor), and DON MATTISON, University of South Carolina (Coordinator). They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
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Acknowledgments
Many people were critical in helping the committee accomplish its charge. The committee gratefully acknowledges the participants at its information-gathering sessions, who provided insights and viewpoints pertinent to the committee’s task (see Appendix B). We thank Lisa Bero, Professor of Medicine and Public Health, University of Colorado, for her presentation at the committee’s first information-gathering session. Importantly, the committee heard from more than 40 individuals who shared their perspectives during the public comment periods of the information-gathering sessions, as well as in written input provided for the committee’s consideration. The committee is very grateful for these valuable contributions to its work.
In addition, we are grateful to the U.S. Environmental Protection Agency (EPA) for sponsoring the study, and to the following EPA staff for their presentations to the committee: Andrew Kraft and Thomas Bateson, Office of Research and Development.
Gratitude is also extended to the staff of the National Academies of Sciences, Engineering, and Medicine who contributed to producing this report, especially the outstanding and tireless study staff: Brenna Albin, Natalie Armstrong, Elizabeth Boyle, Anthony DePinto, Darlene Gros, Kathryn Guyton, and Katherine Kane. Thanks also go to the staff of the Division on Earth and Life Studies Executive Office and other Academies staff who provided additional support.
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Preface
This report documents the lengthy history of the Integrated Risk Information System (IRIS) Program’s assessment of the health risks of formaldehyde, which dates to 1989. The predecessor of the 2022 Draft Assessment is an IRIS assessment completed in 2010 and reviewed by the National Academies in 2011. The 2011 National Research Council (NRC) report on the 2010 Draft Assessment called for substantial revisions to the assessment and to the processes used to develop it. The 2011 NRC report included the recommendation that completion of the formaldehyde assessment not await the possible development of these revisions and their finalization. Over the ensuing twelve years and in response to additional recommendations of the National Academies, the methods used by the IRIS Program have evolved. These evolving methods increasingly reflect the state of practice for carrying out systematic reviews, evidence integration, and quantitative risk estimation for human health risk assessments of environmental contaminants. The 2022 Draft Assessment reviewed by this committee was prepared across this decade of rapid change. Consequently, there was no static benchmark for evaluating the methods used. The committee took a broad view of the state of practice as it evaluated the 2022 Draft Assessment, recognizing that the methods used for that assessment would not correspond in all respects to the state of practice in 2023. Overall, the committee found that the methods used for the assessment were appropriate and reflect EPA’s current practices in some components of the IRIS process.
Not surprisingly, given its length and complexity, there are opportunities to strengthen and clarify the 2022 Draft Assessment. The committee offers numerous recommendations to that end. The committee was asked to prioritize its recommendations in tiers. Tier 1 represents important recommendations that would address critical scientific concepts, issues, or narrative in the assessment. Currently the methods for the 2022 Draft Assessment are located in several places throughout its three documents, which together consist of more than 2000 pages. Perhaps the most critical area for structural and editorial revision is to bring greater clarity as to the methods used and to facilitate their consideration by readers. The committee’s single Tier 1 recommendation calls for the changes needed to make the assessment’s methods sufficiently accessible for its users, and to facilitate access to related sections across the different elements of the assessment for the different outcomes analyzed. In accordance with its statement of task, the committee did not conduct an independent hazard assessment or recommend alternative toxicity values.
Tier 2 recommendations are suggested revisions intended to strengthen or clarify the scientific concepts, issues, or narrative in the assessment, while Tier 3 recommendations are considerations that might inform future evaluations of key science issues. The committee has made many Tier 2 and Tier 3 recommendations regarding methods, the assessment narrative, and the dose-response assessment. We point to opportunities to harmonize the assessment narrative across health outcome domains and to bring greater consistency by structuring them more carefully around a common review framework. We also urge rigorous editing to enhance the overall quality of the assessment.
Quoting the website for the IRIS Program:
EPA’s mission is to protect human health and the environment. EPA’s IRIS Program supports this mission by identifying and characterizing the health hazards of chemicals found in the environment.
The 2022 Formaldehyde Draft Assessment, which addresses a widely used, high-volume production chemical, needs to be completed to support EPA in accomplishing this mission.
Finally, the committee urges closure on the Draft Assessment. The committee members have a long perspective on the Formaldehyde Draft Assessment and the changes in the IRIS Program’s methods over the last decade. The assessment has been revised and improved substantially, and its findings on hazard and quantitative risk are supported by the scientific evidence identified. A confined set of revisions will enhance clarity and transparency. The committee’s recommendations should be undertaken expeditiously to complete a revised assessment document that can be implemented without delay.
Jonathan M. Samet, M.D., M.S
Committee Chair
Committee to Review EPA’s 2022 Draft Formaldehyde Assessment
Contents
The Committee, Its Task, and Its Approach
The State of Practice for Systematic Review
Response to the 2011 NRC Report
Response to the 2014 NRC Report
Alignment of the 2022 Draft Assessment Methods with the State of Practice
Evidence Identification (Steps 1 and 2)
Study Evaluation (Steps 3 and 4)
Evidence Synthesis (Steps 5 and 6)
Dose-Response Assessment (Step 8)
Overview of Inhaled Formaldehyde Toxicokinetics in the 2022 Draft Assessment
Distribution of Inhaled Formaldehyde
Metabolism, Binding, and Removal of Inhaled Formaldehyde
EPA’s Use of Toxicokinetic Data and Dosimetry Models
Noncancer Portal-of-Entry Effects
Reproductive and Developmental Toxicity
Acronyms and Abbreviations
ADAF | age-dependent adjustment factor |
ADME | absorption, distribution, metabolism, and excretion |
ALS | amyotrophic lateral sclerosis |
ATS | American Thoracic Society |
ATSDR | Agency for Toxic Substances and Disease Registry |
BBDR | biologically based dose response |
BMC | benchmark concentration |
BMCL | benchmark concentration lower bound |
BMD | benchmark dose |
BMDL | benchmark dose lower bound |
BMDS | benchmark dose software |
BMR | benchmark response |
CDC | Centers for Disease Control and Prevention |
CFD | computational fluid dynamics |
CIIT | Chemical Industry Institute of Toxicology |
cRfC | candidate reference concentration |
DDCs | DNA–DNA crosslinks |
DPCsX | DNA–protein crosslinks |
ED | effective dose |
EFSA | European Food Safety Authority |
EPA | U.S. Environmental Protection Agency |
EU | European Union |
FDA | Food and Drug Administration |
FEF25-75 | forced expiratory flow 25%–75% |
FEV1 | forced expiratory volume in 1 second |
FVC | forced vital capacity |
GLP | Good Laboratory Practices |
GM | geometric mean |
GRADE | Grading of Recommendations, Assessment, Development, and Evaluations |
HEC | human equivalent concentration |
hm-DNA | hydroxymethyl-DNA |
IARC | International Agency for Research on Cancer |
IPCS | International Programme on Chemical Safety |
IRIS | Integrated Risk Information System |
ISA | integrated science assessment |
IUR | inhalation unit risk |
LOAEL | lowest observed adverse effect level |
MeSH | medical subject headings |
MOA | mode of action |
MSW | Multistage Weibull |
NAM | new approach method |
NASEM | National Academies of Sciences, Engineering, and Medicine |
NIEHS | National Institute of Environmental Health Sciences |
NIH | National Institutes of Health |
NIOSH | National Institute for Occupational Safety and Health |
NOAEL | no observed adverse effect level |
NRC | National Research Council |
NTP | National Toxicology Program |
OHAT | Office of Health Assessment and Translation (now the NIEHS Division of Translational Toxicology’s Integrative Health Assessments Branch) |
ORD | Office of Research and Development |
osRfC | organ- or system-specific reference concentration |
OVA | ovalbumin |
PBPK | physiologically based pharmacokinetic |
PECO | population, exposure, comparator, and outcome |
PEFR | peak expiratory flow rate |
POD | point of departure |
PODADJ | adjusted point of departure |
QSAR | quantitative structure–activity relationships |
RfC | reference concentration |
RfD | reference dose |
ROB | risk of bias |
ROC | Report on Carcinogens |
SAR | structure–activity relationships |
SCC | squamous cell carcinoma |
SEER | surveillance, epidemiology, and end results |
SEM | systematic evidence map |
TCEQ | Texas Commission on Environmental Quality |
TSCA | Toxic Substances Control Act |
TWA | time-weighted average |
UF | uncertainty factor |
UFA | interspecies uncertainty factor |
UFD | database uncertainty factor |
UFH | uncertainty factor for variability across the human population |
UFL | LOAEL-to-NOAEL uncertainty factor |
UFS | subchronic to chronic or lifetime exposure uncertainty factor |
URT | upper respiratory tract |