Epidemiology Evidence for Health Effects of 150 per- and Polyfluoroalkyl Substances: A Systematic Evidence Map

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) comprise a large class of chemicals with widespread use and persistence in the environment and in humans; however, most of the epidemiology research has focused on a small subset.

Objectives: The aim of this systematic evidence map (SEM) is to summarize the epidemiology evidence on approximately 150 lesser studied PFAS prioritized by the EPA for tiered toxicity testing, facilitating interpretation of those results as well as identification of priorities for risk assessment and data gaps for future research.

Methods: The Populations, Exposure, Comparators, and Outcomes (PECO) criteria were intentionally broad to identify studies of any health effects in humans with information on associations with exposure to the identified PFAS. Systematic review methods were used to search for literature that was screened using machine-learning software and manual review. Studies meeting the PECO criteria underwent quantitative data extraction and evaluation for risk of bias and sensitivity using the Integrated Risk Information System approach.

Results: 193 epidemiology studies were identified, which included information on 15 of the PFAS of interest. The most commonly studied health effect categories were metabolic ($n=37$), endocrine ($n=30$), cardiovascular (30), female reproductive ($n=27$), developmental ($n=26$), immune ($n=22$), nervous ($n=21$), male reproductive ($n=14$), cancer ($n=12$), and urinary ($n=11$) effects. In study evaluation, 120 (62%) studies were considered High/Medium confidence for at least one outcome.

Discussion: Most of the PFAS in this SEM have little to no epidemiology data available to inform evaluation of potential health effects. Although exposure to the 15 PFAS that had data was fairly low in most studies, these less-studied PFAS may be used as replacements for "legacy" PFAS, leading to potentially greater exposure. It is impractical to generate epidemiology evidence to fill the existing gaps for all potentially relevant PFAS. This SEM highlights some of the important research gaps that currently exist. https://doi.org/10.1289/EHP11185.

Figure 1.

Summary of study evaluation approach for systematic evidence map. (A) evaluation domains. (B) domain judgments and interpretations. (C) overall study confidence ratings and interpretations. Note: Adapted from Office of Research and Development (ORD) Staff Standard Operating Procedures for Developing Integrated Risk Information System (IRIS) Assessments. This resource provides the full description of the methods used to evaluate risk of bias and sensitivity in the included studies.

Figure 2.

Literature flow diagram for systematic evidence map of epidemiology studies for 150 PFAS. Note: Literature identified in other sources was brought into screening at DistillerSR title-abstract review. References may have multiple supplemental tags. Two human studies did not proceed to study evaluation and data extraction because they were represented by other included studies. ADME, absorption, distribution, metabolism, excretion; ATSDR, Agency for Toxic Substances and Disease Registry; ECHA, European Chemicals Agency; ECOTOX, U.S. Environmental Protection Agency Ecotoxicology Knowledgebase; HAWC, Health Assessment Workspace Collaborative; NTP, National Toxicology Program Chemical Effects in Biological Systems; PBPK, physiologically based pharmacokinetic; PECO, populations, exposure, comparator, outcome criteria; TEDX, PFAS evidence map prepared by The Endocrine Disruptor Exchange; TIAB, title/abstract screening; ToxVal, U.S. Environmental Protection Agency CompTox Chemicals Dashboard; WoS, Web of Science.

Figure 3.

Screenshot of interactive dashboard for systematic evidence map of epidemiology studies for 150 PFAS. The interactive dashboard is available at https://hawcprd.epa.gov/summary/visual/assessment/100500085/Epidemiological-Studies-and-Study-Confidence/. The results are filterable by PFAS, health effect category, population, exposure measure, study design, overall study confidence, and reference by clicking on the relevant cell.

Figure 4.

Heat map of number of studies by health effect category and PFAS. In the interactive dashboard (https://hawcprd.epa.gov/summary/visual/assessment/100500085/Epidemiological-Studies-and-Study-Confidence/), the number of studies by health effect category and/or PFAS can be obtained by clicking on the cell to filter by. This information can also be obtained by filtering Excel Table S4. Note: 8:2-FTOH, 8:2 fluorotelomer alcohol; PFDDA, perfluoro-2,5,dimethyl-3,6-dioxanonanoic acid; PFDeS, sodium perfluorodecanesulfonate; PFHpA, perfluoroheptanoic acid; PFHpS, perfluoroheptanesulfonate and perfluoroheptanesulfonic acid; PFUnDA, perfluoroundecanoic acid; PFOSA, perfluorooctanesulfonamide; PFTrDA, perfluorotridecanoic acid; PFTeDA, perfluorotetradecanoic acid; PFPeA, perfluoropentanoic acid; PFPpA, perfluoropropanoic acid; POSF, perfluorooctanesulfonyl fluoride; NEtFOSE, N-ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide; TFA, trifluoroacetic acid.

Figure 5.

Summary of study evaluations by domain and health effect category. In the interactive dashboard (https://hawcprd.epa.gov/summary/visual/assessment/100500085/Epidemiological-Studies-and-Study-Confidence/, “Study Confidence Summary” tab), each domain/overall confidence rating and rationale is available, filterable by PFAS, health effect category, outcome, and rating. This information is also available in Excel Tables S4 and S5. Note: PFAS, per- and polyfluoroalkyl substances.