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. 2022 May;130(5):56001.
doi: 10.1289/EHP10343. Epub 2022 May 17.

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Laura M Carlson  1 , Michelle Angrish  2 , Avanti V Shirke  3 , Elizabeth G Radke  3 , Brittany Schulz  4 , Andrew Kraft  3 , Richard Judson  5 , Grace Patlewicz  5 , Robyn Blain  6 , Cynthia Lin  6 , Nicole Vetter  6 , Courtney Lemeris  6 , Pamela Hartman  6 , Heidi Hubbard  6 , Xabier Arzuaga  3 , Allen Davis  3 , Laura V Dishaw  2 , Ingrid L Druwe  2 , Hillary Hollinger  1 , Ryan Jones  1 , J Phillip Kaiser  7 , Lucina Lizarraga  7 , Pamela D Noyes  3 , Michele Taylor  2 , Andrew J Shapiro  1 , Antony J Williams  5 , Kristina A Thayer  2
Affiliations

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Laura M Carlson et al. Environ Health Perspect. 2022 May.

Erratum in

  • Erratum: "Systematic Evidence Map for over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)".
    Carlson LM, Angrish M, Shirke AV, Radke EG, Schulz B, Kraft A, Judson R, Patlewicz G, Blain R, Lin C, Vetter N, Lemeris C, Hartman P, Hubbard H, Arzuaga X, Davis A, Dishaw LV, Druwe IL, Hollinger H, Jones R, Kaiser JP, Lizarraga L, Noyes PD, Taylor M, Shapiro AJ, Williams AJ, Thayer KA. Carlson LM, et al. Environ Health Perspect. 2024 Jan;132(1):19001. doi: 10.1289/EHP14191. Epub 2024 Jan 10. Environ Health Perspect. 2024. PMID: 38198380 Free PMC article. No abstract available.

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS.

Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing.

Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata.

Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams.

Discussion: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

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Figures

Figure 1 is set of 3 tables and one flowchart. On the top-left, a tabular representation titled Individual evaluation domains has six rows and one column, namely, Animals. Row 1: Reporting Quality. Row 2: Selection or Performance Bias. Row 3: Confounding or Variable Control. Row 4: Reporting or Attrition Bias. Row 5: Exposure Methods Sensitivity. Row 6: Outcome Measures and Results Display. At the center, a tabular representation titled Domain judgement has four rows and in three columns, lists Color code, Judgement, and Interpretation. Row 1: Good and Appropriate study conduct relating to the domain & minor deficiencies not expected to influence results. Row 2: Adequate and A study that may have some limitations relating to the domain, but they are not likely to be severe or to have a notable impact on results. Row 3: Deficient and Identified biases or deficiencies interpreted as likely to have had a notable impact on the results or prevent reliable interpretation of study findings. Row 4: Critically Deficient and A serious flaw identified that makes the observed effect(s) uninterpretable. Studies with a critical deficiency will almost always be considered overall “uninformative”. At the bottom, a tabular representation titled Overall study rating for an outcome has four rows and two columns, namely, Rating and Interpretation. Row 1: High and No notable deficiencies or concerns identified; potential for bias unlikely or minimal; sensitive methodology. Row 2: Medium and Possible deficiencies or concerns noted but resulting bias or lack of sensitivity would be unlikely to be of a notable degree. Row 3: Low and Deficiencies or concerns were noted, and the potential for substantive bias or inadequate sensitivity could have a significant impact on the study results or their interpretation. Row 4: Uninformative and Serious flaw(s) makes study results unusable for hazard identification or dose response. On the right, a flowchart titled Study evaluation process has six steps, namely, Refined evaluation plan, Criteria development, Pilot testing or refine criteria, Evaluation by 2 reviewers, Conflict resolution, and Final domain judgments and overall study rating.
Figure 1.
Study evaluation approach for experimental animal studies. Note: The approach follows standard methods that are used in systematic evidence maps developed by the U.S. EPA, and have only been adjusted, where appropriate, for the specific needs of this SEM. Note: SEM, systematic evidence map.
Figure 2 is flowchart having six steps. Step 1: Nafion (Chemical Abstracts Service registry number 31175-20-9) Literature searches (June to August 2019; December 2020, December 2021). PubMed: 2605 searches till June 7, 2019; 1421 searches till December 31, 2020; and 246 searches till December 20, 2021. Web of Science: 2359 searches till August 14, 2019; 2326 searches till December 31, 2020; and 371 searches till December 20, 2021. ToxNet: 45 searches till June 7, 2019. Step 2: Following duplicate removal, S W I F T review used to analyzed 4388 records from 2019 database searches identification of potentially relevant based on application of S W I F T-review evidence stream tags which is equal to 1918 searches; following duplicate removal, the December 2020 update results were added directly to Distiller for review which is equal to 88 searches; Following duplicate removal, S W I F T review was used to analyze 545 records from the December 2021 update, identification of potentially relevant records based on application of S W I F T review evidence stream tags which is equal to 24 7 searches. Step 3: Records identified from other sources includes 0 source in Compiling Publicly Available In Vivo Toxicity Data, 0 source in Organization for Economic Co-operation and Development Screening Information Dataset for High Production Volume Chemicals, 0 source in the United States E P A Ecotoxicology Knowledgebase, 0 sources N T P, 0 source from other assessments, and 0 source from reference list of included studies. Step 4: 2253 records in Title and abstract screen in DistillerSR, excluding 2248 records of non-relevant to populations, exposure, comparator, outcome criteria, 15 records are tagged as supplemental, and 2259 records are sum of excluded or supplemental. Step 5: 5 records are full text screen in DistillerSR, excluding 3 non relevant to populations, exposure, comparator, outcome criteria, 1 record tagged as supplemental, and 4 records are sum of excluded or supplemental. Step 6: 2 records of studies included in literature inventory, including 1 human health effects studies and 1 animal studies. There are 16 records tagged as supplemental, including 2 records in mechanistic, 3 records in absorption, distribution, metabolism, excretion, 2 records in exposure, 1 record in non-mammalian model system, 4 records non-inhalation or non-oral route of administration, and 5 records of other supplemental.
Figure 2.
Nafion study flow diagram (May 17, 2022). Note: ADME, absorption, distribution, metabolism, excretion; CASRN, Chemical Abstracts Service Registry Number; ECOTOX, U.S. EPA Ecotoxicology Knowledgebase; OECD SIDS HPV, Organization for Economic Co-operation and Development Screening Information Dataset for High Production Volume Chemicals; PECO, Populations, Exposure, Comparator, Outcome criteria; ToxValDB, U.S. EPA CompTox Chemicals Dashboard; WoS, Web of Science.
Figure 3 is a flowchart having ten steps. Step 1: Per- and polyfluoroalkyl substances 150 literature searches (September 2019, December 2020, December 2021). PubMed: 29813 searches till September 11, 2019, 2148 searches till December 31, 2020, and 2151 searches till December 7, 2021. Web of science: 21677 searches till September 11, 2019, 1307 searches till December 31, 2020, and 1491 searches till December 7, 2021. ToxNet: 2213 searches till September 11, 2019. Step 2: Following duplicate removal, S W I F T review was used to analyze 40623 records from database searches: 10515 searches for sevoflurane, perfluorooctane, flurothyl removed, 5863 searches for per- and polyfluoroalkyl substances already under assessment removed. 10386 searches for identification of potentially relevant records based on application of S W I F T review evidence stream tags. Following duplicate removal, S W I F T review was used to analyze 3433 records from the December 2020 update. 1378 searches for identification of potentially relevant records. Following duplicate removal, S W I F T review was used to analyze 3142 records from the December 2021 update. 1397 searches for identification of potentially relevant records. Step 3: 13161 searches for title or abstract screening in S W I F T active, excluding 11678 searches, including 3907 records manually screened and excluded and 7771 records predicted as not relevant in S W I F T active (and not manually screened). Step 4: 1483 records considered relevant or supplemental material based on S W I F T active. Step 5: 1531 records identified from other sources, including 15 records from ToxValDB, 486 records from European Chemicals Agency, 276 records from reference list from included studies, 159 records from identified after chemical tag updates in S W I F T review, 2 records from National Toxicology Program Chemical Effects in Biological Systems, 384 records from Per- and polyfluoroalkyl substances Tox database, 202 records from Agency for Toxic Substances and Disease Registry, 1 record from Technical expert, and 6 records from The United Sates E P A Ecotoxicology Knowledgebase; HAWC, Health Assessment Workspace Collaborative. Step 6: 3012 records title and abstract screen in DistillerSR, excluding 930 records which did not meet all populations, exposure, comparator, outcome criteria, 1106 records are tagged as supplemental material, and 2039 records are sum of title or abstract screening excluded or supplemental. Step 7: 976 records of Full-text screen in DistillerSR, excluding 168 records. The 168 records include 132 records which has no relevant to exposure, 32 records which are unable to obtain full text, 4 records of wildlife study, and 4 records of no data provided. 471 records are tagged as supplemental materials. 639 records are sum of full-text excluded or supplemental. Step 8: There are 1624 records that are tagged as supplemental material title and abstract screen and full-text inventory, including 321 records from mechanistic (in vitro or ex vivo or in silico studies), 4 records from physiologically based pharmacokinetic, 70 records from non-mammalian model systems, 243 records from non-oral or non-inhalation route of administration, 177 records of absorption, distribution, metabolism, excretion and toxicokinetic, 547 records from exposure characteristics (no health outcome assessment), 162 records from mixture studies, 9 records from case reports, 10 records conference abstract, 213 records or other assessments with no original data, 160 records from European Chemicals Agency read-across, 8 records from European Chemicals Agency presumed duplicate. Step 9: 337 records are included after full text screening, 139 records of animals, and 198 records of humans. Step 10: 337 records from human and animal studies summarized in the literature inventory, including 139 records of animals and 198 records of humans. The study evaluation includes 52 records of animals and the studies extracted into Health Assessment Workspace Collaborative includes 51 records of animals.
Figure 3.
PFAS-150 Study flow diagram (May 17, 2022). Note: References identified from other sources joined screening at DistillerSR TIAB review. Some references may have multiple supplemental or exclusion tags. For the December 2020 and December 2021 searches, the following PFAS were inadvertently excluded: 1-bromoheptafluoropropane (CASRN 422-85-5; DTXSID3059971), 11:1 fluorotelomer alcohol (CASRN 423-65-4; DTXSID80375107), 6H-perfluorohex-1-ene (CASRN 1767-94-8; DTXSID10379850), perfluoroheptanoic acid (CASRN 375-85-9; DTXSID1037303), perfluorooctanesulfonamid (CASRN 76752-79-9; DTXSID001016256), and perfluoroundecanoic acid (CASRN 2058-94-8; DTXSID8047553). Consequently, the literature results reported for these PFAS are only current through 2019. ADME, absorption, distribution, metabolism, excretion; ATSDR, Agency for Toxic Substances and Disease Registry; ECHA, European Chemicals Agency; ECOTOX, U.S. EPA Ecotoxicology Knowledgebase; HAWC, Health Assessment Workspace Collaborative; NTP, National Toxicology Program Chemical Effects in Biological Systems; PFAS, per- and polyfluoroalkyl substances; PBPK, physiologically based pharmacokinetic; PECO, Populations, Exposure, Comparator, Outcome criteria; PFAS Tox Database, 2019 PFAS evidence map,; TIAB, title or abstract screening; ToxValDB, U.S. EPA CompTox Chemicals Dashboard; WoS, Web of Science.
Figure 4 is a flowchart having fourteen steps. Step 1: 14475 literature review in which 337 reviews are included, 12614 reviews are excluded, and 1624 reviews are supplemental. Step 2: 337 included reviews in which 198 reviews are of humans and 139 reviews are of animals. Step 3: 12614 excluded reviews in which 3907 reviews are Manually excluded in S W I F T, 7771 reviews are Automatically excluded via M L in S W I F T Active, 930 reviews are Manually excluded in Distiller (T I A B), and 168 review are Manually excluded in Distiller (full text). 1624 supplemental reviews in which 321 reviews of Mechanistic (in vitro/ex vivo/in silico), 177 reviews of absorption, distribution, metabolism, and excretion studies, 4 reviews of classical pharmacokinetic or physiologically based pharmacokinetic model studies, 70 reviews of Non-mammalian model, 0 review of Transgenic mammalian model, 243 reviews of Non-oral or non-inhalation route, 547 reviews of Exposure only, 162 reviews of Mixture, 9 revies of Case reports/series (less than 3), 213 reviews of no original data, 10 reviews of conference abstract, 160 reviews of European Chemicals Agency read-across, 8 reviews of presumed duplicate, and 0 review of other supplemental. Step 4: 198 human reviews in which 36 reviews are for pregnant women, 44 reviews are for infants, 55 reviews are for children, 73 reviews are for general population, and 4 reviews are for occupational. Step 5: 139 animal reviews in which 64 reviews are for acute, 39 reviews are for short-term, 12 reviews are for subchronic, 3 reviews are for chronic, 24 reviews are for developmental, and 0 review are for multigenerational. Step 6: 168 Manually excluded in Distiller (full-text) reviews in which 4 reviews are for no data provided, 132 reviews are for no relevant exposure, 32 reviews are for unable to obtain full-text, and 4 reviews are for wildlife study. Step 7: 243 non-oral or non-inhalation route reviews in which 243 reviews can either be exposure duration or route of exposure. Step 8: 36 pregnant women reviews in which 5 reviews are for case-control, 17 reviews are for cohort, and 14 reviews are for cross-sections. Step 9: 44 infants reviews in which 3 reviews are for case-control, 23 reviews are for cohort, and 19 reviews are for cross-sections. Step 10: 55 children review in which 11 reviews are for case-control, 32 reviews are for cohort, and 12 reviews are for cross-sections. Step 11: 73 general population reviews in which 16 reviews are for case-control, 20 reviews are for cohort, and 37 reviews are for cross-sections. Step 12: 4 Occupational reviews in which 0 reviews are for case-control, 2 reviews are for cohort, and 2 reviews are for cross-sections. Step 13: 243 exposure duration reviews in which 142 reviews are for acute, 11 reviews are for short-term, 1 review are for subchronic, 1 review are for chronic, 0 review are for developmental, and 93 reviews are for other or unclear. Step 14: 243 route of exposure reviews in which 4 reviews are for oral (gavage), 84 reviews are for dermal, 25 reviews are for injection, 47 reviews are for intravenous, and 85 reviews are for other or unclear.
Figure 4.
PFAS-150 literature inventory tree. Screenshot from interactive image accessed May 17, 2022. References are available in the literature inventory tree by Control-clicking or Command-clicking on a node. A full download of the literature review and study tagging can be found in Excel Table S13. Study counts for 1-bromoheptafluoropropane (CASRN 422-85-5; DTXSID3059971), 11:1 fluorotelomer alcohol (CASRN 423-65-4; DTXSID80375107), 6H-perfluorohex-1-ene (CASRN 1767-94-8; DTXSID10379850), perfluoroheptanoic acid (CASRN 375-85-9; DTXSID1037303), perfluorooctanesulfonamid (CASRN 76752-79-9; DTXSID001016256), and perfluoroundecanoic acid (CASRN 2058-94-8; DTXSID8047553) are only current through 2019. Note: ADME, absorption, distribution, metabolism, and excretion studies; ECHA, European Chemicals Agency; ML, machine learning; PFAS, per- and polyfluoroalkyl substances; PK/PBPK, classical pharmacokinetic/physiologically based pharmacokinetic model studies; TIAB, title or abstract screening.
Figure 5A is a tabular representation having eighteen rows and in five main columns, lists Categories, Case-control, Cohort, Cross-sectional, and Grand Total. The Case-control, Cohort, and Cross-sectional columns each are sub divided into four columns, namely, General population, pregnant women, infants, and children. Row 1: Cancer, 8, 1, 2, 1, and 12. Row 2: Cardiovascular, 2, 1, 1, 4, 1, 2, 1, 9, 2, 2, 1, 5, and 31. Row 3: Dermal, 1, and 1. Row 4: Developmental, 1, 14, 4, 13, and 29. Row 5: Reproductive, 2, 2, 9, 1, 5, 1, 3, 7, 4, 1, 1, and 35. Row 6: Endocrine, 1, 4, 1, 7, 6, 6, 5, 5, 2, and 32. Row 7: Hematologic, 1, 1, 1, 1, and 4. Row 8: Hepatic, 3, 1, 4, 2, 1, and 11. Row 9: Immune, 5, 3, 9, 2, 1, 1, 3, and 24. Row 10: Metabolic, 3, 2, 4, 1, 2, 1, 2, 10, 2, 2, 4, and 33. Row 11: Musculoskeletal, 1 and 1. Row 12: Nervous, 1, 5, 12, 2, 1, and 21. Row 13: Ocular, 1, and 1. Row 14: Other, 1, and 1. Row 15: Renal, 1, 1, 5, 2, 1, and 10. Row 16: Respiratory, 1, 1, 1, 2, 1, 1, and 7. Row 17: Systemic or whole body, 1, 1, 2, and 4. Row 18: Grand total, 16, 5, 3, 11, 20, 2, 17, 23, 32, 37, 3, 14, 19, 12, and 199. Figure 5B is a set of six tables under Epidemiological studies examining exposures to per- and polyfluoroalkyl substances by study design and health system. On the left, a tabular representation titled heat map has fifteen rows and in three main columns, lists Categories, Case-control, Cohort, Cross-sectional, and Grand Total. The Case-control, Cohort, and Cross-sectional columns each are sub divided into four columns, namely, General population, pregnant women, infants, and children. Row 1: Cancer, 8, 1, 2, 1. Row 2: Cardiovascular, 2, 1, 1, 4, 1, 2, 1, 9, 2, 2. Row 3: Dermal, 1. Row 4: Developmental, 1, 14, 4. Row 5: Reproductive, 2, 2, 9, 1, 5, 1, 3, 7, 4. Row 6: Endocrine, 1, 4, 1, 7, 6, 6, 5. Row 7: Hematologic, 1, 1, 1, 1. Row 8: Hepatic, 3, 1, 4, 2, 1. Row 9: Immune, 5, 3, 9, 2, 1, 1. Row 10: Metabolic, 3, 2, 4, 1, 2, 1, 2, 10, 2, 2. Row 11: Musculoskeletal, 1 and 1. Row 12: Nervous, 1, 5, 12, 2, 1, and 21. Row 13: Ocular, 1, and 1. Row 14: Other, 1. Row 15: Renal, 1, 1, 5, 2, 1. Below, a tabular representation titled study details has seven columns, namely, Health system, Study design, Population, Exposure measurement, matrix, sex, and short citation. On the right, a tabular representation titled References, in two columns, lists Categories and Select. A tabular representation titled Chemical evaluated – by name has six rows and in two columns, lists Categories and Ratio. Row 1: 6-2 fluorotelomer sulfonic acid and 1. Row 2: 8-2 fluorotelomer alcohol and 1. Row 3: Nafion and 1, Row 4: Perfluoro-2,5-dimethyl-3,6-dioxano and 1. Row 5: Perfluoroheptanesulfonate and 20. Row 6: Perfluoroheptanesulfonic acid and 22. A tabular representation titled Chemical evaluated – by C A S R N has six rows and in two columns, lists Categories and Ratio. Row 1: 76-05-1 and 1. Row 2: 307-35-7 and 2. Row 3: 375-85-9 and 64. Row 4: 375-92-8 and 22. Row 5: 376-06-7 and 24. Row 6: 422-64-0 and 3. A tabular representation titled Chemical evaluated – by D T X S I D has six rows and in two columns, lists Categories and Ratio. Row 1: D T X S I D 1037303 and 64. Row 2: D T X S I D 3038939 and 38. Row 3: D T X S I D 3059921 and 24. Row 4: D T X S I D 27140 and 2. Row 5: D T X S I D 6062599 and 15. Row 6: D T X S I D 6067331 and 1.
Figure 5.
Survey of human studies that met PECO criteria summarized by study design, population, and health systems assessed. (A) This is a thumbnail image of the interactive dashboard accessed May 17, 2022. The numbers indicate the distinct number of studies that investigated a health system within a particular study design and population, not the number of studies that observed an association with PFAS exposure. If a study evaluated multiple health outcomes or populations, it is shown here multiple times, though totals reflect distinct numbers of studies. (B). This is a thumbnail image of the interactive dashboard that provides additional information like evaluated chemicals (searchable by name, CASRN, and DTXSID), exposure measurement information, and sex. Study counts for 1-Bromoheptafluoropropane (CASRN 422-85-5; DTXSID3059971), 11:1 Fluorotelomer alcohol (CASRN 423-65-4; DTXSID80375107), 6H-Perfluorohex-1-ene (CASRN 1767-94-8; DTXSID10379850), Perfluoroheptanoic acid (CASRN 375-85-9; DTXSID1037303); Perfluorooctanesulfonamid (CASRN 76752-79-9; DTXSID001016256), and Perfluoroundecanoic acid (CASRN 2058-94-8; DTXSID8047553) are only current through 2019. Note: CASRN, Chemical Abstracts Service Registry Number; DTXSID, DSSTox substance identifier; PECO, population, exposure, comparator, and outcome; PFAS, per- and polyfluoroalkyl substances.
Figure 6 is a set of six tables under Toxicological studies examining exposure to per- and polyfluoroalkyl substances by study design and health system. On the left, a tabular representation titled heat map has eighteen rows and in six main columns, lists Categories, Acute, short-term, Sub chronic, Chronic, and developmental, F 1. The Acute column is sub divided into seven columns, namely, mouse, rat, guinea pig, hamster, rabbit, dog, and not reported. The short-term column is sub divided into three columns, namely, mouse, rat, and not reported. The sub chronic column is sub divided into columns, namely, mouse and rat. The chronic column is sub divided into two columns, namely, mouse and rat. The developmental F 1 column is sub divided into three columns, namely, mouse, rat, and rabbit. Row 1: Cancer, 2. Row 2: Cardiovascular, 3, 4, 1, 10, 1, 6, 2, 5. Row 3: Dermal, 1, 2, 2, 2. Row 4: Developmental, 1, 21, 3. Row 5: Reproductive, 4, 1, 12, 1, 9, 2, 1, 20, 3. Row 6: Endocrine. Row 7: Gastrointestinal, 7, 6, 1, 5, 1, 4. Row 9: Hematologic, 11, 1, 10, 2, 1, 7. Row 10: Hepatic, 1, 8, 1, 1, 9, 17, 2, 9, 2, 1, 10, 1. Row 11: Immune, 4, 3, 10, 9, 2, 1, 5. Row 12: Lymphatic,1, 1. Row 13: Metabolic, 3, 3, 1, 3. Row 14: Musculoskeletal, 7, 3, 1, 2. Row 15: Nervous, 2, 6, 1, 9, 1, 7, 2, 7. Row 16: Ocular, 1, 3, 4, 1, 9, 2, 3. Row 17: Renal, 1, 8, 3, 11, 1, 9, 2, 1, 9. Row 18: Respiratory,1, 12, 1, 8, 1, 7, 2, 3. Below, a tabular representation titled study details has seven columns, namely, Health system, Study design, Population, Exposure measurement, matrix, sex, and short citation. On the right, a tabular representation titled References, in two columns, lists Categories and Select. A tabular representation titled Chemical evaluated – by name has six rows and in two columns, lists Categories and Ratio. Row 1: 1-butanesulfonic acid,1,1,2,2,3,3 and 1. Row 2: 1H,1H,2H-perfluorocyclopentane and 6. Row 3:1H,1H,5H-perfluoropentanol and 1. Row 4: 2-chloro-1,1,1,2-teterafluoroethane and 12. Row 5: 3-Methoxyperfluoro(2-methyl) and 3. Row 6: 3,3,4,4,5,5,6,6,6-nonafluorohexene and 5. A tabular representation titled Chemical evaluated – by C A S R N has six rows and in two columns, lists Categories and Ratio. Row 1: 76-05-1 and 15. Row 2: 307-35-7 and 1. Row 3: 335-27-3 and 2. Row 4: 335-99-9 and 2. Row 5: 338-83-0 and 1. Row 6: 355-43-1 and 1. A tabular representation titled Chemical evaluated – by D T X S I D has six rows and in two columns, lists Categories and Ratio. Row 1: D T X S I D 0036926 and 2. Row 2: D T X S I D 0059879 and 1. Row 3: D T X S I D 0061826 and 8. Row 4: D T X S I D 1032646 and 2. Row 5: D T X S I D 1074915 and 3. Row 6: D T X S I D 2044397 and 5.
Figure 6.
Survey of animal studies that met PECO criteria by study design, species, and health systems. This is a thumbnail image of the interactive dashboard accessed May 17, 2022. The interactive dashboard is filterable by health system, study design, PFAS name, CASRN, and DTXSID. The numbers in the heat map inset indicate the distinct number of studies that investigated a health system within a particular study design. If a study evaluated multiple health outcomes or presented several experiments, it is shown here multiple times, though totals reflect distinct numbers of studies. The study design panel includes information on animal model, exposure duration, route of administration, and dose level(s) tested. Study counts for 1-Bromoheptafluoropropane (CASRN 422-85-5; DTXSID3059971), 11:1 Fluorotelomer alcohol (CASRN 423-65-4; DTXSID80375107), 6H-Perfluorohex-1-ene (CASRN 1767-94-8; DTXSID10379850), Perfluoroheptanoic acid (CASRN 375-85-9; DTXSID1037303); Perfluorooctanesulfonamid (CASRN 76752-79-9; DTXSID001016256), and Perfluoroundecanoic acid (CASRN 2058-94-8; DTXSID8047553) are only current through 2019. Note: CASRN, Chemical Abstracts Service Registry Number; DTXSID, DSSTox substance identifier; PFAS, per- and polyfluoroalkyl substances.
Figure 7 is a horizontal bar graph, plotting Chemical, Endpoint, study, animal description, route, and exposure duration (bottom to top), Rat, Wistar Rj is to Wi (lops Han), oral diet, 90 days; Unnamed Report (2016 a) (E C H A Summary), 6298442 Rat, Wistar Rj is to Wi (lops Han), oral diet, 90 days; F1 Rat, SD, oral gavage, G D 10 to 20; Saillenfait and others 1997, 3043578 PO Rat, SD oral gavage GD10-20; P O Rat, C D (S D) I G S, B R, oral gavage, 38 days (premating-sacrifice); Liver Weight, Relative Unnamed Report (2012 b), (E C H A Summary), 6299209, P O Rat, C D (S D) I G S, B R, oral gavage, up to 57 days (premating- lactation); Rat, Wistar Rj is to Wi (lops Han), oral diet, 90 days ;Unnamed Report (2016 a), (E C H A Summary), 6298442, Rat, Wistar Rj is to Wi (lops Han), oral diet, 90 days; F 1 Rat, S D, oral gavage, G D 10 to 20; Saillenfait and others 1997, 3043578, P O Rat, S D, oral gavage, G D 10 to 20; P O Rat, C D (S D) I G S, B R, oral gavage, 38 days (premating-sacrifice); Unnamed Report (2012 b), (E C H A Summary), 6299209 P O Rat, C D (S D) I G S, B R, oral gavage, up to 57 days (premating-lactation); Trifluoroacetic acid Liver Weight, Absolute Unnamed Report (2010 a) (E C H A Summary), 6299211 P O Rat, C D (S D) I G S, B R, oral gavage, G D 6 to 19; Liver Weight, Relative Sheng N and others 2017 , 3860066 Mouse, C D-1, oral gavage, 28 days; 6:2 Fluorotelomer sulphonate ammonium, Liver Weight, Absolute, Sheng N and others 2017 , 3860066 Mouse, C D-1, oral gavage, 28 days; Rat, C D (S D), oral gavage; 28 days; Liver Weight, Relative, Recovery, E C H A, 2007 , 6299223 Rat, C D (S D), oral gavage, 28 days; Rat, C D (S D), oral gavage, 28 days; Liver Weight, Relative, E C H A, 2007 , 6299223 Rat, C D (S D), oral gavage, 28 days; Rat, C D (S D), oral gavage, 28 days; Liver Weight, absolute, Recovery, E C H A, 2007, 6299223 Rat, C D (S D), oral gavage, 28 days; 6:2 Fluorotelomer methacrylate, Liver Weight, Absolute E C H A , 2007 , 6299223 Rat, C D (S D), oral gavage, 28 days; Serex and others 2014, 3857378 Rat, C D (S D), oral gavage, 90 days; E C H A, 2007 , 5701160 Rat, C D (S D), oral gavage, 28 days; Serex and others 2014, 3857378 Rat, C D (S D), oral gavage, 90 days; E C H A, 2007 , 5701160 Rat, C D (S D), oral gavage, 28 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Liver Weight, Relative Mukerji and others 2015 , 4985717, P O Mouse, C D- 1(1 C R) B R, oral gavage, 70 days (premating-lactation); Unnamed Report (2005 a), (E C H A Summary), 5701141 Rat, C D (S D) oral gavage 28 days; Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378 Rat, C D (S D), oral gavage, 90 days; P O Mouse, CD-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); 6:2 Fluorotelomer alcohol, Liver Weight, Absolute, Mukerji and others 2015 , 4985717, PO Mouse, CD-1(1 C R)B R, oral gavage, 70 days (premating -lactation) (y-axis) across Dose (milligram per kilogram per day), ranging from 0 to 1100 in increments of 100 (x-axis) for no apparent treatment related effect, treatment related increase, and treatment related decrease.
Figure 7.
Survey of liver weight findings among the most studied PFAS included in the systematic evidence map with animal toxicology evidence (trifluoroacetic acid, 6:2 fluorotelomer alcohol, 6:2 fluorotelomer sulphonate ammonium, 6:2 fluorotelomer methacrylate). Screenshot is shown of interactive version accessed May 17, 2022. Note: 6-digit number in “Study” column, Health and Environmental Research Online (HERO) identification; d, days; ECHA, European Chemicals Agency; GD, gestation day; PFAS, per- and polyfluoroalkyl substances.
Figure 8 is horizontal bar graph, plotting Chemical, Endpoint, study, animal description, route, and exposure duration (bottom to top), Stomach Contents, Absent Unnamed Report (2012 b), (E C H A Summary) , 6299209, F 1 Rat, C D (S D) I G S, B R, oral gavage, up to 57 days (premating-lactation); Trifluoroacetic acid Litters with Fetal Alterations Unnamed Report (201O a), (E C H A Summary) , 6299211, F 1 Rat, C D (S D) I G S, B R, oral gavage, G D 6 to 19; Fetal Viscera l Abnormalities Unnamed Report, (2017 d), (E C H A Summary) , 6299227, F 1 Rat, Hsd. Han: Wist, oral gavage, G D S-19; Fetal Skeletal Variations Unnamed Report, (2017 d), (E C H A Summary) , 6299227, F 1 Rat, Hsd. Han: Wist, oral gavage, G D S-19; Fetal Skeletal Abnormalities Unnamed Report, (2017 d), (E C H A Summary), 6299227, F 1 Rat, Hsd. Han: Wist, oral gavage, G D S-19; 6:2 Fluorotelomer methacrylate, Fetal External Abnormalities, Unnamed Report (2017 d), (E C H A Summary), 6299227, F 1 Rat, Hsd. Han Wist oral gavage, G D S-19; Zygomatic Arch, Incomplete Ossification O’Connor and others 2014 , 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20; Supraoccipital, Incomplete Ossification O’Connor and others 2014 , 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20; Skeletal Malformation Unnamed Report (2005 b), (E C H A Summary) , 5701142, F 1 Rat, C D (S D), oral gavage, 14 days (premating- L D3); Pelvis, Pubis Incompletely Ossified O’Connor and others 2014 , 3043436, F 1 Rat, C D (S D) oral gavage, G D 6 to 20; Pelvis, lschium Incompletely Ossified O’Connor and others 2014, 3043436 F 1 Rat, C D (S D), oral gavage, G D 6 to 20; Parietal, Incomplete Ossification O’Connor and others 2014 , 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20; Litters with Fetal Alterations O’Connor and others 2014, 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20; lnterparietal, Incomplete Ossification O’Connor and others 2014, 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20; 6:2 Fluorotelomer alcohol Frontal, Incomplete Ossification O’Connor and others 2014 , 3043436, F 1 Rat, C D (S D), oral gavage, G D 6 to 20 (y-axis) across Dose (milligram per kilogram per day), ranging from 0 to 1000 in increments of 100 (x-axis) for no apparent treatment related effect, treatment related increase, and treatment related decrease.
Figure 8.
Survey of developmental findings among the most studied PFAS included in the systematic evidence map with animal toxicology evidence (trifluoroacetic acid, 6:2 fluorotelomer alcohol, 6:2 fluorotelomer methacrylate). Screenshot of interactive version accessed May 17, 2022 is shown. Note: 6-digit number in “Study” column, Health & Environmental Research Online (HERO) identification; d, days; ECHA, European Chemicals Agency; GD, gestation day; PFAS, per- and polyfluoroalkyl substances.
Figure 9 is horizontal bar graph, plotting Chemical, Endpoint, study, animal description, route, and exposure duration (bottom to top), Rat, C D (S D), oral gavage, 90 days; Serex and others 2014 , 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(I C R) B R, oral gavage, 109 days (premating-sacrifice); White Blood Cell (W B C), Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1 (1 C R) B R, oral gavage, 109 days (premating-sacrifice); Reticulocytes, Mukerji and others 2015, 4985717, P O Mouse, C D-1( 1 C R)B R, oral gavage, 70 days (premating-lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R)B R, oral gavage, 109 days (premating-sacrifice); Reticulocytes, Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R)B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Red Blood Cell (R B C), Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Prothrombin Time (P T), Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Platelets (P L T), Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Neutrophils Mukerji and others 2015, 4985717, P O Mouse, C D-1 (1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1 (1 C R) B R, oral gavage, 109 days (premating-sacrifice); Monocytes Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Mean Corpuscular Volume (MCV), Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Mean Corpuscular Hemoglobin Concentration (M C H C), Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Mean Corpuscular Hemoglobin (M C H), Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Lymphocyte, Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage , 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Hemoglobin (H G B), Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; P O Mouse, C D-1(1 C R) B R, oral gavage, 109 days (premating-sacrifice); Hematocrit (H C T), Mukerji and others 2015, 4985717, P O Mouse, C D-1(1 C R) B R, oral gavage, 70 days (premating- lactation); Rat, C D (S D), oral gavage, 90 days; Eosinophils, Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Basophils, Serex and others 2014, 3857378, Rat, C D (S D), oral gavage, 90 days; Rat, C D (S D), oral gavage, 90 days; Activated Partial Thromboplastin Time (A P T I), Serex and others 2014, 3857378 Rat, C D (S D), oral gavage, 90 days (y-axis) across Dose (milligram per kilogram per day), ranging from 0 to 280 in increments of 20 (x-axis) for no apparent treatment related effect, treatment related increase, and treatment related decrease.
Figure 9.
Survey of hematological findings for 6:2 fluorotelomer alcohol for animal toxicology studies. Screenshot of interactive version accessed May 17, 2022 is shown. Note: 6-digit number in “Study” column, Health & Environmental Research Online (HERO) identification; d, days.
Figure 10 is a heatmap, plotting Overall confidence, Results presentation, outcome assessment, study design applicability, exposure characterization, selective reporting or attrition, confounding or variable control, blinding, allocation, and reporting (y-axis) across Biodynamics 1991, 5381154; Bodin J and others 2016, 4563763; Case, York, and Christian 2001 1291129; Covance 2000, 5385932; Dupont 1991, 5381147; E C H A, 1976, 6299236; E C H A, 1992, 6299232; E C H A, 1995, 6299219; E C H A, 2001 6299228; E C H A, 2001 6299250; E C H A, 2007, 5701160; E C H A, 2007, 5701160; E C H A, 2011, 5701148; Feng M and others 2015, 5161756; Grossman, Mispagel, and Bowen 1992, 3981622; Haskell Laboratory 1995, 5380968; Hirata-Koizumi and others (2015) 10165634; Ladies and others 2008, 2850411; Li C and others 2021, 8437286; Malley and others 1996, 4934891; Malley and others 1998, 5380426; Mukerji and others 2015, 4985717; Mylchreest E, Munley, and Kennedy 2005, 3859272; O’Connor and others 2014, 3043436; Peden-Adams, 2007, 1424799; Saillenfait and others 1997, 3043578; Serex and others 2014, 3857378; Takahashi M and others 2014, 2543502; Unnamed report (1981) (E C H A summary), 6299231; Unnamed report (2005 a) (E C H A summary), 5701141; Unnamed report (2005 b) (E C H A summary), 5701142; Unnamed report (2010 a) (E C H A summary), 6299211; Unnamed report (2012 b) (E C H A summary), 6299209; Unnamed report (2016 a) (E C H A summary), 629844; Unnamed report (2016 b) (E C H A summary), 6299220; Unnamed report (2017 a) (E C H A summary), 5701139; Unnamed report (2017 b) (E C H A summary), 5708371; Unnamed report (2017 c) (E C H A summary), 5708380; Unnamed report (2017 d) (E C H A summary), 6299227; Unnamed report (2017 e) (E C H A summary), 6299229; Unnamed report (2017 f) (E C H A summary), 6299235; Unnamed report (2017 g) (E C H A summary), 6299237; Unnamed report (2018 a) (E C H A summary), 6299240; Unnamed report (2018 b) (E C H A summary), 6299241; Unnamed report (2018 c) (E C H A summary), 6299238; Unnamed report 1993 (E C H A summary), 6299238; Unnamed report undated (E C H A summary), 6302358; Wang, 2019, 5082132; Woodlief T and others (2011); Xie, 2009, 1277446; Zhang and others (2021) 9962191, and Zou and others (2021), 9960710 (x-axis) for good (metric) or high confidence (overall), Adequate (metric) or medium confidence (overall), deficient (metric) or low confidence (overall), critically deficient (metric) or uninformative (overall), not reported, multiple judgements exist, and bias away from null.
Figure 10.
Study evaluation results for animal studies. Figure is presented as a thumbnail for reference. Screenshot of interactive version accessed May 17, 2022 is shown. A full download of study evaluation summaries is also available in Excel Table S12. Note: ECHA, European Chemicals Agency.
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