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Appendix D: Evidence Review: Methods and Approach
Pages 223-239

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From page 223...
... The committee's review approach improved efficiency while minimizing the risk of excluding scientific findings that would inform the committee's recommendations. The committee was charged with assessing the strength of evidence for the spectrum of putative health effects suggested by human studies (including immune response, lipid metabolism, kidney function, thyroid disease, liver disease, glycemic parameters and diabetes, cancer, and fetal and 223
From page 224...
... Therefore, the ATSDR's Toxicological Profile for Perfluoroalkyls was used by the committee as the basis for the next stages of the review process. TABLE D-1 Authoritative Reviews Found by the Committee PFAS Chemicals Date of Last Literature Search by Review Covered in Review Health Endpoints Covered in Review the Organization ATSDR PFBA, PFHxA, PFHpA, Not limited September 2018 Toxicological PFOA, PFNA, PFDA, Profile for PFUnA, PFDoDA, PFBS, Perfluoroalkyls PFHxS, PFOS, FOSA EFSA Risk to PFOA, PFNA, PFHxS, Fertility and pregnancy outcomes, March 2013 Human Health PFOS development effects, neurotoxic outcomes, Related to the immune outcomes, endocrine effects, Presence of metabolic effects, kidney function, Perfluoroalkyl cardiovascular disease and mortality, bone Substances in Food mineral density EPA Health Effects PFOA Serum lipids, cardiovascular disease, liver 2015 Document (PFOA)
From page 225...
... Third, the process to assess the strength of the evidence is not always clear. REVIEW OF SYSTEMATIC REVIEWS The committee's review of systematic reviews consisted of the following steps: literature search, screening of abstracts, full text review of studies identified in the abstract screening, evaluation of a final set of relevant studies, evidence assessment, and synthesis.
From page 226...
... 49 12 Limit 10 to (English language humans and "review" or "scientific integrity review" or "systematic 51 review") Scopus Search Terms ( ( ( TITLE-ABS-KEY ( "MeFOSAA" OR "PFHxS" OR "n-PFOA" OR "Sb-PFOA" OR "PFOA" OR "PFDA" OR "PFUnDA" OR "n-PFOS" OR "Sm-PFOS" OR "PFOS" OR "PFNA" OR "Perfluorinated chemical*
From page 227...
... statement: Population: Systematic reviews of health effects of PFAS in humans Exposure: PFAS species measured in the CDC's National Report on Human Exposure to Environmental Chemicals (see Chapter 1, Table 1-3) Comparison: Any comparison groups, including internal controls Outcome: Any human health outcome The inclusion and exclusion criteria related to the PECO statement were as follows: Inclusion Criteria: Includes human evidence; includes the PFAS species measured in the CDC's National Report on Human Exposure to Environmental Chemicals; assesses the evidence for an association of PFAS and a health outcome in humans; and has a methods section Exclusion Criteria: Did not review health effects of PFAS; reviewed only animal or mechanistic studies; reviewed chemicals other than the PFAS included in the Statement of Task; reviewed generic classes of chemicals such as "endocrine disruptors" or "persistent organic pollutants;" or reviewed the ecological effects of PFAS or PFAS exposure pathways Title and abstract screening was completed by two screeners.
From page 228...
... The committee conducted a critical appraisal of the systematic reviews because systematic reviews can be subject to a range of biases.
From page 229...
... As a result, the systematic reviews were used as sources for reference in the committee's determination of the biologic plausibility between PFAS and a health effect, but they were not formally included as part of the final strength-of-evidence determination. ORIGINAL LITERATURE REVIEW The original literature review consisted of the following steps: literature search, screening of abstracts, full text review of studies identified in the abstract screening, evidence mapping and evaluation, and data abstraction.
From page 230...
... not exp human/ 6205240 13 11 not 12 5435 14 Limit 13 to english language 5232 15 Limit 14 to "pubmed/medline" 540 16 14 not 15 4692 17 Limit 16 to article 3517 Scopus Search Terms5 ( ( ( TITLE-ABS-KEY ( "MEFOSAA" OR "PFHXS" OR "N-PFOA" OR "SB-PFOA" OR "PFOA" OR "PFDA" OR "PFUNDA" OR "N-PFOS" OR "SM-PFOS" OR "PFOS" OR "PFNA" OR "PERFLUORINATED CHEMICAL*
From page 231...
... The titles and abstracts were screened for relevance to the research questions for the review. The review used the following PECO statement: Population: Studies of health effects of PFAS in humans Exposure: PFAS species measured in the CDC's National Report on Human Exposure to Environmental Chemicals Comparison: Any comparison groups, including internal comparisons Outcome: Any health outcome measured in humans The inclusion and exclusion criteria related to the PECO statement were as follows: Inclusion Criteria: Is an epidemiologic or human study; includes a quantitative measure of the PFAS species measured in the CDC's National Report on Human Exposure to Environmental Chemicals; assesses the evidence for an association of PFAS and a health outcome in humans; and English language only 6 See https://picoportal.net (accessed July 1, 2022)
From page 232...
... , 5,060 articles were subject to title and abstract screening by two independent reviewers. Full Text Review For the full text review, 4,434 of the articles identified in the literature search were excluded because the titles and abstracts did not meet the inclusion criteria, so 626 articles were subject to full text review.
From page 233...
... Appendix D 233 FIGURE D-2 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram for the committee's reviews on the health effects of PFAS.
From page 234...
... 234 FIGURE D-3 Evidence map describing the number of studies found by PFAS for each health outcome category.
From page 235...
... Source of Funding: Description of the disclosed sources of funding for the paper Data Abstraction Data abstraction was completed by a trained scientist from ICF, the EPA, the National Academies, or Johns Hopkins.8 The data abstraction form included the following: Reference: Author year and DOI number if relevant Chemical: Acronym of specific PFAS Endpoint: Name of the specific outcome for the risk estimate Subpopulation: Description of the specific subpopulation for the risk estimate N: Sample size that informs risk estimate Exposure Levels: That apply to the risk estimate Comparison: Description of type of risk estimate, such as "SMR for bladder cancer in the high exposure group compared to no workplace exposure" or "change in ln (TSH) per standard unit increase in serum PFOA." Risk/Effect Estimate: Reported number Lower Confidence Interval: Reported number Upper Confidence Interval: Reported number 8 For some studies included in the committee's review, the data had been previously abstracted by ICF or the EPA to support the EPA's ongoing assessments of PFAS; newer evidence was abstracted by ICF or consultants at Johns Hopkins University.
From page 236...
... STRENGTH-OF-EVIDENCE DETERMINATION To assess the strength of evidence regarding the potential for PFAS to cause a particular health effect, the committee then integrated the evidence reviewed in the ATSDR's Toxicological Profile for Perfluoroalkyls and other authoritative reviews with the evidence from the original literature review from the epidemiologic studies. The synthesis of available data was guided by a framework based on the Hill considerations (Hill, 1965)
From page 237...
... Inadequate or Insufficient Evidence to Determine an Association If there was not enough reliable scientific data to categorize the potential association with a health effect as "sufficient evidence of an association," "limited or suggestive evidence of an association," or on the other end of the spectrum, "limited or suggestive evidence of no association," the health outcome was placed in the category of "inadequate or insufficient evidence to determine an association" by default. In this category, the available human studies may have inconsistent findings or be of insufficient quality, validity, consistency, or statistical power to support a conclusion regarding the presence of an association.
From page 238...
... 2021. The Use of Systematic Review in EPA's Toxic Substances Control Act Risk Evaluations.
From page 239...
... 2014. The Navigation Guide systematic review methodology: A rigorous and transparent method for translating environmental health science into better health outcomes.


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