PFAS (per-and polyfluoroalkyl substances) are a large class of synthetic chemicals widely used in consumer products and industrial processes. The scientific literature on PFAS has increased dramatically in the last decade. Many stakeholders, including regulators, scientists, non-governmental organizations, and concerned individuals could benefit from an efficient way to access the health and toxicological literature related to PFAS. To create a systematic evidence map of the available peer-reviewed health or toxicological research for 29 PFAS. A protocol for conducting this systematic evidence map was initially published on Zenodo (Pelch et al. 2019c), then peer reviewed and published in Environment International (Pelch et al. 2019d). PubMed database was searched through January 25, 2021. Studies were screened for inclusion and exclusion according to the Populations, Exposures, Comparators, and Outcomes (PECO) statement. Inclusion criteria were intentionally broad and included any human, animal, and/or in vitro study that investigated exposure to one of the 29 PFAS of interest and a human health or toxicological effect. Selected study details were extracted from included studies as described in the protocol. Study appraisal was not conducted. The included studies and extracted meta-data are freely available in the online, interactive systematic evidence map at https://pfastoxdatabase.org. Over 15,000 studies were retrieved from the PubMed literature searches. After manual screening, 1,067 studies were identified and included as investigating the health or toxicological effect of one or more PFAS of interest. There were 505 human, 385 animal, and 220 in vitro studies. Summary tables of the extracted data and overall observations are included in this report. The PFAS-Tox Database is a useful tool for searching, filtering, and identifying peer reviewed research on the health and toxicological effects of the included PFAS. In this summary of the evidence map we provide examples of data gaps and clusters revealed by the database, with the goal of helping direct future research efforts, facilitate systematic reviews (e.g. on immune effects, mixtures of PFAS, or effects of short chain PFAS), inform regulatory risk assessments, and improve opportunities for cross-disciplinary coordination. We also discuss how this tool supports scientists, regulatory agencies, and other individuals by increasing awareness and access to current evidence regarding the health effects associated with PFAS exposure.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50%–100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3–2.8 (95% confidence limits from 1.2–3.1) ng/ml compared to ≤0.5 ng/ml for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5–3.4) and 3.6 (95% CI: 2.2–3.1) ng/ml, respectively, compared to <1 ng/ml for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.