Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research
Open accessAbstract
Reports of environmental and human health impacts of per- and polyfluoroalkyl substances (PFAS) have greatly increased in the peer-reviewed literature. The goals of the present review are to assess the state of the science regarding toxicological effects of PFAS and to develop strategies for advancing knowledge on the health effects of this large family of chemicals. Currently, much of the toxicity data available for PFAS are for a handful of chemicals, primarily legacy PFAS such as perfluorooctanoic acid and perfluorooctane sulfonate. Epidemiological studies have revealed associations between exposure to specific PFAS and a variety of health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer. Concordance with experimental animal data exists for many of these effects. However, information on modes of action and adverse outcome pathways must be expanded, and profound differences in PFAS toxicokinetic properties must be considered in understanding differences in responses between the sexes and among species and life stages. With many health effects noted for a relatively few example compounds and hundreds of other PFAS in commerce lacking toxicity data, more contemporary and high-throughput approaches such as read-across, molecular dynamics, and protein modeling are proposed to accelerate the development of toxicity information on emerging and legacy PFAS, individually and as mixtures. In addition, an appropriate degree of precaution, given what is already known from the PFAS examples noted, may be needed to protect human health. Environ Toxicol Chem 2021;40:606–630. © 2020 SETAC Abstract Many health effects have been reported in association with or due to per- and polyfluoroalkyl substance (PFAS) exposures in humans and toxicologic models. Species concordance of effects is evident for a handful of legacy PFAS. With hundreds of PFAS in commerce that lack exposure and health effects data, contemporary and novel methods must be implemented to inform exposed communities, risk assessors, and concerned citizens and prioritize those most likely to affect human health.
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Extensive human health research has identified possible carcinogenic, reproductive, endocrine, neurotoxic, dyslipidemic, and immunotoxic effects from PFAS exposure.
“Human-health effects from exposure to PFAS have been studied extensively, identifying possible carcinogenic, reproductive, endocrine, neurotoxic, dyslipidemia, and immunotoxic effects (6, 108, 109).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [6]
The Abstract (page not available) reports human epidemiological associations with cancer, reproductive outcomes, altered thyroid and immune function, and lipid dysregulation. The Neurotoxicity section (page not available) says potential nervous-system effects have not been widely investigated and cites mainly cell and rodent findings; the Reproductive and developmental outcomes section describes human neurodevelopment studies as inconclusive. Thus, the source supports most of the list, but not the implication that extensive human research has identified neurotoxic effects. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPFAS are globally persistent and are detectable in the blood of nearly all humans.
“Widespread global persistence of PFAS has resulted in detectable concentrations of the compounds in the blood of almost the entire human population (6).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [6]
The Introduction says that widespread exposure, together with the environmental persistence and biological half-lives of some PFAS, has led to measurable PFAS in the blood of nearly the entire population in developed countries. The citing sentence extends that finding to almost the entire global population and attributes it to persistence alone; the passage does not support those extensions. No page number was supplied for the passage. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMultiple PFAS analytes detected in this study have been associated with adverse health effects in humans, including cancers, developmental delays, and reproductive dysfunction.
“Multiple PFAS analytes detected in this study have been associated with adverse health effects in humans, including cancers, developmental delays, and reproductive dysfunction.7,8”
From Per- and Polyfluoroalkyl Substances in Surface Water and Fluvial Sediments of a Rural Gulf Coast Watershed: A Year-long Spatiotemporal Assessment (2026) · cites this paper as [7]
The review’s Reproductive and developmental outcomes section reports human associations with testicular cancer, impaired fertility, and adverse infant-development outcomes. But its explicit reference to “developmental delays” is in the Reproductive and developmental toxicity section’s discussion of exposed animal offspring; the review describes human neurodevelopmental evidence as inconclusive. The source also cannot establish which analytes were detected in the citing study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPFASs cause thyroid hormone disruption by binding to thyroid hormone transport proteins, displacing T4, and interfering with thyroid peroxidase activity, leading to altered feedback in the hypothalamic-pituitary-thyroid axis.
“PFASs also cause thyroid hormone disruption by binding to thyroid hormone transport proteins, displacing thyroxine (T4), and interfering with thyroid peroxidase activity, leading to altered feedback in the hypothalamic-pituitary-thyroid axis.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [201]
The Endocrine disruption section describes displacement of thyroxine from transport proteins as a possible mechanism, not an established causal pathway. The Thyroid function section reports PFAS interactions with thyroid-hormone binding proteins and interference with thyroid peroxidase activity in vitro, but does not establish that these mechanisms together cause the claimed change in hypothalamic-pituitary-thyroid feedback. Page numbers were not supplied. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDisruption of neurotransmitters and neuromodulators by PFAS may contribute to increased risk of neuropsychiatric disorders, as well as other health risks associated with PFAS exposure, such as obesity, cancer, and thyroid disease.
“Disruption of neurotransmitters and neuromodulators by PFAS may contribute to increased risk of neuropsychiatric disorders, as well as other health risks associated with PFAS exposure, such as obesity, cancer, and thyroid disease”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Fenton et al., 2021
The Neurotoxicity section (page unavailable) reports limited evidence of PFAS-related nervous-system effects, including altered behavior in rodents, but does not describe disruption of neurotransmitters or neuromodulators or link it to neuropsychiatric disorders. The Obesity, Tumor induction, and Thyroid function sections discuss PFAS-related evidence for the other named health risks, with qualifications; they do not connect those risks to neurotransmitter disruption. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Both laboratory and community medical studies have found direct links between PFAS and human health conditions.
“Both lab oratory and community medical studies have found direct links between PFAS and human health conditions.”
From Review of emerging contaminants in green stormwater infrastructure: antibiotic resistance genes, microplastics, tire wear particles, PFAS, and temperature (2024) · cites this paper as Fenton et al., 2021
The Liver disease and cancer section reports experimental evidence of PFAS toxicity and significant associations between PFAS exposure and higher liver enzymes in population studies. The Current Knowledge of PFAS Toxicity in Humans section likewise discusses human and experimental reports, but describes epidemiological findings as associations rather than established direct causal links to human health conditions. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEpidemiological evidence indicates health impacts for legacy PFAS.
“coupled with epidemiological evidence of the health impacts for legacy PFAS (5, 6)”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [6]
PFAS are detected in sera across the human population.
“with their detection in sera across the human population”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [6]
PFAS exposure is associated with changes in thyroid hormone levels, with some evidence of sex-specific effects and non-monotonic dose responses.
“Epidemiological and experimental data indicate PFAS exposure is associated with changes in thyroid hormone levels, with some evidence of sex-specific effects and non-monotonic dose responses [200,201].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [201]
PFAS exposure leads to immune suppression, with multiple studies reporting significant associations between PFAS exposure and reduced immune function, particularly in children.
“Furthermore, PFAS exposure leads to immune suppression, with multiple studies reporting significant associations between PFAS exposure and reduced immune function, particularly in children.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [201]
Suppressed immune function and other adverse health effects are associated with exposures to PFOS at concentrations less than 1 ng L-1.
“Suppressed immune function and other adverse health effects have been associated with exposures to PFOS at concentrations less than 1 ng L–1, which is more than 10 billion times lower than concentrations found in AFFF.3,4”
From Centurial Persistence of Forever Chemicals at Military Fire Training Sites (2023) · cites this paper as [4]
Most of the toxicological data currently available for PFAS are limited to a few compounds, mainly PFOA and PFOS.
“Most of the toxicological data currently available for PFAS are limited to a few compounds, mainly PFOA (perfluoro-octanoic acid) and PFOS (perfluoro-octane sulfonate) (Fenton et al., 2021)”
From Review of emerging contaminants in green stormwater infrastructure: antibiotic resistance genes, microplastics, tire wear particles, PFAS, and temperature (2024) · cites this paper as Fenton et al., 2021
PFAS are linked to health conditions including reduced immune response, thyroid functions, liver and kidney diseases, cancer, and adverse reproductive and developmental outcomes.
“Some of these include reduced immune response, thyroid functions, liver and kidney diseases, cancer, and adverse reproductive and developmental outcomes (Anderko and Pennea, 2020; Fenton et al., 2021; Kirk et al., 2018; Sunderland et al., 2018).”
From Review of emerging contaminants in green stormwater infrastructure: antibiotic resistance genes, microplastics, tire wear particles, PFAS, and temperature (2024) · cites this paper as Fenton et al., 2021
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Chronic perfluorooctanesulphonic acid (PFOS) exposure produces estrogenic effects in zebrafish
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Contemporary incidence and mortality rates of kidney cancer in the United States
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“A meta‐analysis of 12 child and adult studies that excluded populations with higher exposures noted that PFAS exposure is negatively associated with serum total thyroxine levels and that “PFAS could induce thyroid dysfunction and disease” (Lee and Choi 2017).”
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Per- and polyfluoroalkyl substances in the environment
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“Widespread global persistence of PFAS has resulted in detectable concentrations of the compounds in the blood of almost the entire human population (6).”
PFAS Molecules: A Major Concern for the Human Health and the Environment
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“exposure, such as obesity, cancer, and thyroid disease, as these chemical messengers regulate diverse physiological processes and organ systems (Blake and Fenton, 2020; Fenton et al., 2021).”
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Centurial Persistence of Forever Chemicals at Military Fire Training Sites
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Poly- and Perfluoroalkyl Substances (PFAS) Exposure through Infant Feeding in Early Life
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Survey of per- and polyfluoroalkyl substances (PFAS) in surface water collected in Pensacola, FL
da Silva, B. F., Aristizabal-Henao, J. J., Aufmuth, J., Awkerman, J., & Bowden, J. A. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e10239 · Cited by 43 · see citing works
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Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS
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“Epidemiological and experimental data indicate PFAS exposure is associated with changes in thyroid hormone levels, with some evidence of sex-specific effects and non-monotonic dose responses [200,201].”
Reproductive Toxicity of Per- and Polyfluoroalkyl Substances
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Occurrence of emerging and persistent organic pollutants in the rivers Cam, Ouse and Thames, UK
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- Authors
- Fenton, S. E., Ducatman, A., Boobis, A., DeWitt, J. C., Lau, C., Ng, C., Smith, J. S., & Roberts, S. M.
- Affiliations
- National Institutes of Health (US)
- West Virginia University (US)
- Imperial College London (GB)
- East Carolina University (US)
- Environmental Protection Agency (US)
- University of Pittsburgh (US)
- Navy and Marine Corps Force Health Protection Command (US)
- University of Florida (US)
- Corresponding author
- Roberts, Stephen M.
- ORCID
- Venue
- Environmental Toxicology and Chemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-10-05
- Volume
- 40
- Issue
- 3
- Pages
- 606-630
- ISSN
- 0730-7268 (ISSN-L)
- 1552-8618
- PMC
- PMC7906952
- OpenAlex
- W3091745167
- Semantic Scholar
- 0a6fbc90c497407cb5123bfeb9d20a235e035dc2
- Cited by
- 2,445
- References
- 308
- Citations by year
- 2026: 638 · 2025: 643 · 2024: 520 · 2023: 360 · 2022: 212 · 2021: 67 · 2020: 4
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Environmental Toxicology and Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- U.S. Environmental Protection Agency
- New Jersey Department of Environmental Protection
- National Institutes of Health
- U.S. Navy
- National Institute of Environmental Health Sciences (ZIAES102785)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Fluorine in Organic Chemistry
- Keywords
- per- and polyfluoroalkyl substances, PFAS toxicity, perfluorooctanoic acid, PFOS, human health effects, immune function, thyroid function, liver disease, insulin dysregulation, kidney disease, reproductive and developmental toxicity, cancer, toxicokinetics, sex differences, life stage differences, read-across, molecular dynamics, protein modeling, PFAS mixtures, precautionary approach, risk assessment
- MeSH terms
- Adverse Outcome Pathways, Animals, Fluorocarbons, Humans, Reproduction, Alkanesulfonic Acids
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