A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects
Open accessAbstract
Here, we review present understanding of sources and trends in human exposure to poly- and perfluoroalkyl substances (PFASs) and epidemiologic evidence for impacts on cancer, immune function, metabolic outcomes, and neurodevelopment. More than 4000 PFASs have been manufactured by humans and hundreds have been detected in environmental samples. Direct exposures due to use in products can be quickly phased out by shifts in chemical production but exposures driven by PFAS accumulation in the ocean and marine food chains and contamination of groundwater persist over long timescales. Serum concentrations of legacy PFASs in humans are declining globally but total exposures to newer PFASs and precursor compounds have not been well characterized. Human exposures to legacy PFASs from seafood and drinking water are stable or increasing in many regions, suggesting observed declines reflect phase-outs in legacy PFAS use in consumer products. Many regions globally are continuing to discover PFAS contaminated sites from aqueous film forming foam (AFFF) use, particularly next to airports and military bases. Exposures from food packaging and indoor environments are uncertain due to a rapidly changing chemical landscape where legacy PFASs have been replaced by diverse precursors and custom molecules that are difficult to detect. Multiple studies find significant associations between PFAS exposure and adverse immune outcomes in children. Dyslipidemia is the strongest metabolic outcome associated with PFAS exposure. Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of PFAS exposures on neurodevelopment. Preliminary evidence suggests significant health effects associated with exposures to emerging PFASs. Lessons learned from legacy PFASs indicate that limited data should not be used as a justification to delay risk mitigation actions for replacement PFASs.
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Dietary exposure through drinking water and contaminated food is among the largest PFAS exposure sources for both ecosystems and humans.
“PFAS exposures via food chains are more difficult to resolve, and dietary exposure through drinking water and contaminated food sources (e.g., seafood and other animal products) are among the greatest exposure sources for ecosystems and human populations alike (109, 111).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [109]
The ‘Approaches for quantifying exposure sources’ section (page unavailable) says dietary intake is generally the largest source of human PFAS exposure and identifies drinking water, seafood, and other animal products as important sources, with contributions varying by population. The paper discusses PFAS accumulation in marine food chains, but does not establish that dietary exposure is among the greatest PFAS exposure sources for ecosystems. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWaterborne rather than dietary exposure was associated with lower amphipod survival and reproduction, while higher trophic-level organisms are exposed mainly by ingestion.
“Solubilized (i.e., waterborne) rather than dietary exposure was linked to reduced amphipod survival and reproduction (133) while higher trophic-level organisms are exposed primarily through ingestion (109).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [109]
Citation (109) is attached to the claim about higher trophic-level organisms, not the amphipod finding. In “Approaches for quantifying exposure sources” (page unavailable), the review says dietary intake is generally the largest PFAS exposure source for human adults. It does not establish that ingestion is the primary exposure route for higher trophic-level organisms generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredFluoropolymer manufacturing plants, wastewater treatment plants, landfills, and military bases are major sources of PFAS pollution in the environment.
“Fluoropolymer manufacturing plants, wastewater treatment plants [10,11], landfills, and military bases [89,90] are major sources of PFAS pollution in the environment.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
The Introduction and Drinking water section link PFAS contamination to military bases and fluoropolymer manufacturing facilities. The Biosolids and agriculture section explicitly calls wastewater treatment plants point sources, but mentions landfills only as destinations for PFAS-containing sludge; it does not establish landfills as major pollution sources. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPFASs can activate PPARα, disrupt nuclear receptor signaling, and interfere with genes regulating lipid and cholesterol homeostasis.
“Mechanistically, PFASs can activate peroxisome proliferatoractivated receptor alpha (PPAR α ), disrupt nuclear receptor signaling, and interfere with genes regulating lipid and cholesterol homeostasis.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
The Metabolic effects section (page unavailable) links PFAS exposure to dyslipidemia and identifies PPAR-alpha as a nuclear receptor involved in a possible toxicological pathway. It does not establish that PFASs activate PPAR-alpha, disrupt nuclear receptor signaling, or interfere with genes regulating lipid and cholesterol homeostasis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPFAS 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 [90]
The Immune effects section reports that four of five vaccination-response studies found statistically significant associations between higher PFAS exposure and suppressed immune response, including findings in children. It also describes the human epidemiological evidence as mounting and the causal interpretation as conditional (Academic studies section: “If this effect is causal”). Thus, the claim's statement that PFAS exposure *leads to* immune suppression is stronger than the review establishes for humans. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Only a small fraction of thousands of known PFAS compounds are routinely studied; most human and wildlife exposure assessments focus on just 2-30 legacy PFASs, leaving the uses and risks of the vast majority unknown.
“Significant gaps exist in PFAS research, with only a small fraction of the thousands of known PFAS compounds being routinely studied-most human and wildlife exposure assessments focus on just 2-30 legacy PFASs, leaving the uses and risks of the vast majority unknown [90,237,238].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
The Introduction states that more than 4,000 PFASs exist, and ‘Approaches for quantifying exposure sources’ says regular human epidemiological studies usually report six legacy PFASs. ‘Future directions’ says the toxicity of emerging PFASs is poorly understood. The paper does not establish the claimed 2–30 range for most human and wildlife exposure assessments or say that the uses of the vast majority are unknown; page numbers were not supplied. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHundreds to thousands of PFASs are used in global commerce, but analytical methods and available standards lag behind, making it difficult to identify or quantify many compounds.
“For example, hundreds to thousands of PFASs are used in global commerce, but analytical methods and available standards lag behind, making it difficult to even identify or quantify many compounds [90,237].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
The Introduction says more than 4,000 PFASs have been manufactured and widely used. Future directions describes difficulty quantifying the full diversity of PFASs and reports unidentified compounds; the consumer-products section says typical measurement techniques capture only a fraction of measured fluorine. The paper does not establish the claim that available analytical standards lag behind. (LLM, conf=0.86)
Experimental — accuracy not yet measuredExposure estimates can vary by two orders of magnitude due to uncertainties in source contributions and lack of standardized methods.
“Exposure estimates can vary by two orders of magnitude due to uncertainties in source contributions and lack of standardized methods [90].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
In “Approaches for quantifying exposure sources” (page unavailable), the review reports large uncertainties about PFAS exposure sources and cites scenario-based estimates spanning two orders of magnitude. It attributes that range to varying chemical concentrations and contact frequencies, but does not identify a lack of standardized methods as a cause. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn environmental and biomonitoring studies, up to 48% of total organofluorine in human plasma remains unaccounted for, indicating that a substantial proportion of exposure is from unidentified PFASs.
“In environmental and biomonitoring studies, up to 48% of total organofluorine in human plasma remains unaccounted for, indicating that a substantial proportion of exposure is from unidentified PFASs [90].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
The Future directions section reports that quantified PFASs accounted for 52–100% of extractable organic fluorine in plasma samples from two German cities, leaving up to 48% unaccounted for. It describes exposure to new and unidentified organofluorine compounds as a hypothesis, not an established finding that a substantial proportion of exposure comes from unidentified PFASs. No page number is provided in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHuman exposure to PFASs occurs primarily through contaminated food and water, inhalation of household dust, and dermal or parenteral contact with PFAS-containing products.
“Human exposure occurs primarily through contaminated food and water, inhalation of household dust, and dermal or parenteral contact with PFAS-containing products [9].”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [9]
The Human exposure pathways section identifies contaminated drinking water and seafood, indoor air, and contact with contaminated media as exposure routes. The Consumer products, indoor air and dust section also discusses dust and dermal exposure, but says dermal exposure to PFOS and PFOA from products is thought to be low. It does not identify parenteral contact as a route or establish that dust inhalation and product contact are primary routes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPFAS exposure is associated with immunotoxic, neuro-developmental toxicity, thyroid and kidney disorders, hormonal effects, carcinogenic potency, infertility, and cancers.
“Extensive studies have found positive associations between PFAS exposure and immunotoxic, neuro-developmental toxicity, thyroid and kidney disorders, hormonal effects, carcinogenic potency, infertility, and cancers [98,111,119].”
From Investigating the extent of PFAS contamination in the Upper Danube Basin across environmental compartments (2025) · cites this paper as [119]
The Immune effects and Academic studies sections (pages unavailable) report associations with immune suppression, renal function, thyroid disease, and kidney and testicular cancer. But the Neurodevelopmental effects section calls the human evidence mixed, the Metabolic effects section calls most thyroid findings inconclusive, and the Cancer section limits the strongest evidence to highly exposed communities. The copy does not establish infertility or a general association with hormonal effects; its Early industry studies section reports conflicting findings on reproductive hormones. (LLM, conf=0.90)
Experimental — accuracy not yet measuredExtensive 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 [109]
PFAS exposure is robustly linked to dyslipidemia and altered lipid metabolism.
“In the realm of lipid metabolism, PFAS exposure is robustly linked to dyslipidemia and altered lipid metabolism.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [90]
PFASs are highly persistent in natural environments due to their chemical stability and resistance to degradation.
“PFASs are highly persistent in natural environments due to their chemical stability and resistance to degradation.”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [9]
Exposure to PFAS has been associated with adverse human health consequences.
“exposure to PFAS has been associated with adverse human health consequences (Sunderland et al., 2019).”
From Per and poly-fluoroalkyl substances (PFAS) as a contaminant of emerging concern in surface water: A transboundary review of their occurrences and toxicity effects (2021) · cites this paper as Sunderland et al., 2019
Some PFAS are known or suspected to be associated with adverse human-health effects.
“some PFAS are known or suspected to be associated with adverse human-health effects.11−13”
From Perfluoroalkyl and Polyfluoroalkyl Substances in Groundwater Used as a Source of Drinking Water in the Eastern United States (2022) · cites this paper as [13]
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- Authors
- Sunderland, E. M., Hu, X. C., Dassuncao, C., Tokranov, A. K., Wagner, C. C., & Allen, J. G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sunderland, Elsie M.
- ORCID
- Venue
- Journal of Exposure Science & Environmental Epidemiology
- Published
- 2018-11-23
- Volume
- 29
- Issue
- 2
- Pages
- 131-147
- ISSN
- 1559-0631 (ISSN-L)
- 1559-064X
- PMC
- PMC6380916
- OpenAlex
- W2901377336
- Semantic Scholar
- da9ab49d9dc184966e90b5c960d678e87cb4df51
- Cited by
- 2,786
- References
- 153
- Citations by year
- 2026: 540 · 2025: 586 · 2024: 483 · 2023: 382 · 2022: 328 · 2021: 249 · 2020: 180 · 2019: 34
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Exposure Science & Environmental Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Environmental Protection Agency
- National Institute for Health and Care Research
- National Health Research Institutes
- National Institute of Environmental Research
- National Institutes of Health
- National Institute of Environmental Health Sciences (P30ES000002, P42ES027706)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Physical Sciences › Materials Science › Polymers and Plastics › Synthesis and properties of polymers
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Keywords
- per- and polyfluoroalkyl substances, human exposure, emerging PFASs, PFAS precursors, seafood contamination, drinking water contamination, groundwater contamination, aqueous film-forming foam, food packaging, indoor air exposure, cancer risk, immune function, dyslipidemia, brain development, serum PFAS concentrations, risk mitigation
- MeSH terms
- Environmental Exposure, Environmental Pollutants, Fluorocarbons, Humans, Water Pollutants, Chemical, Water Pollution, Chemical, Groundwater, Drinking Water
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