Abstract
Background and Aims:
Per- and poly-fluoroalkyl substances (PFAS) are persistent chemicals that contaminate air, water, soil, and food. Due to their widespread use, PFAS are detectable in most of the US population, raising concerns about potential health impacts, including a possible association with colorectal cancer (CRC). We conducted a scoping review of previously published studies to consolidate the current understanding of PFAS and its effect on CRC risk, identify knowledge gaps, and propose future directions for research.
Methods:
We systematically searched PubMed, Scopus, and Web of Science for studies published through December 2024 that examined PFAS exposure in relation to CRC risk or progression. Data were independently extracted using a standardized protocol and structured according to a predefined Population, Exposure, Comparator, Outcome (PECO) framework. To evaluate internal validity, studies were categorized by evidence stream (in vitro, animal, and epidemiological) and assessed using established quality appraisal criteria.
Results:
Twenty-six studies were identified, including 5 reviews, 3 in vitro studies, 6 animal studies, and 12 epidemiological studies. In vitro research consistently demonstrates that PFAS exposure promotes CRC cell proliferation and migration, highlighting key mechanistic pathways. However, findings from animal and epidemiological studies are mixed, with some indicating increased intestinal tumorigenesis while others report null or protective effects. Notably, major studies were cross-sectional, retrospective, or ecological, emphasizing the need for high-quality longitudinal research to clarify PFAS’s role in CRC risk and progression.
Conclusion:
Evidence on the relationship between PFAS exposure and CRC risk remains limited and inconclusive. Large-scale, prospective epidemiological studies that incorporate biomarker-based exposure assessment, including pre-diagnostic PFAS levels, diverse populations, and rigorous study design are needed to clarify the role of PFAS in CRC development. Such research could provide the role of PFAS in CRC development and progression, guiding public health policies and support targeted interventions to reduce CRC risk.
Keywords: Per- and polyfluoroalkyl substances (PFAS), Colorectal Cancer, Scoping Review, Epidemiological Studies, Animal Studies, In Vitro Studies
1. Introduction
Colorectal cancer (CRC) is the third most common cancer diagnosed in the US and the second leading cause of cancer-related deaths, with an estimated 152,810 new cases and 53,010 deaths expected in 2024 (Siegel et al., 2024). The lifetime risk of developing CRC is about 1 in 23 for men and 1 in 25 for women (American Cancer Society 2024). While incidence rates have been declining in older adults due to improved screening and treatment, an alarming trend has emerged among younger adults (under age 50), where CRC incidence has been increasing by 1–2 % per year since the mid-1990 s. Similarly, CRC mortality rates in younger individuals have risen by about 1 % annually since the mid-2000s (Siegel et al., 2024; Cancer Facts & Figures, 2024). Notably, rising incidence rates for CRC are particularly prevalent among African American and Native American populations (Siegel et al., 2023; Carethers, 2021), underscoring the importance of identifying additional modifiable risk factors—especially those that are highly prevalent and can be mitigated by societal level strategies—to prevent and reduce the burden of CRC.
Per- and poly-fluoroalkyl substances (PFAS) are a class of persistent synthetic chemicals used in consumer products and industrial processes. Due to the strong carbon-fluoride bonds, PFAS break down extremely slowly, leading to prolonged exposure in both humans and animals. As a result, blood levels of certain PFAS can accumulate over time. Overall, there are >15,000 types of PFAS, many of which have been identified and detected in the blood of adults in the US and various regions of Europe (Jain, 2018; Schrenk et al., 2020). Notably, PFAS are detectable not only in 97 % of the U.S. population (Lewis et al., 2015) but also globally, with significant and widely-spread contamination reported in water (Sims et al., 2022) and soil (Rankin et al., 2016). Contamination sources are often unevenly distributed geographically, frequently concentrated in or near low-income and racial and ethnic minority communities due to historical industrial practices (Li et al., 2025; Tan et al., 2024). As a result, residents in these areas tend to have higher PFAS concentrations (Barton et al., 2020; Lin et al., 2021; Park et al., 2019). Legacy PFAS compounds, such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), are classified by IARC as class 1 and 2B carcinogens, respectively and have been linked to several cancers, including renal, testicular, and thyroid cancers (Zahm et al., 2024). Moreover, efforts to reduce emissions of hazardous long-chain and legacy PFAS (C7-C14) have led to both regulatory actions and voluntary measures by manufacturers. As a result, non-regulated PFAS, including short-chain alternatives (C4-C6), have seen increased use. However, these short-chain PFAS, despite initially being considered less harmful due to their lower bioaccumulation potential, are equally persistent and appear to have similar adverse effects on human health (Kabadi et al., 2020; Rice et al., 2020). Both long- and short-chain PFAS are widely present in the environment, raising concerns about their continued use and impacts on human health as highlighted by the EPA’s PFAS Strategic Roadmap, which outlines commitments to address these chemicals and their risks (PFAS Strategic Roadmap, 2021).
Emerging evidence indicates that PFAS exposure may contribute to increased risk of cancer, including hepatic, kidney, testicular, breast, ovarian, prostate, and thyroid cancers (Shearer et al., 2021; Purdue et al., 2023; Cathey et al., 2023; Goodrich et al., 2022). Less is known about the relationship between PFAS and CRC. PFAS may disrupt metabolic (Kingsley et al., 2019; Stratakis et al., 2020; Prince et al., 2023) and inflammatory pathways (Wang et al., 2021; Zhou et al., 2017), which are key in CRC development (Di Ciaula et al., 2017; Wei et al., 2020). The primary route of PFAS exposure is through dietary intake (DeLuca et al., 2022), leading to direct exposure in the gastrointestinal tract, which may contribute to an increased risk of CRC. Additionally, PFAS exposure may influence lipid metabolism (Zheng et al., 2023; Tessmann et al., 2024) and oxidative stress pathways (Temkin et al., 2020) that could exacerbate inflammatory responses and DNA damage in the colon, increasing the risk of tumorigenesis. Though animal-based experiments (Tessmann et al., 2024; Hansen et al., 2019) and epidemiologic studies (Messmer et al., 2022; Alexander et al., 2024; Cui et al., 2024) indicate PFAS may be carcinogenic to the large bowel, findings remain inconsistent (Ngo et al., 2014; Wimsatt et al., 2016; Wimsatt et al., 2018; Innes et al., 2014; Barry et al., 2013; Vieira et al., 2013; Li et al., 2022). Additionally, studies suggest that PFAS exposure disrupts tight junction barriers and triggers intestinal inflammation (Li et al., 2022). This may potentially increases the risk of Inflammatory Bowel Disease (IBD) (Fart et al., 2021; Xu et al., 2020; Steenland et al., 2013; Agrawal et al., 2024), which is an established and independent risk factor of a CRC subtype known as colitis associated cancer (CAC) (Eaden et al., 2001; von Roon et al., 2007; Birch et al., 2022). Supporting this, the C8 Science Panel reported a probable link between PFOA exposure and ulcerative colitis, a major form of IBD, reinforcing concerns about colorectal carcinogenesis (Nicole, 2013). These findings, along with PFAS-induced barrier dysfunction and chronic inflammation in the gut, provide a strong rationale for investigating PFAS as a potential contributor to CRC development.
Given the rising public health concerns about PFAS and its potential link to CRC, our goal was to systematically evaluate existing evidence, assess the strengths and limitations of past study designs, identify research gaps, and propose future directions to better understand how ubiquitous environmental exposures like PFAS may influence CRC risk. We applied a structured approach to delineate key conceptual boundaries and assumptions that define the scope of this review. To accomplish this, we examined in vitro, animal, and epidemiological studies. While previous reviews have explored the relationship between PFAS exposure and CRC risk (Durham et al., 2023; Murphy and Zaki, 2024; Mutalib, 2023; Rosenfeld et al., 2023; Steenland and Winquist, 2021), they have primarily focused on epidemiological evidence without including results from in vitro and animal models, indicating a consistent lack of systematic methodological rigor and evaluations. Existing reviews have primarily adopted narrative approaches or focused on specific aspects of PFAS toxicity, often lacking a structured methodology to capture the full spectrum of available data. Our main assumption is that PFAS exposure influences biological mechanisms that contribute to the initiation or progression of CRC. In order to comprehensively evaluate the evidence linking PFAS exposure to CRC, we structured our review using a Populations, Exposures, Comparators, and Outcomes (PECO) framework (Whaley and Roth, 2022). This review systematically identifies and maps the existing literature on PFAS exposure and CRC across in vitro, animal, and human studies, offering a comprehensive synthesis of the available evidence. It critically evaluates study design quality, exposure assessments, and outcome measures to assess the reliability of findings. Mechanistic insights from in vitro and animal models are integrated to explore potential biological pathways through which PFAS may influence CRC development and progression, strengthening the interpretation of epidemiological associations. By comparing evidence across all three of these research domains, this review assesses the consistency of findings linking PFAS to CRC risk. Ultimately, it highlights methodological limitations, data gaps, and uncertainties, providing recommendations for more rigorous and targeted future research to advance scientific understanding and public health decisionmaking.
2. Methods
2.1. Protocol
This scoping review follows the guidelines from PRISMA Extension for Scoping Reviews (PRISMA-ScR) checklist to develop our search and charting of results (Tricco et al., 2018). The protocol was drafted in pro tocols.io, reviewed and approved by the research team and registered with Open Science Framework (https://osf.io/68xr5). The full protocol is provided in the supplemental file as well.
2.2. Objective and specific aims
The overarching objective of this scoping review is to evaluate the breadth and depth of evidence on the association between PFAS exposure and colorectal cancer (CRC) risk across in vitro, animal, and human studies.
Systematically identify and catalog in vitro, animal, and human studies investigating the relationship between PFAS exposure and CRC outcomes.
Assess the quality of study designs, exposure assessment methods, and outcome measures across different study types to evaluate the reliability and validity of findings.
Synthesize mechanistic insights from in vitro and animal models to elucidate potential molecular pathways through which PFAS may influence CRC risk and progression.
Compare and contrast findings across in vitro, animal, and human studies to evaluate the consistency of evidence linking PFAS exposure to CRC.
Identify limitations, research gaps, and uncertainties in the existing literature and propose evidence-based recommendations to inform future research directions.
2.3. Selection of the source of evidence
Briefly, we conducted an extensive search of relevant peer-reviewed publications using multiple databases, including PubMed, Scopus, and Web of Science. Following this, Google scholar was used to screen for additional studies that may not have been indexed in other databases. We included studies, published up until December 2024 that included any assessment of the association between at least one type of PFAS chemical and CRC. Our analysis included research articles, review papers, systematic reviews, and meta-analyses that examined the associations between PFAS exposure and CRC risk or progression. While review papers, systematic reviews and meta-analyses were not a part of the systematic scoping review, we summarized the findings from past assessments in a separate section. The search strategy employed a comprehensive set of keywords related to PFAS and CRC to ensure thorough and extensive coverage of the relevant literature for this scoping review. Our search strategy was developed through a collaborative process involving the research team and referencing existing reviews on PFAS and CRC risk (Mutalib, 2023; Steenland and Winquist, 2021) and the final search strings were tailored for each database using the Boolean operators. We used the PECO framework to define inclusion concepts and develop search terms. We also applied free-text synonyms for a wide range of PFAS compounds. While review articles and meta-analyses were excluded from the main synthesis, their reference lists were screened to ensure no primary studies were missed. Although systematic search strategies cannot be validated in a statistical approach, the transparency of our methods, including search strings, detailed screening protocols, and mapping frameworks are provided as supplementary material ensuring our approach is both reproducible and comprehensive.
2.4. Keywords
As summarized in Supplemental Data 1 (S1), scientific publication databases included Pubmed, Scopus, and Web of science were searched using the following keywords: (“PFAS” OR “perfluoroalkyl” OR “polyfluoroalkyl” OR “perfluorinated” OR “PFOA” OR “perfluorooctanoic acid” OR “perfluorooctanoate” OR “PFOS” OR “perfluorooctane sulfonic acid” OR “perfluorooctanesulfonic acid” OR “perfluorooctane sulfonate” OR “perfluorooctanesulfonate” OR “PFHxS” OR “perfluorohexane sulfonic acid” OR “PFNA” OR “perfluorononanoic acid” OR “PFDA” OR “perfluorodecanoic acid” OR “PFOSA” OR “perfluorooctane sulfonaminde” OR “MeFOSAA” OR “2-N-Methyl-perfluorooctane sulfonamido acetic acid” OR “PFHPA” OR “perfluoroheptanoic acid” OR “perfluoroheptanoate” OR “PFBA” OR “perfluorobutanoic acid” OR “HFPO-DA” OR “hexafluoropropylene oxide-dimer acid” OR “GenX”) AND (“Colorectal cancer” OR “colon cancer” OR “rectal cancer” OR “colorectal carcinoma” OR “colon carcinoma” OR “rectal carcinoma” OR “colorectal malignancy” OR “colon malignancy” OR “rectal malignancy” OR “colorectal neoplasia” OR “colon neoplasia” OR “rectal neoplasia” OR “colorectal sarcoma” OR “colon sarcoma” OR “rectal sarcoma” OR “colorectal adenocarcinoma” OR “colon adenocarcinoma” OR “rectal adenocarcinoma”).
2.5. Screening and eligibility
We screened the titles of all articles identified through our search and reviewed abstracts and full manuscripts as needed to ensure they met our inclusion and exclusion criteria (Supplemental Data 1, S1). The inclusion and exclusion criteria were designed to align with the PECO framework (Table 1), ensuring a structured and systematic selection of relevant studies. Our review included studies across three research domains: in vitro studies using relevant human colorectal cell lines or cellular components, animal studies employing appropriate models such as mice and rats or xenograft models with controlled dosing, and human studies involving participants. Studies obtained from database search were screened for duplicates using Endnote Web. After removing duplicates, studies underwent further screening based on inclusion and exclusion criteria. Eligible studies reported a quantifiable measure of PFAS exposure such as measured concentrations, dosing regimens, or exposure classifications and compared groups with high PFAS exposure against those with minimal or no exposure. Additionally, studies had to examine colorectal cancer-related endpoints, including incidence, progression, or mechanistic markers and mortality (e.g., effect sizes, dose–response relationships, tumor counts, cell viability, or molecular pathway alterations). Studies were excluded if they were unrelated to the exposure or outcome, they employed unsuitable designs (e.g., case reports, commentaries, perspectives), they lacked quantitative estimates, they did not specifically focus on PFAS or CRC, or if full versions of the study were unavailable. The exclusion criterion “quantitative estimates” referred to measurable and reportable numerical data relevant to the study type such as effect sizes or confidence intervals in epidemiological studies, dose–response relationships or tumor counts in animal studies, and cell viability or molecular pathway alterations in in vitro studies. The initial search criteria, screening strategies, and final lists of studies were compiled by one reviewer (D.P.) and then independently verified by two additional experts (H.L. and T.L.A.) to ensure that only relevant studies were included and that no pertinent studies were overlooked. Since the initial screening and compilation were conducted by a single reviewer, it may have increased the risk of missing relevant studies, although two additional experts subsequently verified the list after duplicates were removed to mitigate this concern. All the authors discussed search outcomes, results, figures, discussions, limitations, and future directions with a goal of minimizing bias and enhancing the credibility of our findings. Any disagreements on study selection and data extraction process were resolved through consensus and discussion.
Table 1.
Population, Exposure, Comparator, and Outcome (PECO) Framework.
| Study Type |
Population | Exposure | Comparators | Outcomes |
|---|---|---|---|---|
| In Vitro | Human colorectal cancer cell lines or cellular components | Concentration of one or more PFAS compounds added to cell culture media | Concentration ranges (nanomolar to micromolar) and duration of exposure | Cell viability, proliferation, apoptosis, gene expressions |
| Animal | Animals (whole organism, mammals only; laboratory models such as mice and rats), xenograft models | PFAS administered via oral gavage, diet, drinking water, or intraperitoneal (IP); single PFAS or as exposure mixtures | Animals exposed to high PFAS compared to those exposed to no or low levels of PFAS | Tumor incidence, metastasis, histopathological changes or molecular markers in the colon and rectum |
| Human | Humans without restriction based on age, sex, stage of exposure and outcome assessment | Measured or modeled internal dose or estimated external exposure to PFAS | Low, minimal, or undetectable PFAS exposure (e.g., lowest exposure quantile or non-exposed groups) | CRC incidence quantified as odds ratios, hazard ratios or relative risks; CRC progression and mortality; increased risk ratio of episodes of care or malignant neoplasms of colon |
A structured framework for categorizing studies based on the core elements of Population, Exposure, Comparator, and Outcome (PECO), ensuring a consistent approach to evidence synthesis.
2.6. Quality appraisal
To evaluate the internal validity of the included studies, we employed a tiered quality appraisal approach. For human studies, we used criteria adapted from the United States Environmental Protection Agency’s Integrated Risk Information System (IRIS) ORD staff Handbook (Link: https://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=356370) (U.S. EPA, 2022). These criteria assess key domains such as exposure measurement, outcome ascertainment, participant selection, control of confounding, analytic methods, selective reporting, and sensitivity concerns, from which an overall confidence rating is derived. For the purposes of the current review, when human studies assessed more than one cancer type, quality appraisals were conducted specifically and exclusively for the CRC-related findings. For animal studies, we applied the IRIS framework tailored to animal research, evaluating reporting quality, allocation methods, observational bias and blinding, confounding, selective reporting and attrition, chemical administration and characterization, exposure details (timing, frequency, and duration), endpoint sensitivity and specificity, results presentation, and overall confidence of findings. For in vitro studies, where standard appraisal tools are lacking, we developed customized criteria (Supplemental Data 2, S2). This approach was informed by the preliminary and evolving considerations outlined in the IRIS Handbook, which acknowledges that its current in vitro evaluation framework is still under development and subject to refinement through pilot testing and field experience. Our customized criteria incorporated the core domains identified in the IRIS handbook, including risk of bias and sensitivity, while also integrating established best practices in experimental design. These include rigor in exposure protocols, appropriateness of controls, reproducibility, and the robustness of mechanistic endpoints. By tailoring the evaluation criteria, we aim to ensure both methodological relevance and practical applicability across diverse in vitro study designs, including more complex or assay-specific systems that may not be fully addressed by existing general frameworks. Two independent reviewers conducted these assessments. Following this, assessments were verified by two additional experts and any discrepancies were resolved through discussion. The full quality appraisal outcomes are provided in Fig. 2, which highlights the methodological strengths and weaknesses across study types. These strengths and weakness were used to inform the interpretation of findings and guided the evidence synthesis in the review.
Fig. 2.
Quality Appraisal of Included In vitro, Animal, and Epidemiological Studies on PFAS Exposure and Colorectal Cancer Risk. Quality appraisal for studies included in this scoping review, categorized by evidence stream. (A) Quality was assessed using tailored appraisal criteria for (A) in vitro, (B) Animal, and (C) human studies based on established frameworks and guidelines provided in EPA IRIS guidelines for human and animal studies. Each row represents an individual study, and each column reflects a specific appraisal domain such as participant selection, exposure measurement, confounding control, outcome assessment, or reporting quality. The “overall confidence” column summarizes the cumulative rating for each study. For the purposes of the current review, when human studies assessed more than one cancer type, quality appraisals were conducted specifically and exclusively for the CRC-related findings. *The appraisal of Cui et. al, 2024 should not be directly compared with the other studies since this study focused on assessing the association between serum PFAS levels in CRC patients with MLNs and TLNs numbers. This was used as a marker of disease progression rather than CRC incidence or mortality.
2.7. Synthesis of results and data charting
Data were systematically extracted from studies that met eligibility criteria, including publication year, study design, type of PFAS examined, exposure levels, concentration and duration, disease outcome, and primary findings (Table 2-4). Data were extracted into a standardized Microsoft Excel spreadsheet developed for this review. The spreadsheet included fields for study characteristics, such as study design, population, PFAS type, exposure assessment, outcomes, and key findings. Summarized data were later transferred into structured Word tables and relevant figures for synthesis and presentation. Discrepancies were resolved through discussion with a third reviewer. Data were extracted only based on information reported in the published articles. Studies were grouped into in vitro, animal, and human categories to reflect different levels of biological evidence. This grouping was determined a priori based on study designs commonly used in environmental health research and specified in the protocol. The synthesis utilized the PECO framework, ensuring that each study was systematically evaluated based on Population, Exposure, Comparator, and Outcome. Evidence mapping followed the Synthesis Without Meta-Analysis (SWiM) reporting guideline developed by Campbell et al. (2020) and incorporated principles from the Popay et al. (2006) framework for narrative synthesis utilizing textual descriptions, groupings and clustering, transforming data, tabulation and vote counting as a descriptive tool. The SWiM checklist guided the systematic presentation of results to ensure transparency in reporting. Interrelationships between evidence streams were analyzed by identifying trends across in vitro, animal, and human studies. For in vitro studies, key endpoints such as cell viability, proliferation, mechanistic pathway activation, gene and protein expression, and toxicity measures were documented. In animal studies, extracted data included histopathological changes, tumor counts, dose–response relationships, and systemic toxicity. Results from in vitro and animal studies were assessed based on methodological quality and direct relevance to PFAS and CRC using narrative and qualitative synthesis methods (Fig. 3). For population-based studies, quantitative associations between PFAS exposure and CRC outcomes were analyzed, with standardized effect estimates and confidence intervals plotted in a forest plot (Fig. 5). Reported odds ratios (OR), risk ratios (RR), standardized mortality ratios (SMR), and standardized incidence ratios (SIR) were log transformed. Study design, PFAS exposure assessment, types of PFAS measured, outcome measures, and outcome ascertainment were evaluated through narrative synthesis. After data extraction, the number of studies in each category was enumerated and visualized using donut plots (Fig. 4) to provide a clear quantitative overview of study distribution. Additional visual summaries, including tabulated evidence matrices, were generated using R statistical software and Microsoft PowerPoint. When multiple results were reported in a single study, we reported all the findings relevant to CRC to ensure comprehensive reporting. Given the heterogeneity in study designs and exposure assessment, a formal meta-analysis was not feasible. Instead, we applied structured narrative synthesis methods and qualitatively examined sources of variation across studies, particularly in exposure levels, outcome definitions, and confounder adjustments. The certainty of evidence was assessed through a structured quality appraisal of all the included studies. The quality appraisal results directly informed the synthesis, prioritization and interpretation of findings.
Table 2.
Summary of the In Vitro Studies Examining the Effects of PFAS using Colorectal Cancer Cell Lines.
| Study | Country | Exposure | Cell Line | Concentrations | Primary Findings | Limitations |
|---|---|---|---|---|---|---|
| (Li et al., 2024) | China | PFOS (7 days) | HCT116, colon | 1, 2, 5, and 10 μmol/L |
|
|
| (Miao et al., 2015) | China | PFOA (72 h) | DLD-1, colon | 1 nM, 10 nM, 100 nM, 1000 nM (1 μM), and 10000 nM (10 μM) |
|
|
| (Zheng et al., 2023) | USA | PFOS, PFOA (7 days) | KRAS G12A, colon | 2 μM and 10 μM |
|
|
A summary of the findings of three in vitro studies that investigated the effects of PFAS in colorectal cancer cell lines. Studies are and ordered alphabetically based on the first author’s last name. Table includes information on authors and year of publication, the country of origin, PFAS studied, PFAS concentrations, primary findings, and study limitations. (Abbreviations: PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonic acid; KRAS G12A: Kirsten rat sarcoma viral oncogene homologue G12A; MMP: matrix metalloproteinase; PI3K: phosphoinositide 3-Kinase; Akt: protein kinase B; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; CRC: colorectal cancer).
Table 4.
Summary of the Epidemiological Studies Examining the Association between PFAS and CRC.
| Study | Country | Exposure | Design, Sample | Concentrations | Sex | Race/ Ethnicity |
CRC Risk Findings | Limitations |
|---|---|---|---|---|---|---|---|---|
| (Alexander et al., 2024) | USA | PFOS | Retrospective cohort (occupation based, n = 26) | Exposed individuals: 941 ng/mL General population: 30.4 ng/mL (as reported by NHANES in 1999–2000) |
80 % M 20 % F |
Not reported |
|
|
| (Barry et al., 2013) | USA | PFOA | Retrospective cohort (community based, n = 264) | Community resident’s median: 24.2 ng/mL Dupont worker’s median: 112.7 ng/mL |
46 % M 54 % F |
White (97.4 %) Other (2.6 %) |
|
|
| (Grice et al., 2007) | USA | PFOS | Retrospective cohort (occupation based, n = 12, validated CRC) | Nonexposed range: 0.11 to 0.29 ppm Low exposure range: 0.39 to 0.89 ppm High exposure range: 1.30 to 1.97 ppm |
81 % M 19 % F |
Not reported |
|
|
| (Innes et al., 2014) | USA | PFOS, PFOA | Cross-sectional (community based, n = 48 PFOS 4th quartile and 65 PFOA 4th quartile) | PFOA average: 86.6 ng/mL PFOS average: 23.4 ng/mL |
48 % M 52 % F |
White 97 % Minority 3 % |
|
|
| (Li et al., 2022) | Sweden | PFAS | Retrospective cohort study (community based, n = 50 colon and 41 rectal males; 45 colon and 32 rectal females on ever-high group) | PFHxS, PFOS, and PFOA levels in the ‘ever-high’ group were 176 ng/mL, 199 ng/mL, and 11 ng/mL, respectively, compared to 0.84 ng/mL, 3.9 ng/mL, and 1.5 ng/mL in the reference group (geometric means) | 53 % M 47 % F |
Not reported |
|
|
| (Messmer et al., 2022) | USA | PFOA | Ecological (community based, n = not reported) | Merrimack Village District public water usage: 140 ppt Private well usage: 4.4 μg/L (1.56 μg/L national average between 2015 and 2016) |
51 % M 49 % F |
White 92 % Hispanic 4 % Asian 2 % Black 1 % (Merrimack location) |
|
|
| (Olsen et al., 2004) | USA | PFOS | Retrospective cohort (occupation based, n = 4 colon and 4 rectal) | Assumed geometric mean based on previous study (Olsen et al., 1999): 0.5 to 2 PPM | 89 % M 11 % F (chemical plant) |
Not reported |
|
|
| (Vieira et al., 2013) | USA | PFOA | Retrospective cohort (community based, total exposed = 383, n = 20 little hocking community, Ohio CRC; 63 based on predicted serum) | Study population median: 28.2 μg/L General US population median = 3.9 μg/L |
51 % M 49 % F (Both WV and OH) |
Not reported |
|
|
| Study | Country | Exposure | Design, Sample | Concentrations | Sex | Race/ Ethnicity |
CRC Mortality Findings | Limitations |
| (Gilliland and Mandel, 1993) | USA | PFOA | Retrospective cohort mortality (occupation based, n = 4) | Study used months of employment in the Chemical Division as a surrogate measure for cumulative PFOA exposure | 100 % male | >99 % White <1% Non-white |
|
|
| (Girardi and Merler, 2019) | Italy | PFOS, PFOA | Retrospective cohort mortality (occupation based, n =5) | PFOA geometric mean: 4048 ng/mL PFOS geometric mean: 148.8 ng/mL |
100 % male | Not reported |
|
|
| (Leonard et al., 2008) | USA | PFOA | Retrospective cohort mortality (occupation based, n = 17 large intestine and 5 rectum) | Study did not provide details on the range or distribution of PFOA concentrations | 81 % M 19 % F |
95 % White |
|
|
A summary of the findings from 12 epidemiological studies that investigated the associations between PFAS exposure and CRC. Studies are group based on CRC risk (top) and CRC mortality (bottom) and ordered alphabetically based on the first author’s last name. Table includes information on authors and year of publication, the country of origin, PFAS studied, PFAS concentrations, primary findings, and study limitations. The table also provides information on the study design, participant sex, and race/ethnicity. Percentages for sex and race/ethnicity are rounded to the nearest whole number, which may result in totals that do not equal exactly 100 %. Study from Cui et al. (2024) was removed from the table because their study is focused on analyzing the association of serum PFAS levels in CRC patients with MLNs and TLNs numbers, which is study design compared to the other epidemiological studies examined. (Abbreviations: PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonic acid; PFHxS: perfluorohexanesulfonic acid; PFNA: perfluorononanoic acid; 6:2CL-PFESA: 6:2 chlorinated perfluoroalkyl ether sulfonic acid; FOSA: perfluorooctane sulfonamide; CRC: colorectal cancer; SMR: standardized mortality ratio; CI: confidence interval; OR: odds ratio; AOR: adjusted odds ratio; RR: risk ratio; HR: hazard ratio).
Fig. 3.
Summary of Findings from In vitro, Animal, and Human Studies that Examined the Impact of PFAS Exposure on CRC. Created in BioRender. Paudel, D and Alderete TL. (2025) https://BioRender.com/v23q558.
Fig. 5.
Forest Plots Illustrate the Associations* Between PFAS Exposure and CRC Incidence, Prevalence, or Mortality in Human Studies. A-D. Forest plots display the effect sizes from human studies assessing the association between PFAS exposure and CRC risk (A and C) and mortality (B and D), reported as either odds ratios (OR), risk ratios (RR), standardized mortality ratios (SMR), or standardized incidence ratios (SIR). *In each forest plot, the log of the effect size (e.g., OR, HR) is reported for different exposure contrasts, which are further described in panels C and D. The effect sizes are shown on the log scale with 95% confidence intervals. The red dashed line at zero denotes a null association, where values above it suggests increased risk. Although not explicitly stated, it was assumed that Leonard et. al. reported a SMR on a scale of 100 where 100 indicates no effect. To ensure consistency with other effect estimates, this value was rescaled to a scale of one, where one indicates no effect. Cui et. al., 2024 was excluded from the forest plot since their study focused on assessing the association between serum PFAS levels in CRC patients with MLNs and TLNs numbers. This was done since MLSs and TLNs are an indicator of disease progression rather than CRC incidence or mortality risk. C-D. Additional details regarding each study is provided to deliver additional context for each plotted effect size. Abbreviations: ND: Not detected; MN: Minnesota, up arrow: high exposure, and down arrow: low exposure.
Fig. 4.
Synthesis of the Evidence from Human Studies Showing Differences in Various Attributes Related to PFAS Exposure and CRC Risk and Mortality. Summary of the study characteristics from human studies that examined the associations between PFAS exposure and CRC. The upper left section titled “Studies” serves as an overview of studies included, while the remaining panels provide detailed counts and categorizations regarding key study characteristics. *PFAS mixture considered in the study by Li et. al included perfluoropentanoic acid (PFPeA), perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorobutane sulfonic acid (PFBS), perfluorohexane sulfonic acid (PFHxS), perfluoroheptane sulfonic acid (PFHpS), and perfluorooctane sulfonic acid (PFOS). Similarly, Cui et. al included PFOS (perfluorooctanesulfonic acid), PFOA (perfluorooctanoic acid), FOSA (perfluorooctane sulfonamide), 6:2CL-PFESA (6:2 chlorinated polyfluorinated ether sulfonate), PFNA (perfluorononanoic acid).
3. Results
The methodological steps used to identify and summarize available studies for this scoping review are outlined in Fig. 1. Our search criteria initially identified 1,003 articles published between the years 1993 and 2024, from which 339 duplicates and 334 irrelevant studies were removed, leaving 330 articles for further evaluation. After examining titles and abstracts, 304 studies were excluded because they did not meet the inclusion criteria (e.g., lack of relevance to PFAS or CRC, absence of quantitative estimates for associations between PFAS and CRC or not peer reviewed). This filtering process resulted in 26 studies (5 previously published reviews, 3 in vitro, 6 animal and 12 epidemiological studies) selected for final review. The reviews were evaluated independently to summarize their overall findings and to understand past evidence on the topic. Of the remaining 21 studies identified, one in vitro and one human study examined the associations between PFAS with measures of CRC progression that included metastasis in CRC spheroids and human lymph nodes, respectively. Details regarding the included studies and their primary findings are presented by type in Tables 2, 3, and 4.
Fig. 1.
Flow chart showing literature search strategy to assess of PFAS exposure with CRC. Flowchart summarizing the study selection process. PubMed, Scopus, Web of Science, and Google Scholar were used to search for relevant literature using keywords related to per- and polyfluoroalkyl substances (PFAS) exposure and colorectal cancer (CRC). After removing duplicates and irrelevant papers, the titles of all articles were screened, and abstracts and complete papers were subsequently reviewed to ensure they met the inclusion requirements. All in vitro, animal model-based experiments, and human studies examining the link between at least one type of PFAS chemical and CRC were included. After including 5 reviews, a total of 26 studies were included in the final review.
Table 3.
Summary of Animal Studies Examining PFAS and CRC.
| Study | Country | Exposure | Concentrations | Primary Findings | Limitations |
|---|---|---|---|---|---|
| (Hansen et al., 2019) | Norway | Mixture: PCBs, OCPs, BFRs, and PFAS (exposed via diet for 10 weeks) | Based on human estimated daily intake levels, adjusted to the mouse weighing 25 g and consuming 3 g feed/d Low dose feed: 17.7 ng/g High dose: 364 ng/g |
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| (Johanson et al., 2020) | Norway | Mixture: PCBs, OCPs, BFRs, and PFAS (exposed via diet for 24 weeks, in utero) | Based on human estimated daily intake levels, adjusted to the mouse weighing 25 g and consuming 3 g feed/d Low dose feed: 17.7 ng/g High dose feed: 364 ng/g |
|
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| (Ngo et al., 2014) | Norway | PFOS, PFOA (exposed via gavage for 14–17 days, in utero and 3 weeks post-natal) | 0.01, 0.1 or 3.0 mg/kg BW/day |
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| (Tessmann et al., 2024) | USA | PFOS (exposed via drinking water for 3 weeks) | 3 μg/g BW/day |
|
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| (Wimsatt et al., 2016) | USA | PFOS (exposed via drinking water for 10 weeks) | Female: 0, 20, 250 mg/kg Male: 0, 10, 50, 200 mg/kg |
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| (Wimsatt et al., 2018) | USA | PFOS (exposed via drinking water for 10 weeks) | 100 mg/kg over a 10-week period |
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|
A summary of the findings of six animal studies that investigated the effects of PFAS on different mouse models. Studies are and ordered alphabetically based on the first author’s last name. Table includes information on authors and year of publication, the country of origin, PFAS studied, PFAS concentrations, primary findings, and study limitations. (Abbreviations: PFOA: Perfluorooctanoic acid; PFOS: perfluorooctanesulfonic acid; PCBs: polychlorinated biphenyls; OCPs: organochlorine pesticides; BFRs: brominated flame retardants; CRC: colorectal cancer; HMGCS2: 3-hydroxymethylglutaryl-CoA synthase 2; c-MYC: cellular myelocytomatosis oncogene; mTOR: mammalian target of rapamycin; AOM: azoxymethane; GI: gastrointestinal; POP: persistent organic pollutant).
3.1. Current status and insights from published reviews on PFAS exposure and CRC
To date, there have been five review articles, one scoping, and four narratives that have assessed the associations between PFAS exposure and CRC (Durham et al., 2023; Murphy and Zaki, 2024; Mutalib, 2023; Rosenfeld et al., 2023; Steenland and Winquist, 2021). Three of these reviews specifically examined associations between PFAS exposure and CRC (Durham et al., 2023; Murphy and Zaki, 2024; Mutalib, 2023) while the other two included CRC as part of a broader review of evidence linking PFAS exposures to inflammation and various cancer types (Rosenfeld et al., 2023; Steenland and Winquist, 2021). Among these, Steenland and Winquist’s scoping review (Steenland and Winquist, 2021) offers an important overview of epidemiologic links between PFAS exposure and a range of cancers, including CRC, yet this review has several limitations. First, the authors excluded mechanistic data from in vitro and animal studies, omitting an important line of evidence for causation. Second, their search and selection strategy were not structured around the PECO framework, and they did not largely follow the PRISMA-ScR reporting and other evidence synthesis guidelines that enhance transparency and reproducibility in scoping reviews. Third, they chose not to conduct a formal critical appraisal, an optional but highly informative step thereby providing no systematic assessment of risk of bias across studies. As a result, heterogeneity in PFAS congeners, exposure metrics, and study designs received only cursory mention; there were no evidence maps or other visual syntheses, and the review concluded with broad narrative statements rather than prioritized research directives. Notably, CRC received little attention within the review’s broader examination of PFAS-related malignancies, leaving key questions about this outcome unresolved. Our scoping review addresses these gaps by integrating in vitro, animal, and human evidence, using a structured synthesis, conducting a full quality appraisal, and outlining clear future research directions. Lastly, since publication, four additional studies (Tessmann et al., 2024; Alexander et al., 2024; Cui et al., 2024; Li et al., 2024) have been published between 1993 and 2024 that have examined PFAS and CRC. Although there is some overlap (Durham et al., 2023; Mutalib, 2023; Rosenfeld et al., 2023; Steenland and Winquist, 2021) in the studies included in previous reviews, the current analysis is more comprehensive and focuses specifically on PFAS and CRC, which previous reviews did not thoroughly address. All reviews depict a complex relationship between PFAS exposure with CRC risk or measures of progression (i.e., metastasis), consistently concluding that current evidence is insufficient to establish a definitive causal link. Consequently, these reviews highlight the need for continued research utilizing larger-scale, longitudinal epidemiological studies that include demographic diversity and repeated measures of PFAS exposure over time, to enable a clearer assessment of temporal relationships. Furthermore, the reviews indicate that findings from both animal and epidemiological studies are mixed, making it challenging to draw conclusions about the direct impact of PFAS on CRC development. One review noted the rising global incidence and mortality of CRC, emphasizing a ‘birth cohort effect’ in which CRC rates are significantly higher among individuals born after the early 1950 s. This trend suggests that factors influencing the early stages of carcinogenesis may play a crucial role (Murphy and Zaki, 2024). Environmental chemicals such as PFAS are considered potential contributors to these birth cohort effects, as the timing of their widespread introduction aligns with the observed increase in CRC rates. While the widespread use of PFAS aligns temporally with increasing CRC incidence in younger populations, it is important to note that other environmental and dietary changes may also play a role as potential co-contributors, including increased consumption of processed foods, preservatives, and synthetic additives. Lastly, a review on PFAS exposure among firefighters concluded that further research is needed to clarify the role of occupational PFAS exposure (found in aqueous film-forming foams) in the increased CRC risk observed in this profession (Rosenfeld et al., 2023).
3.2. In vitro studies suggest pro-oncogenic effects of PFAS in CRC
Three in vitro studies investigated the effects of PFAS, especially PFOA and PFOS, on CRC cells (Table 2). Overall, these three studies received a rating of High Confidence (Fig. 2B) and all three studies found that PFOS and PFOA promote the proliferation and migration of CRC cells, potentially increasing the risk of CRC development and progression (Zheng et al., 2023; Li et al., 2024; Miao et al., 2015). These studies highlighted the role of the PI3K/Akt-NF-κB signaling pathway, matrix metalloproteinases (MMPs), and epithelial-mesenchymal transition in mediating the effects of PFAS on CRC cells. All studies utilized various human colorectal carcinoma and adenocarcinoma cell lines, ultimately reaching similar conclusions that indicated a positive association between PFAS exposure and CRC development. Specifically, the study by Li et al. investigated the effects of 7-day exposure to PFOS on CRC cell migration and proliferation (1,2,5 and 10 μmol/L), reporting that PFOS promotes these processes by activating the PI3K/Akt-NF-κB signaling pathway and stimulating epithelial-mesenchymal transition (Li et al., 2024). Miao et al. found that PFOA increases the invasiveness of CRC cells at concentrations over a 72-hour exposure (of 1, 10, 100, 1,000, and 10,000 nM), demonstrating that it enhances the invasion of DLD-1 CRC cells by activating NF-κB. This activation subsequently upregulates the expression of matrix metalloproteinases (MMPs) 2 and 9, which are key enzymes involved in the degradation of the extracellular matrix (Miao et al., 2015). Both studies highlight the potential for PFAS exposure to contribute to the development and progression of CRC. The study by Zheng et al. found that a 7-day exposure to PFOS and PFOA (2 and 10 μM) induced the migration of SW48 KRAS WT and G12A 3D spheroids, potentially through epithelial-mesenchymal transition, as indicated by downregulated E-cadherin and upregulated N-cadherin and vimentin expression. Exposure also altered metabolic pathways related to epithelial mesenchymal transition, including perturbations in fatty acid β-oxidation and the synthesis of proteins, nucleotides, and lipids metabolism (Zheng et al., 2023).
3.3. Mixed findings on the effects of PFAS exposure in rodent CRC models
Six animal studies were identified that examined the effects of PFAS on CRC using mouse models, with most focusing on the impacts of long-chain PFAS (Table 3). Although most studies were assessed to have - High or Medium Confidence, several were noted to have methodological concerns, such as observational bias, residual confounding, or insufficient exposure assessment (Fig. 2D). In many cases, internal PFAS concentrations were not measured, and exposure levels were not confirmed. Additionally, the protocols used to administer PFAS, or vehicles lacked important details. These issues substantially limit confidence in whether the observed outcomes were directly attributable to PFAS exposure, resulting in a deficient rating in study quality. Two studies examined various PFAS types (i.e., PFHxS, PFOS, PFOA, PFNA, PFDA, and PFUnDA) alongside mixtures of other organic pollutants, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and brominated flame retardants (BFRs) (Hansen et al., 2019; Johanson et al., 2020). One study focused specifically on PFOA and PFOS (Ngo et al., 2014), while the remaining three studies exclusively assessed PFOS to evaluate PFAS effects (Tessmann et al., 2024; Wimsatt et al., 2016; Wimsatt et al., 2018). Johanson et. al. reported that maternal exposure to a mixture of persistent organic pollutants (POPs), including PFAS, reduced the incidence of colonic but not small intestinal tumors in the offsprings of A/J Min/+ mice, suggesting a potential protective effect of PFAS against colonic tumorigenesis (Johanson et al., 2020). In contrast, Hansen et al. (2019) utilized the same mouse strain and PFAS-containing POP mixtures and found a synergistic effect of POPs with the carcinogen azoxymethane (AOM) in weaned pups, resulting in increased intestinal tumorigenesis. Ngo et al. exposed pregnant C57BL/6J-Min/+ (multiple intestinal neoplasia) mice to PFOA and PFOS via gavage and found that maternal exposure did not increase the incidence or number of intestinal tumors in the offspring (Ngo et al., 2014). Wimsatt et al. conducted two studies to investigate the potential protective effects of PFOS on gastrointestinal tumor development. In one study, they utilized male and female APCmin mice, which is a model for familial adenomatous polyposis. Overall, they observed a significant, dose-dependent reduction in the total number of tumors, in both the small and large intestine, following chronic PFOS exposure through drinking water (Wimsatt et al., 2016). In a second study, they utilized a patient-derived xenograft (PDX) model, where human colorectal cancer tumors were implanted into NSG mice. PFOS treatment in this model led to a reduction of tumor growth, particularly for tumors originating from the right ascending colon suggesting a potential protective role of PFAS, particularly PFOS, in CRC development (Wimsatt et al., 2018). However, a recent study led by Tessmann et al. (2024) reported that PFOS exposure via drinking water downregulated 3-hydroxy-3-methyl-glutaryl-CoA synthase 2 (HMGCS2), a ketogenic enzyme, expressed in both mice intestinal cells and human intestinal organoids model in this study. This downregulation was associated with increased proliferation and lipid accumulation in normal colonic epithelial cells, suggesting a role of PFOS in promoting intestinal metabolic changes and increasing the risk of CRC in C57BL/6 mice. Although Tessmann et al. (2024) did not directly assess colorectal tumorigenesis, the study identified gene expression changes and pathway disruptions, including those related to inflammation, oxidative stress, and epithelial cell turnover, which may play a role in CRC development. Additionally, we categorized this study under animal studies even though it also included mechanistic assessments in a human intestinal organoid model. These in vitro findings supported the in vivo results, showing disrupted epithelial signaling, inflammation, and barrier function, further strengthening the biological plausibility of PFAS-induced intestinal injury relevant to CRC development.
In summary, our review identified one study showing no impact of PFAS on CRC risk (in utero, diet, dose: 0.01,0.1 and 3 mg/kg BW/day) (Ngo et al., 2014). Two studies indicated detrimental effects—one reported increased tumor incidence in mice after exposed to a PFAS-containing mixture (diet, dose: 17.7–364 ng/g) (Hansen et al., 2019), while another mechanistic study by Tessmann et al. (2024) identified transcriptional and pathway-level alterations related to inflammation, oxidative stress, and cell proliferation, which could be relevant to colorectal carcinogenesis (drinking water, dose: 3 μg/g BW/day). In contrast, two studies suggested a protective role of PFOS specifically, and one study indicated a protective effect from a POPs mixture that included PFAS among other compounds (in utero, diet, dose: 7.7–364 ng/g; drinking water, dose: male: 0,10,50,200 mg/kg and female: 0,20,250 mg/kg; drinking water, dose: 100 mg/kg over 10 weeks) (Wimsatt et al., 2016; Wimsatt et al., 2018; Johanson et al., 2020). Differences in the rodent model utilized as well as the PFAS dose, exposure window, and route of exposure may have contributed to these mixed findings. In interpreting the mixed findings across studies, it is important to distinguish between studies that investigated individual PFAS compounds and those that evaluated PFAS in combination with other environmental chemicals (e.g., persistent organic pollutants). Studies using mixtures may reflect real-world exposures more accurately but can introduce additional complexity in attributing observed effects to PFAS. Overall, findings from animal studies were heterogeneous, with most showing no association or a decrease in tumor burden following PFAS exposure. One study reported exacerbation of tumorigenesis, but only in the context of co-exposure to a known carcinogen (AOM) (Hansen et al., 2019), highlighting a potential interaction effect. While the direction of effects varied, the majority did not support a direct tumor-promoting effect of PFAS exposure in isolation. Overall, findings from animal studies were heterogeneous, with most showing no association or a decrease in tumor burden following PFAS exposure. While the direction of effects varied, the majority did not support a direct tumor-promoting effect of PFAS exposure in isolation.
3.4. Existing human studies provide mixed evidence on PFAS and CRC
Using our predefined search criteria, we identified 12 human studies investigating the association between PFAS exposure and the risk or mortality of various cancer types. The overall quality of evidence linking PFAS exposure specifically to CRC was rated as Low Confidence to Deficient. Among the human studies, three were rated as ‘critically deficient’ based on EPA risk of bias criteria. These ratings were primarily driven by important limitations in study design, including lack of individual-level PFAS exposure measurements (e.g., relying on geographic or occupational proxies, based on assumption), insufficient control for key confounders such as diet and lifestyle factors, sensitivity concerns and unclear outcome ascertainment methods. For instance, some studies used mortality data without specifying cancer subtypes or had used death certificates without medical validation (Leonard et al., 2008; Gilliland and Mandel, 1993). Detailed domain-specific justifications for each study’s rating are based on EPA’s staff handbook guidelines. Specifically, CRC diagnoses were not confirmed using standard clinical validation or cancer registry linkage. Instead, outcomes were identified through self-reported data or cause-of-death information from mortality records, which may lack specificity or sensitivity and introduce potential misclassification. These issues were either not sufficiently addressed or inconsistently reported, thereby limiting the strength and reliability of the conclusions that can be drawn. Although many epidemiologic studies were rated as low or critically deficient, four studies were classified with moderate confidence. These studies utilized individual-level serum PFAS concentrations, adjusted for key confounders, and used cancer registry data for outcome verification, enhancing their internal validity. In summary, as shown in Table 4, human studies found varying associations between PFAS exposure and CRC, with some studies reporting positive, inverse, or null associations. Most of the studies examined PFAS exposure in relation to the risk of several cancer types, with CRC included as one of the outcomes. To date, most human studies have focused on individuals with presumed occupational PFAS exposure (occupation-based n = 6) (Alexander et al., 2024; Leonard et al., 2008; Gilliland and Mandel, 1993; Girardi and Merler, 2019; Grice et al., 2007; Olsen et al., 2004) or those residing in regions with high contamination levels (community-based n = 5) (Messmer et al., 2022; Innes et al., 2014; Barry et al., 2013; Vieira et al., 2013; Li et al., 2022) and one study was conducted on CRC patients to investigate serum PFAS association with number of lymph nodes indicating disease progression (Cui et al., 2024). Thus, most studies focused on populations with elevated PFAS exposure due to workplace or environmental factors, using various methodologies—including retrospective cohorts (Alexander et al., 2024; Barry et al., 2013; Li et al., 2022; Leonard et al., 2008; Gilliland and Mandel, 1993; Girardi and Merler, 2019; Grice et al., 2007; Olsen et al., 2004), cross-sectional studies (Cui et al., 2024; Innes et al., 2014), ecological studies (Messmer et al., 2022), and geographic analyses (Vieira et al., 2013)—to investigate potential correlations between high PFAS exposure and CRC risk and mortality. The articles reviewed also reveal a lack of diversity in study populations. While information on sex was generally provided by all studies, details on race and ethnicity were frequently omitted (Alexander et al., 2024; Barry et al., 2013; Vieira et al., 2013; Li et al., 2022; Grice et al., 2007; Olsen et al., 2004). Many of the studies were conducted in the United States and Europe and focused on predominantly white populations. Among studies evaluating PFAS and CRC, Cui et al. (2024) focused on CRC patients and examined the relationship between serum PFAS levels and disease progression markers, including total and metastatic lymph node counts, rather than incidence or mortality.
Occupation-based studies have explored associations in various worker populations exposed to PFAS, offering mixed evidence on its role in CRC development and progression. For example, Alexander et al. (2024) reported a slight positive association between PFOS exposure and CRC incidence (HR = 1.03, 95 %CI: 0.98–1.08) among workers at a perfluorooctanesulfonyl fluoride (POSF, a precursor to PFOS) manufacturing facility where exposure was estimated based on job duties. Another study examined the risk ratio of episodes of care (RREpC) to quantify healthcare utilization for colon or rectal cancer and found a slightly higher RREpC of malignant colon and rectum neoplasms in fluorochemical facility workers compared to non-fluorochemical/film plant employees based on the RREpC for malignant neoplasms of colon and rectum (Colon, RREpC = 5.4, 95 % CI: 0.5- >100; Rectum, RREpC = 1.8, 95 % CI: 0.3–12.4) (Olsen et al., 2004). In this study, exposure was based on job history at the same worksite and serum data from a previous study (Olsen et al., 2004; Olsen et al., 1999). In contrast, four other occupation-based studies, including those by Girardi et al. (SMR = 1.72, 95 % CI: 0.72–4.14; serum) (Girardi and Merler, 2019), Leonard et al. (SMR large intestine = 66.8, 95 % CI: 38.9–107.0; SMR rectum = 91.7, 95 % CI: 29.8–213.9; presumed exposure) (Leonard et al., 2008), Grice et al. (high exposure group OR = 1.69, 95 % CI: 0.68–4.17; exposure based on job history) (Grice et al., 2007), and Gilliland et al. (SMR = 1.15, 95 % CI: 0.31–4.01; exposure based on job history) (Gilliland and Mandel, 1993) found no significant link between PFAS exposure and CRC mortality. Most of these studies reported elevated effect estimates for PFAS exposure and CRC; however, the associations were not statistically significant, largely due to the small number of cases and resulting wide confidence intervals. A major limitation across most of the occupation-exposed studies was a tendency to report CRC mortality rather than incidence. Mortality can be influenced by factors such as disease stage at diagnosis, treatment availability, and healthcare disparities, which may obscure the underlying relationships between occupational exposures and CRC risk. Additionally, many studies had relatively small sample sizes and low reported CRC case numbers, further limiting the conclusions that could be drawn. In the only human study that was a not an occupational study, the authors investigated 305 CRC patients and found a positive correlation between serum PFAS and the number of metastatic lymph nodes (87 %, 95 % CI: 4 %, 238 %, 95th percentile group), suggesting that PFAS exposure may worsen CRC prognosis (Cui et al., 2024).
Community-based studies also reported mixed results. In Merrimack, NH, residents with PFAS-contaminated drinking water had a 49 % higher colon cancer risk compared to PFAS-unexposed community of Colchester, VT (RR = 1.49, 95 % CI: 1.07–2.08), though risk ratio estimates varied based on the control group used (Messmer et al., 2022). For example, the association between PFAS and CRC risk was null when the control group was pooled unexposed communities (RR = 0.91, 95 % CI: 0.74–1.12) or the US population (RR = 1.05, 95 % CI: 0.88–1.26) (Messmer et al., 2022). In Ronneby, Sweden, high PFAS levels in drinking water were associated with a moderately increased risk of rectal cancer (male, SIR: 1.25, 95 % CI: 0.89, 1.69; female, SIR: 1.33, 95 % CI: 0.91, 1.88) but not colon cancer (male, SIR: 0.99, 95 % CI: 0.73, 1.30; female, SIR: 0.84, 95 % CI: 0.62, 1.13) compared to low exposure Ronneby residents (Li et al., 2022). Conversely, a large cross-sectional study in Appalachia found a significant inverse association between high PFOS (OR = 0.24, 95 % CI: 0.16, 0.37) and PFOA (OR = 0.64, 95 % CI: 0.44, 0.94) serum levels and CRC diagnoses, particularly among long-term residents and those recently diagnosed (Innes et al., 2014). No significant associations were observed between estimated cumulative serum PFOA concentrations and CRC risk in a geographic study examining Appalachia’s cancer registry (AOR = 1.3, 95 % CI: 1.0, 1.7, high vs unexposed group) (Vieira et al., 2013). Additionally, a retrospective cohort study in the Mid-Ohio Valley reported no significant association between estimated serum PFOA exposure and CRC risk (HR = 0.99, 95 % CI = 0.92, 1.07) (Barry et al., 2013).
Variability in the associations between PFAS and CRC in previous studies may stem from differences in study populations, including sociodemographic factors such as age, sex, socioeconomic status, and migration patterns, which could lead to community-based studies missing cancer cases among individuals who moved away. Furthermore, differences in PFAS exposure levels and assessment methodologies likely contribute to this variability. Only one study, which was cross-sectional, specifically examined CRC as the primary outcome in relation to PFAS exposure (Innes et al., 2014). This study provided a detailed characterization of CRC risk, considering a range of covariates, making it unique in its focused analysis compared to other studies that grouped CRC with other cancer sites and provided less comprehensive assessments. Most studies focused on legacy PFAS compounds like PFOA and PFOS (n = 11) (Messmer et al., 2022; Alexander et al., 2024; Innes et al., 2014; Barry et al., 2013; Vieira et al., 2013; Li et al., 2022; Leonard et al., 2008; Gilliland and Mandel, 1993; Girardi and Merler, 2019; Grice et al., 2007; Olsen et al., 2004), while only one included a broader range of PFAS compounds and evaluated their presence in mixtures and potential combined effects on health (Cui et al., 2024). Exposure assessments were post-CRC diagnosis and were primarily serum-based, using direct measurements (n = 3), (Cui et al., 2024; Innes et al., 2014; Girardi and Merler, 2019) data from previous reports (n = 1), (Messmer et al., 2022) or modeled serum levels from historical data or geocoded addresses (n = 1) (Barry et al., 2013). Additional studies relied on job history records (n = 3), (Gilliland and Mandel, 1993; Grice et al., 2007; Olsen et al., 2004) drinking water (n = 1), (Li et al., 2022) a comprehensive exposure data matrix (n = 1), (Alexander et al., 2024) and a combination of water district and modeled serum (n = 1), (Vieira et al., 2013) with one study not specifying the PFAS exposure source (Leonard et al., 2008). There was a wide range in the number of CRC cases (4–264), reflecting differences in study design, population size, and case identification and validation methods. Several studies adjusted for similar covariates when examining PFAS associations. Common adjustments include age, sex, and smoking status, which were used to control for potential confounding across studies. For example, Olsen et. al. adjusted for age and sex while more adjustments were employed by Alexander et. al., (Alexander et al., 2024) who adjusted for age, sex, birth year, smoking, and employment duration as well. Grice et. al., (Grice et al., 2007) adjusted the model for age and sex. Barry et al. (2013) further adjusted the model for time-varying smoking and alcohol use, education, and stratified analyses by 5-year birth cohorts to mitigate cohort effects. Similarly, Vieira et al. (2013) included age, sex, diagnosis year, smoking status, and insurance provider to adjust for diagnostic practice changes over time. A comprehensive adjustment approach was taken by Innes et. al (Innes et al., 2014), incorporating covariates such as demographic characteristics, socioeconomic status, lifestyle factors, health and medical history, laboratory values, and other PFAS measured in the study. Other studies adjusted their models for a limited set of potential confounders, without comprehensively accounting for a broader range of covariates (Messmer et al., 2022; Li et al., 2022; Leonard et al., 2008; Gilliland and Mandel, 1993; Girardi and Merler, 2019). Lastly, most studies were conducted in the USA (n = 9), though others were conducted in China (n = 1), (Cui et al., 2024) Sweden (n = 1), (Li et al., 2022) and Italy (n = 1) (Girardi and Merler, 2019). Therefore, findings from each of these human studies illustrate a wide range of associations between PFAS exposure and CRC, which is likely due to differences in exposure levels, population characteristics, and methodological approaches across studies.
3.5. Summary of results
Our investigation reveals limited and inconsistent evidence linking PFAS exposure to CRC. In vitro studies consistently show that PFAS, particularly PFOA and PFOS, can stimulate CRC cell proliferation and migration through mechanisms like PI3K/Akt-NF-κB pathway activation, MMPs upregulation, and epithelial-mesenchymal transition. Animal studies, all conducted in mice with either in utero exposure or exposure via food or water or gavage, present mixed findings: some suggest a protective effect of PFAS mixtures on CRC tumorigenesis, while others link PFAS exposure, especially combined with carcinogens, to increased tumor development. Epidemiological studies also show mixed results, with varied associations observed in populations exposed to high PFAS levels, including occupational cohorts and communities with contaminated water. Overall, the evidence for a PFAS-CRC link remains limited. These quality assessments informed our evidence synthesis process, and it is essential to carefully assess each study’s strengths and limitations to draw conclusions about PFAS’s potential impact on CRC risk.
3.6. Variability in PFAS exposure: composition, dosage, and duration across studies
When comparing in vitro studies, a narrow PFAS exposure range (2–10 μM) and short exposure duration of 3–7 days was utilized. These studies provided mechanistic insights under controlled conditions but did not account for long-term, cumulative exposure or metabolic factors. PFAS doses in rodent studies were reported inconsistently, making direct comparison of concentrations across studies challenging. Some studies reported doses relative to estimated daily intake levels for humans, (Hansen et al., 2019; Johanson et al., 2020) while others based their exposures on mice body weight (Tessmann et al., 2024; Ngo et al., 2014; Wimsatt et al., 2016; Wimsatt et al., 2018). For instance, one animal based study adjusted the exposure levels to 5,000 and 100,000 times the estimated daily intake for humans to account for background exposure and interspecies differences in metabolism (Hansen et al., 2019). Similarly, some had in utero exposure and some had exposure via food or drinking water or gavage. Additionally, exposure duration varied across studies, ranging from 3 to 24 weeks making comparisons challenging. Most studies focused on exposure to a single legacy PFAS (Tessmann et al., 2024; Ngo et al., 2014; Wimsatt et al., 2016; Wimsatt et al., 2018) (i.e., PFOA, PFOS), although two also examined mixtures of six different PFAS along with other organic pollutants (Hansen et al., 2019; Johanson et al., 2020).
Human studies examined a broader range of PFAS exposures. Studies mainly included populations highly exposed to PFAS either from occupation or being a resident in highly exposed area. However, none of the studies were focused on populations with exposures that are nationally representative. Leonard et al. examined SMR among a subset of DuPont workers. This work assumed occupational exposure to PFOA based on previous studies and did not include any direct PFAS measurements (Leonard et al., 2008). Additionally, studies quantified PFAS exposure differently, including using serum PFAS levels, assumed PFAS exposure (based on job history and environmental data), estimated PFAS exposure categories based on job exposure matrices, and estimated PFAS exposure categories based on source of drinking water source at residential area. For example, in the only prospective study, Li et al. (2022) found no evidence for a link between PFAS exposure and CRC risk in the Ronneby Register Cohort in Sweden. However, this study used residential address histories to estimate individual exposure from PFAS-contaminated water sources. Moreover, of the studies that included individual PFAS exposures via blood measures, only post diagnostic assessment was performed, which may not accurately reflect an etiologically relevant period. Without having pre-diagnostic samples, it is difficult to determine whether PFAS exposure levels have changed over time due to the disease itself or lifestyle modifications following diagnosis. Further, while prospective study designs are needed, it is also essential to include repeat assessment of blood PFAS levels to better capture long-term exposure, which is important to understand their potential role in CRC risk.
3.7. Impact of experimental models and study designs on PFAS-CRC findings
Study designs, whether experimental or population-based, can yield varied PFAS-CRC associations. In vitro studies using different CRC cell lines (n = 3 in our review) (Zheng et al., 2023; Li et al., 2024; Miao et al., 2015) help assess PFAS effects on a range of cellular responses, as each cell type brings unique characteristics and responses to PFAS exposure. However, in vitro experiments may not reflect complex biological systems and long-term exposure to PFAS mixtures, and the genetic backgrounds of commonly used cell lines also may not fully represent human diversity. Furthermore, these cell lines can undergo mutations, limiting the robustness of findings. In animal models, strain-specific sensitivity to PFAS exposure is crucial for relevance in CRC research. The A/J Min/+ mouse strain used in the studies, (Hansen et al., 2019; Ngo et al., 2014; Johanson et al., 2020) for instance, is genetically predisposed to develop numerous colon lesions, making it useful for studying PFAS impact on lesion proliferation. The C56BL6/J strain, (Tessmann et al., 2024) since it is susceptible to the carcinogen AOM, develops CRC more readily, allowing for an examination of PFAS effects on tumor promotion and progression. The choice of strain impacts the study’s applicability to human CRC risk. Among the epidemiologic studies, most were conducted in highly exposed populations, involving individuals exposed to PFAS in workplace or residential settings. These studies allow clear comparisons of high and low exposure levels, though the number of cases (range: 4–264) within these high-exposure groups were small, affecting statistical power (Steenland and Winquist, 2021). Most of the past studies were predominantly cross-sectional (Cui et al., 2024; Innes et al., 2014) or retrospective, (Messmer et al., 2022; Alexander et al., 2024; Barry et al., 2013; Vieira et al., 2013; Leonard et al., 2008; Gilliland and Mandel, 1993; Girardi and Merler, 2019; Grice et al., 2007; Olsen et al., 2004) which limits their ability to draw causal inferences. Additionally, serum PFAS levels measured post-diagnosis may not accurately represent exposure levels during CRC initiation due to the disease’s latency period. Geographic and ecological studies, (Messmer et al., 2022; Vieira et al., 2013) using comparison groups from lower PFAS-exposed regions, also face potential bias, where regional differences correlated with both PFAS exposure and disease (i.e., confounders) may have influenced the observed associations. Additionally, there is the challenge of intra-individual variation in PFAS exposure levels over time, which complicates the interpretation of epidemiological studies that rely on a single exposure measurement. Single measurements may not accurately reflect long-term exposure, potentially affecting the interpretation of observed associations. Furthermore, it remains uncertain how many exposure assessments are needed to capture long-term variability or how this limitation impacts statistical power.
To enhance interpretation of findings, we considered study quality ratings when discussing results. Among the four epidemiologic studies rated as moderate confidence, Barry et al. (2013) reported no association between PFAS exposure and CRC; Innes et al. (2014) observed an inverse association; Vieira et al. (2013) identified a positive association, but only at the highest exposure levels. Cui et al., (Cui et al., 2024) also found a positive association, but evaluated different outcomes focused on disease initiation and progression, specifically the relationship between serum PFAS levels and the number of total and metastatic lymph nodes (TLNs and MLNs) among CRC patients rather than CRC incidence or mortality. In contrast, studies rated as low or deficient confidence showed mixed findings, often limited by suboptimal exposure assessment methods, small sample sizes, or inadequate adjustment for confounders. These findings underscore the importance of both rigorous study design and clear outcome definitions when evaluating potential links between PFAS exposure and CRC.
3.8. Impact of outcome assessment methods on PFAS-CRC findings
The method used to assess the association between PFAS exposure and CRC outcomes can significantly influence study findings. Various outcomes were assessed in the studies we reviewed, including CRC incidence (via cancer registries, self-reported and validated by medical chart, registry, and medical records) and CRC mortality (via death certificates and vital records) (Messmer et al., 2022; Alexander et al., 2024; Innes et al., 2014; Barry et al., 2013; Vieira et al., 2013; Li et al., 2022; Grice et al., 2007; Olsen et al., 2004). Each of these offers different levels of accuracy, comprehensiveness, and potential for causal insights. While mortality data may underestimate the association between CRC and PFAS due to the lag between diagnosis and death, it can also reflect a more aggressive CRC phenotype. Additionally, mortality outcomes are influenced by factors such as treatment availability, access to care, and socioeconomic disparities, which further shape the observed patterns. Despite these complexities, mortality data remain valuable for understanding the outcomes of the most aggressive forms of CRC. In contrast, incidence data more accurately captures less severe CRC cases, but are affected by screening, active surveillance, and registry completeness. Self-reported CRC diagnosis is susceptible to recall bias and requires validation. Finally, health claims data, while valuable for accessing large, population-level datasets and identifying disease diagnoses across time, often lack detailed individual-level information. This includes exposure histories, behavioral or lifestyle factors, and clinical context—limiting the ability to fully control for confounding or assess causal relationships. Moreover, while summarizing the findings from human studies, we observed that few studies (Li et al., 2022; Leonard et al., 2008; Olsen et al., 2004) separately reported colon and rectal cancers when assessing the risk associated with PFAS exposure. Given that colon and rectal cancers may have distinct risk factors and etiological pathways, (Jain et al., 2024) future research should evaluate these cancer types separately.
3.9. Gaps and future directions
Only 10–15 % of CRC cases are hereditary; therefore, environmental exposure to pervasive toxicants, including PFAS, if causally related, could play an important role in disease burden in the population. However, conflicting findings in the existing literature underscore the complexity of PFAS exposure and its impact on tumorigenesis in the large intestine. To better capture the relationship between PFAS exposures and CRC risk, future research should address several key research gaps. Prospective cohort studies are essential to establish a temporal link between PFAS exposures and CRC, considering factors like age, sex, race and ethnicity, socioeconomic status, family history, history of polyps, weight, diet, smoking, alcohol, physical activity, and access to medical care to control for potential confounders. These studies should also address critical questions about the timing of exposure assessment during the life course and the frequency of measurements to enable time-based exposure assessments. Identifying critical exposure time windows such as early-life, mid-life, or late-life exposures may have distinct biological implications for CRC development. Moreover, multiple outcomes should be evaluated, including incident adenomas (ensuring comparable opportunities for detection), incident CRC (examining stage at diagnosis and tumor location within the large bowel), CRC mortality (reflecting aggressive CRC phenotypes), and CRC-specific mortality among those diagnosed with CRC (considering exposure levels at diagnosis and subsequent changes). Studies should also explore the effect of PFAS exposure on treatment efficacy as well as the combined effects of PFAS mixtures, as real-world exposure typically involves multiple compounds. Furthermore, investigations should prioritize expanding their investigation to include short-chain PFAS, which are increasingly replacing legacy PFAS and may have distinct biological implications. Although PFAS has immuno-toxic effects, (Ehrlich et al., 2023) its relevance to CRC has not been adequately studied. PFAS can suppress antibody production, alter cytokine profiles, and impair T-cell function, (Tursi et al., 2024; Bline et al., 2024) which may hinder immune activity and reduce the body’s ability to detect and eliminate colonic tumor initiation and progression. Future studies should investigate these mechanisms, particularly in conjunction with early CRC biomarkers such as fecal immunochemical tests and fecal calprotectin, which remain underutilized in PFAS research. Integrating these clinical assessments could allow for earlier detection of inflammation-associated carcinogenesis and provide stronger biological evidence. Future research should also examine whether PFAS exposure contributes to rising CRC rates in younger adults, particularly in vulnerable populations, such as African American and Hispanic communities, which face higher levels of PFAS exposure (Liddie et al., 2023). Finally, investigating the mechanisms by which PFAS might influence CRC, such as through metabolic or inflammatory pathways, is essential.
A recent review highlights that PFAS exposure Is consistently linked with alterations in metabolic pathways, including lipid, amino acid, carbohydrate, nucleotide, and energy metabolism (India-Aldana et al., 2023). Metabolites belonging to these same pathways have been observed to be altered in those with CRC; however, it remains unclear that whether such changes are either a cause or consequence of the disease (Yi et al., 2023; Tan et al., 2013; Sun et al., 2024; Guo et al., 2023; Martín-Blázquez et al., 2019). Additionally, emerging evidence suggests that PFAS can disrupt the gut microbiome, which is implicated in CRC development (Naspolini et al., 2022; Sen et al., 2024; Lamichhane et al., 2023). The International Cancer Microbiome Consortium highlights the need for cohort studies to confirm the human microbiome’s role in CRC pathogenesis (Scott et al., 2019). Metabolites produced by gut microbes support gastrointestinal health, strengthen the gut barrier, interact with the immune system, and protect against pathogens (Wong and Yu, 2019). Analyzing the metabolome could provide insights into how PFAS exposure affects gut microbial function and contributes to CRC risk. Integrating multi-omics into future PFAS and CRC studies is vital for understanding the interplay between environmental exposures, gut health, and cancer. By analyzing multiple omics layers (e.g., genomics, metabolomics, microbiome) within the same participants, researchers can gain a more comprehensive understanding of these complex relationships. This approach allows for the identification of shared biological pathways, molecular mechanisms, and potential biomarkers linking PFAS exposure to colorectal cancer risk and progression.
3.10. Limitations
Although this scoping review provides a comprehensive overview of the existing research on PFAS and CRC, it is important to note several limitations. The review did not employ the same level of rigor and structured methodology as a systematic review. We relied on keyword-based searches in specific databases that might have inadvertently excluded relevant studies published in other sources or indexed differently. Although we tried to mitigate bias through multiple reviewers verifying the study selection, the process still relies on subjective interpretation of inclusion criteria. Additionally, the review primarily focuses on summarizing and categorizing findings from various study designs, without performing a quantitative synthesis or meta-analysis of the data, which could have provided a more robust assessment of the overall evidence. This approach may limit the ability to draw definitive conclusions regarding the strength and direction of the association between PFAS exposure and CRC risk. Study heterogeneity precluded meta-analysis leading to reliance on narrative synthesis for most part. Additionally, exposure assessment methods varied widely, making direct comparisons challenging. Notably, four of the included occupational studies (Alexander et al., 2024; Gilliland and Mandel, 1993; Grice et al., 2007; Leonard et al., 2008).
) received funding or author contributions from PFAS manufacturing companies. While these studies disclosed such affiliations, the potential for industry influence over study design, data interpretation, or reporting cannot be excluded and should be carefully considered when interpreting results.
4. Conclusion
In conclusion, this scoping review examines the potential link between PFAS and CRC, evaluating evidence from in vitro, animal, and epidemiological studies to explore PFAS’s role in CRC development. The evidence linking PFAS exposure to CRC risk remains inconclusive due to gaps and limitations in the current body of research. For example, while in vitro studies suggest that PFAS can promote CRC cell proliferation and migration, animal and population-based studies have yielded inconsistent results. This inconsistency is likely due to differences in study design, PFAS exposure assessment, outcome assessment, and population characteristics. However, it is also possible that PFAS exposure may not be causally associated with CRC in humans, with the mixed results of past studies being driven by chance. Hence, future research should prioritize prospective cohort studies, standardized exposure assessment via strong biomarker measurements, and investigation into the combined effects of PFAS mixtures, focusing on populations at higher risk of CRC, including those with higher PFAS exposure as well as ethnically and geographically diverse populations. Future studies should also investigate the effects of emerging short-chain PFAS compounds. Investigating the impact of PFAS exposure on the gut microbiome and metabolome and its potential contribution to CRC risk represents another crucial area for future research. Exploring these connections may help to clarify the inconsistent findings in existing studies as PFAS exposure can disrupt metabolic pathways, leading to changes in the microbiome and metabolome. By studying these changes, researchers can identify potential biomarkers for early CRC detection, inform individualized prevention strategies, and guide societal efforts to reduce PFAS exposure through regulatory actions and public health policies.
4.1. Funding sources
Investigators involved in this work were supported by grants, including R01ES035035 and R01ES035056 (PI: Tanya Alderete) from the National Institutes of Health (NIH) National Institute of Environmental Health Science (NIEHS). Elizabeth Holzhausen was supported by the National Institute on Minority Health and Health Disparities (K01 MD020215). The Harvard JPB Environmental Health Fellowship and P3 0ES007048 provided support for Max Aung. David Conti was supported by P30ES007048. Jesse M. Goodrich was supported by NIEHS (K01 ES036193) and NIDDK (R01DK140831). Douglas I. Walker was supported by NIEHS (R01ES032831; U24ES036819) and NCI (R01CA279668; UH3CA265846). Brian Z. Huang was supported by NIH/NCI career development award (R00CA256525). Loic L. Marchand was supported by NCI (U01 CA164973). Donghai Liang was supported by NIEHS (R01ES035738). Lida Chatzi was supported by NIH (U01HG013288, R01ES036253, R01ES029944, R01ES030691, R01ES030364, and P30ES007048), and the European Union: The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project, grant agreement number 874583.
Supplementary Material
Acknowledgements
We gratefully acknowledge the editor, Nicolas Roth, for his guidance throughout the review process, and the anonymous reviewers for their insightful and constructive comments. Their expertise and thoughtful suggestions have substantially improved the clarity, rigor, and overall quality of this work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.envint.2025.109778.
Footnotes
CRediT authorship contribution statement
Devendra Paudel: Writing – review & editing, Writing – original draft, Visualization, Methodology, Formal analysis, Conceptualization. Haonan Li: Writing – review & editing, Methodology. Elizabeth A. Holzhausen: Writing – review & editing, Methodology. Nathan Young: Writing – review & editing, Methodology. Elizabeth A. Platz: Writing – review & editing. Douglas I. Walker: Writing – review & editing. Donghai Liang: Writing – review & editing. Max Aung: Writing – review & editing. Jesse A. Goodrich: Writing – review & editing. Veronica Wendy Setiawan: Writing – review & editing. Loic Le Marchand: Writing – review & editing. Brian Z. Huang: Writing – review & editing. David V. Conti: Writing – review & editing. Lida Chatzi: Writing – review & editing. Tanya L. Alderete: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Methodology, Funding acquisition, Conceptualization.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lida Chatzi has served as an expert consultant for plaintiffs in litigation related to PFAS-contaminated drinking water.
Data availability
No data was used for the research described in the article.
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