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Published in final edited form as: Toxicol Lett. 2024 Jul 22;399:52–58. doi: 10.1016/j.toxlet.2024.07.910

Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer: systematic review and meta-analysis

Maaike van Gerwen 1,2,*, Tony Chung 1, Mathilda Monaghan 1, Roel Vermeulen 3,4, Lauren Petrick 5,6,7, Angela M Leung 8,9
PMCID: PMC11959417  NIHMSID: NIHMS2059548  PMID: 39047923

Abstract

Per- and polyfluoroalkyl substances (PFAS) exposure is a potential risk factor for thyroid cancer and may be a contributor to the increasing thyroid cancer incidence rates. A systematic review and meta-analysis was performed to summarize all human studies to date investigating the association between PFAS exposure and thyroid cancer. A search of the National Library of Medicine and National Institutes of Health PubMed and Scopus databases was done to identify relevant articles published in English through January 2024. Studies reporting the association between PFAS exposure and thyroid cancer using odds ratios (OR) were included in the meta-analysis with summary estimate calculated using a random effects model (n=5). Perfluorooctanoic acid (PFOA) was the most investigated PFAS. Results of the included studies varied, ranging from significant positive to significant negative associations with thyroid cancer incidence for different PFAS. Meta-analyses of PFOA, Perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS) were not significant. This comprehensive review of the current literature highlights the limited knowledge and inconsistent results of this association. Large longitudinal cohort studies with varying time between sample collection and thyroid cancer diagnosis are needed to better understand the role of PFAS exposure on thyroid carcinogenesis.

Keywords: Environmental exposures, forever chemicals, thyroid cancer, PFAS

Introduction

Thyroid cancer is the most common endocrine malignancy and its incidence rate has been increasing in the United States (US) and worldwide. (Davies and Welch 2006, Kitahara and Sosa 2016, Lim, Devesa et al. 2017, Miranda-Filho, Lortet-Tieulent et al. 2021) Despite this trend, there remain gaps in understanding the etiologies and genetic, demographic, and environmental risk factors of thyroid cancer. Improved access and quality of diagnostic imaging and increased detection only partially explain the increase over the past decades. (Kitahara and Sosa 2016)Although the overall thyroid cancer incidence rate has appeared to have leveled off over the last decade, rates of thyroid cancers measuring more than one centimeter are still on the rise, which suggests a true, continuing increase. (Powers, Marcadis et al. 2019, Yan, Li et al. 2020) Besides known modifiable risk factors that include ionizing radiation exposure, iodine deficiency, obesity, and familial inheritance for some subtypes, exposure to environmental pollutants, in particular endocrine disrupting chemicals (EDC), has been suggested as a potential risk factor for thyroid cancer as some of these chemicals are known to alter thyroid function and have been associated with other cancers. (Soto and Sonnenschein 2010, Steenland and Winquist 2021, Alsen, Sinclair et al. 2021)

Per- and polyfluoroalkyl substances (PFAS) are persistent EDCs that have been used in industry and consumer products since the 1940s, including nonstick cookware, stain-resistant fabric, firefighting foams. (Steenland and Winquist 2021) PFAS are ubiquitous in the environment due to their stable chemical structure and are found in soil, air, and water, thus leading to almost universal exposure of the general population. (Fromme, Tittlemier et al. 2009) Exposure to the legacy PFAS (e.g. perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA)) has declined for the last two decades in the US and other developed countries since companies phased out manufacturing of these PFAS. (Göckener, Weber et al. 2020, Agency for Toxic Substances and Disease Registry, 2024, Hull, Deen et al. 2023) Although serum levels of certain other long-chain PFAS have followed a similar declining trends, numerous new (short-chain) PFAS have been introduced of which exposure levels and health impact remains to be elucidated. (Buck, Korzeniowski et al. 2021, Sonnenberg, Ojewole et al. 2023)

PFAS exposure has been associated to thyroid dysfunction. PFOA, and to a lesser extent PFOS, has been associated with the occurrence of hypothyroidism in the general population as well as exposed communities. (Coperchini, Croce et al. 2020) A meta-analysis reported thyroid dysfunction for PFOS (positive correlation with serum free thyroxin [T4] levels and negative correlation with total T4 and total triiodothyronine [T3] levels), PFOA (negative correlation with total T4 levels) and perfluorohexanesulfonic acid (PFHxS) (negative correlation with total T4 levels), suggesting that PFAS exposure negatively impacts thyroid hormone availability. (Kim, Moon et al. 2018) Certain regulatory authorities have extensively reviewed the literature on the potential health impact of PFAS exposure. In 2018 and 2020, the European Food and Safety Authority (EFSA) concluded that there is insufficient data from human epidemiological studies to support a causal association between PFAS (including PFOS, PFOA, perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)) exposure and thyroid dysfunction. (Knutsen, Alexander et al. 2018, Schrenk, Bignami et al. 2020) In 2024, the US Environmental Protection Agency (EPA) noted moderate evidence from animal studies associating PFOA and PFOS with thyroid irregularities. (Environmental Protection Agency, PFOS. 2024, Environmental Protection Agency, PFOA. 2024) An expert panel in Australia found consistent reports on PFAS exposure and altered levels of thyroid hormones. (PFAS Expert Health Panel Report to the Minister, Australia, 2018)

Research investigating the potential association between PFAS exposure and overall cancer is limited. Furthermore, the mechanistic pathway linking PFAS exposure to thyroid cancer remains to be elucidated and the adverse outcome pathway (AOP), a framework linking a molecular initiated event to an adverse outcome through multiple key events, for PFAS is still unknown. (Ankley, Bennett et al. 2010, Boyd, Ahmad et al. 2022) Following local drinking water contamination with PFOA in Ohio and West Virginia in the early 2000’s, a scientific panel concluded that there were probable links between this exposure and kidney and testicular cancer, while no conclusion could be drawn regarding thyroid cancer. (Steenland, Fletcher et al. 2020)The International Agency for Research on Cancer (IARC) recently reviewed the carcinogenicity of PFOA and PFOS and classified PFOA as “carcinogenic to humans” (Group 1), based on strong mechanistic and sufficient evidence in experimental animal studies and PFOS as “possibly carcinogenic to humans (Group 2B), which was published as a short communication prior to the full IARC monograph. (Zahm, Bonde et al. 2024) It is also important to note that the thyroid was not considered a target organ so conclusions were mainly drawn based on liver, pancreas, kidney, and testis studies. (Zahm, Bonde et al. 2024) The 2024 US EPA Human Health Toxicity Assessments also classified both PFOA and PFOS as “likely carcinogenic to humans”. (Environmental Protection Agency, Additional Supporting Materials Final PFAS NPDWR, 2024)

To summarize the available literature to date on PFAS exposure and thyroid cancer, we performed a systematic review and meta-analysis of the literature.

Materials and methods

Search strategy

A systematic review of the literature was performed searching the National Library of Medicine and National Institutes of Health PubMed and Scopus databases for articles published through January 2024. The databases were searched with the keywords “thyroid cancer” AND “perfluoroheptanesulfonic acid” OR “PFHpS” OR “n-methylperfluorooctanesulfonamidoacetic acid” OR “N-MeFOSAA” OR “Genx” OR “perfluorohexanesulfonic acid” OR “PFHxS” OR “perfluorooctylphosphonic acid” OR “PFOPA” OR “perfluorononanoic acid” OR “PFNA” OR “perfluorooctanoic acid” OR “PFOA” OR “PFOS” OR “perfluorooctanesulfonic acid” OR “PFAS” OR “Per- and polyfluoroalkyl substances.” Additionally, reference lists of identified reviews were searched for eligible articles, with no additional articles identified. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page, McKenzie et al. 2021) and the search strategy and supporting documentation were registered in PROSPERO in accordance with the PRISMA standards for the transparent reporting of systematic reviews and meta-analyses (ID: CRD42023485433).

Selection criteria

Imported articles were collated and deduplicated using Covidence systematic review software. (Covidence) Titles and abstracts were evaluated for eligibility by two independent reviewers (M.v.G. and T.C.), with any conflict resolved by reaching a consensus. Inclusion criteria were defined as follows: 1) PFAS exposure, 2) diagnosis of thyroid cancer (any histological subtype), 3) reporting on the association between PFAS exposure and thyroid cancer, and 4) human studies. Animal or in vitro studies, case reports, ecological studies, meta-analyses, or systematic reviews were excluded. Research focusing on environmental exposures unrelated to PFAS or thyroid conditions other than cancer was also excluded.

Relevant articles were subjected to full-text review based on the established criteria by the same two independent reviewers (M.v.G. and T.C.). Any disagreements encountered during the screening of abstracts and full texts were resolved by involving an independent third reviewer (M.A.) to mediate and assist in reaching a consensus.

Data extraction and quality assessment

Data was extracted for the following variables from the included studies: primary author name, year of publication, country, study design, total number of study participants, number of participants in each patient group, number of female participants, mean age of the study population, PFAS types studied, PFAS measurement methods, and outcomes, (odds ratio (OR) with the 95% confidence interval (CI)). In instances where studies provided multiple results or conducted sensitivity analyses, preference was given to comparisons that represented the main findings of the study. Data were extracted by one reviewer (M.v.G or T.C.) and independently reviewed for accuracy by another reviewer (M.v.G. or T.C.) with disagreements resolved by reaching a consensus.

Quality assessment of retrieved studies was conducted using the Newcastle-Ottawa Scale (NOS), designed to evaluate the quality of nonrandomized studies, developed by the Universities of Newcastle, Australia, and Ottawa. (Wells, Shea et al. 2001) The NOS applies a rating system across three main categories: selection, comparability, and ascertainment of exposure/ outcome for case-control or cohort studies, respectively, with scores ranging from 0 to 4 stars per category, allowing a maximum score of 9. High quality studies were defined as ≥ 7 points. (Stang 2010) Quality evaluations were performed by two independent reviewers (M.v.G. or T.C.), with any conflicts resolved by reaching a consensus.

Statistical analysis

Following a systematic review of the literature, studies reporting the association between PFAS exposure and thyroid cancer using odds ratios (OR) were included in the meta-analysis part of the study. Summary estimates were then calculated using a random effects model fit using the weighted OR for each comparison for the following PFAS: PFOA, PFOS, PFNA, PFHxS, which are the most common PFAS. (Alsen, Sinclair et al. 2021) Studies were weighted based in their inverse variance to account for sample size and variance of the study population. Heterogeneity was tested using the Q and I2 statistics. I2 statistics of < 25 %, 25–50 % and > 50 % represented a low, moderate, and high heterogeneity, respectively and was used as a confirmatory test of the Q statistics. (Higgins and Thompson 2002, Ioannidis, Patsopoulos and Evangelou 2007) Finally, assessment of publication bias through visual inspection of funnel plots and statistical evaluation using Egger’s test that defines evidence of asymmetry on P<0.1 was not performed due to lack of interpretability due to low number of included studies. (Egger, Davey Smith et al. 1997) All statistical analyses were completed using metafor package of Rstudio (version 4.4–0; R Foundation for Statistical Computing, Vienna, Austria). (Viechtbauer 2023)

Results

Review of the literature yielded 1,125 studies, of which 171 duplicate studies were removed. Another 933 irrelevant studies were removed after screening of title and abstract. After full-text review of the remaining 21 studies, 16 were excluded for reasons including: wrong study design (n = 9), overview/review/commentary (n = 5), and wrong outcomes (n = 2) (Figure 1).

Figure 1.

Figure 1.

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Search and selection strategy.

Study characteristics

A total of 5 studies met the inclusion criteria. (Liu, Zhang et al. 2022, Cathey, Nguyen et al. 2023, Li, Yang et al. 2023, van Gerwen, Colicino et al. 2023, Madrigal, Troisi et al. 2024) (Table 1) Four studies were case-control studies, and one study had a cross-sectional study design. All studies met the criteria of high quality following the NOS. Studies were published between 2022 and 2024; two studies were performed in the US, two in China and one in Finland Included populations varied widely ranging from 176 to 800 participants in the case-control studies, and 13,246 participants in the cross-sectional study. (Table 1)

Table 1.

Characteristics of included studies.

Author Year Country Study design QA n Patient groups (n) Female n (%) Mean age (years) Type of PFAS
Cathey 2023 USA Retrospective Cross-sectional 8 13,246 Cancer cases (35) 28 (80.0) NR PFOA, PFOS, PFHS, MPAH, PFDE, PFNA, PFUA
Healthy controls (13,211) 6,858 (51.9) NR
Li 2023 China Retrospective case-control 8 300 Cancer cases (150) 121 (80.7) 45.9 PFOA, PFOS, PFNA, PFHxS, PFDA, PFUnDA, Total PFAS
Healthy controls (150) 121 (80.7) 46.4
van Gerwen 2023 USA Prospective case-control 8 176 Cancer cases (88) 73 (83.0) 46.0 n-PFHxS, PFOA, PHFpS, PFOPA, Sb-PFOS, n-PFOS, PFNA, NMeFOSAA
Healthy controls (88) 73 (83.0) 46.0
Madrigal 2024 Finland Retrospective case-control 8 800 Cancer cases (400) 400 (100) NR PFAS with ≥60% detection (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, MeFOSAA)
Healthy controls (400) 400 (100) NR
Ever-high females (7,636) 7,636 (0) 31
Liu 2022 China Retrospective case-control 7 319 Cancer cases (134) 102 (77.3) 47.2 PFOA, PFNA, PFDA, PFUnDA, PFHxS, PFOS, C8 CI-PFESA
Healthy controls (185) 121 (65.4) 43.9
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NR: not reported; QA: quality assessment

PFAS abbreviations in text, except: MPAH: 2-(N-methyl-PFOSA) acetic acid; PFDE: perfluorodecanoic acid; PFUA: perfluoroundecanoic acid

PFAS exposure and thyroid cancer: systematic review

Van Gerwen et al found an increased risk odds of thyroid cancer associated with increasing linear PFOS levels (OR: 1.56 (95% CI: 1.17– 2.15). (van Gerwen, Colicino et al. 2023)

Other studies reported negative associations between different PFAS and thyroid cancer. Madrigal et al reported a decreased odds of thyroid cancer with increasing PFHxS (OR: 0.82 (95% CI: 0.70– 0.97), while no significant associations were reported for the other included PFAS (PFOA, PFOS, PFNA, ethyl perfluorooctane sulfonamido acetic acid (EtFOSAA), methyl perfluorooctanesulfonamidoacetic acid (MeFOSAA)). (Madrigal, Troisi et al. 2024) Li et al (2023) reported decreased odds of thyroid cancer for perfluorononanoic acid (PFNA) (OR: 0.56 (95% CI: 0.35– 0.91), perfluorodecanoic acid (PFDA) (OR: 0.52 (95% CI: 0.34– 0.80), perfluoroundecanoic acid (PFUnDA) (OR: 0.69 (95% CI: 0.56– 0.85), while no significant association were reported for PFOA, PFOS, and PFHxS. (Li, Yang et al. 2023) Liu et al found decreased odds of thyroid cancer for all the PFAS (PFOA, PFNA, PFDA, PFUnDA, PFHxS, PFOS, and chlorinated polyfluoroalkyl ether sulfonic acid (C8 CI-PFESA)) they included in their study. (Liu, Zhang et al. 2022) (Table 2)

Table 2.

Association of PFAS exposure and thyroid cancer from individual studies.

Author Year Measurement of Exposure Type of PFAS Outcomes (95% CI)
Cathey 2023 IQR increase in PFAS levels PFOA OR: 0.70 (0.38 – 1.30)*
PFOS OR: 0.53 (0.28 – 1.00)*
PFHS OR: 0.62 (0.36 – 1.06)*
MPAH OR: 1.32 (0.70 – 2.51)*
PFDE OR: 1.44 (0.81 – 2.56)*
PFNA OR: 0.93 (0.55 – 1.60)*
PFUA OR: 1.12 (0.66 – 1.92)*
Li 2023 Continuous PFAS levels; models adjusted for age, sex, BMI, smoking and drinking status PFOA OR: 1.01 (0.73 – 1.41)
PFOS OR 1.11 (0.88 – 1.39)
PFNA OR: 0.56 (0.35 – 0.91)
PFHxS OR: 0.85 (0.61 – 1.19)
PFDA OR: 0.52 (0.34 – 0.80)
PFUnDA OR: 0.69 (0.56 – 0.85)
Total PFAS OR: 0.91 (0.58 – 1.45)
van Gerwen 2023 Continuous PFAS concentrations; models adjusted for age, BMI, sex, race, storage time of plasma samples n-PFHxS OR: 1.00 (0.77 – 1.30)
PFOA OR: 0.99 (0.63 – 1.56)
PFHpS OR: 1.33 (0.81 – 2.24)
PFOPA OR: 1.17 (0.90 – 1.54)
Sb-PFOS OR: 1.32 (0.99 – 1.81)
n-PFOS OR: 1.56 (1.17 – 2.15)
PFNA OR: 1.30 (0.93 – 1.85)
NMeFOSAA OR: 1.14 (0.78 – 1.68)
Madrigal 2024 Continuous PFAS concentrations; matched on age and year of sample collection PFOA OR: 0.95 (0.76 – 1.20)
PFOS OR: 1.05 (0.82 – 1.35)
PFNA OR: 0.97 (0.82 – 1.14)
PFHxS OR: 0.82 (0.70 – 0.97)
EtFOSAA OR: 1.04 (0.91 – 1.17)
MeFOSAA OR: 0.99 (0.87 – 1.12)
Liu 2022 Quartiles of PFAS in serum (Q4 vs Q1); model adjusted for age, sex, and diabetes status PFOA OR: 0.20 (0.09 – 0.44)
PFNA OR: 0.22 (0.10 – 0.50)
PFDA OR: 0.47 (0.24 – 0.93)
PFUnDA OR: 0.37 (0.18 – 0.74)
PFHxS OR: 0.02 (0.00 – 0.06)
PFOS OR: 0.28 (0.12 – 0.66)
C8 CI-PFESA OR: 0.64 (0.31 – 1.30)
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*

Numeric results only reported for females

BMI: body mass index; CI: confidential interval; OR: odds ratio. PFAS abbreviations in text, except: MPAH: 2-(N-methyl-PFOSA) acetic acid; PFDE: perfluorodecanoic acid; PFUA: perfluoroundecanoic acid

Cathey et al, did not report a significant association between PFAS exposure and thyroid cancer. (Cathey, Nguyen et al. 2023) (Table 2)

PFAS exposure and thyroid cancer: meta-analysis

Five studies were included in the meta-analysis on the association thyroid cancer and PFOS, PFOA, PFNA, or PFHxS. (Liu, Zhang et al. 2022, Cathey, Nguyen et al. 2023, Li, Yang et al. 2023, van Gerwen, Colicino et al. 2023, Madrigal, Troisi et al. 2024) No significant associations were found between PFOA (OR: 0.80 (95% CI 0.54– 1.19)), PFOS (OR: 0.95 (95% CI: 0.63– 1.43)), PFNA (OR: 0.79 (95% CI: 0.51– 1.25)) or PFHxS (OR: 0.43 (95% CI: 0.12– 1.58)) and thyroid cancer, with no significant heterogeneity. (Figures 3–5)

Figure 3.

Figure 3.

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Summary Estimate on the association between PFOS and thyroid cancer

Figure 5.

Figure 5.

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Summary Estimate on the association between PFHxS and thyroid cancer

Because critical concerns regarding study design were expressed about Lui et al (2022), which may have affected their study results leading to the reported significant negative association, and thus impacted this meta-analysis, a sensitivity analysis was performed excluding this study. (Phosri, Paoin and Harada 2022) No significant association was found for between PFOA (OR: 0.93 (95% CI 0.61– 1.41)), PFOS (OR: 1.09 (95% CI: 0.74– 1.60)), PFNA (OR: 0.94 (95% CI: 0.64– 1.39)) or PFHxS (OR: 0.84 (95% CI: 0.58– 1.21)) and thyroid cancer, with no significant heterogeneity

Discussion

While the separate studies reported positive and negative association as well as null findings, the meta-analyses on the associations between PFOA, PFOS, PFNA, of PFHxS exposure and thyroid cancer was not significant. This systematic review and meta-analysis therefore mainly highlight the limited knowledge and inconsistent results on the role of PFAS exposure in thyroid carcinogenesis and the heterogeneity in the published studies.

Although the current literature is inconsistent for thyroid cancer, there is evidence linking exposure to certain PFAS to increased cancer risk in some organs. The 2024 US EPA Human Health Toxicity Assessments classified both PFOA and PFOS as “likely carcinogenic to humans”. (Environmental Protection Agency, Additional Supporting Materials Final PFAS NPDWR, 2024) PFOA was associated with kidney and testicular cancer and with breast cancer in one susceptible subpopulation in human following epidemiological studies. In animal studies, an association was found with hepatocellular and pancreatic tumors. PFOS was associated with bladder, prostate, liver, kidney, and breast cancer in epidemiological studies however, evidence was limited or mixed for some cancer types; these findings were supported by animal toxicological studies supported findings. (Environmental Protection Agency, Additional Supporting Materials Final PFAS NPDWR, 2024) Recently, IARC published the summary of their review of PFOS and PFOA classifying PFOA as a “carcinogenic for humans” (Group 1) and PFOS as “possibly carcinogenic to humans” (Group 2B) although publication of the full monograph is still pending. (Zahm, Bonde et al. 2024) Following this recent review of available studies on PFOA and PFOS carcinogenicity, further investigation this exposure on the thyroid gland is clearly warranted.

Only two studies included in the meta-analysis collected blood samples prior to thyroid cancer diagnosis. Time between blood samples collection and cancer diagnosis was 1.5 years (range: 0–8.5 years) in van Gerwen et al. (van Gerwen, Colicino et al. 2023) Although Madrigal et al did not report the mean time between blood sample collection and thyroid cancer diagnosis, all cases were part of the Finnish Maternity Cohort with blood samples collected during the first trimester of pregnancy. Most females were between 24 and 29 years at sample collection while the mean age at thyroid cancer diagnosis was 40.9 years. (Madrigal, Troisi et al. 2024) It is therefore likely that the time between blood sample collection and thyroid cancer diagnosis was longer in the study done by Madrigal et al versus van Gerwen et al. Evidence suggests that PFAS are not directly mutagenic but potentially lead to cancer progression through previously described mechanisms. (Boyd, Ahmad et al. 2022) This may explain why increased thyroid cancer risk was found in van Gerwen et al with exposure to PFOS as the time between PFAS measurement and thyroid cancer was shorter compared to Madrigal et al. (van Gerwen, Colicino et al. 2023, Madrigal, Troisi et al. 2024) Higher PFAS exposure may lead to cancer progression and thus cancer detection. Future studies taken the time between sample collection and cancer diagnosis into consideration are needed to understand the latency period following PFAS exposure.

PFOA and PFOS, also known as the legacy PFAS, have been in use since the 1940’s. (Steenland and Winquist 2021) In the early 2000’s, the major American chemical companies voluntarily agreed to eliminate the use of PFOA- and PFOS-related chemicals and thus these PFAS chemicals are no longer manufactured in the US. (National Institute of Environmental Health Sciences) However, measurable levels of PFOS and PFOA remain in the US and Europe due to their persistence in the environment with half-lives in water, a major source of exposure, of 41 and 92 years, respectively. (WHO 2022) This means that contaminated water sources will continue to be exposure sources to these (possible) carcinogens. (Social Science Environmental Health Research Institute) Furthermore, PFOS, PFOA and other long-chain legacy PFAS are only a small proposition of PFAS and there are emerging carcinogenic concerns associated with replacement PFAS, such as GenX. (Coperchini, Croce et al. 2020) The impact of PFAS exposure on (thyroid) carcinogenesis will therefore remain an important field of future studies.

This systematic review provides on overview of all human studies reporting on the association between PFAS and thyroid cancer risk published to date. Because multiple institutions, including the US Environmental Protection Agency and the European Union, have identified PFAS exposure as a potential health risk, it is expected that new studies will be published in the near future. Another limitation is that the meta-analysis was limited to only five studies. Furthermore, most studies (4 out of 5) were done in the US and China potentially impacting the generalizability of the results. The included studies also have individual weaknesses that are important to note. First, conclusions on causality between PFAS exposure and thyroid cancer diagnosis is limited for most included studies: Cathey at al used a cross-sectional study design, and both Li et and Liu et al evaluated PFAS levels in patients already diagnosed with thyroid cancer. Van Gerwen et al included a low number of study participants. Madrigal et al included females from a national maternity cohort therefore limiting the generalizability of the results. Lastly, the study of Liu et al received critical concerns regarding study design, which may have affected their study results leading to a significant negative association, and thus impacted this meta-analysis. (Phosri, Paoin and Harada 2022) We therefore added the results of a sensitivity analysis, excluding Liu et al. The results remained not significant but tended towards a positive association for PFOS.

This comprehensive review of the current literature on the association between PFAS exposure and thyroid cancer highlights that large longitudinal cohort studies with varying time between sample collection and thyroid cancer diagnosis are needed to understand the impact on thyroid carcinogenesis. Furthermore, human studies need to be complemented with in vitro and animal studies to establish the mechanistic and adverse outcome pathways linking PFAS exposure to (thyroid) cancer, including the emerging PFAS.

Figure 2.

Figure 2.

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Summary Estimate on the association between PFOA and thyroid cancer

Figure 4.

Figure 4.

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Summary Estimate on the association between PFNA and thyroid cancer

Funding:

This work was supported by funding though the National Institute of Health (NIH) (P30ES023515 and U2CES030859).

Footnotes

Conflict of Interest: A.L. is on the Science Advisory Board of the U.S. Environmental Protection Agency (EPA) and has served on the peer review draft toxicity panels for the EPA regarding perfluoro(2-methyl-3-oxahexanoate) (GenX), perfluorobutane sulfonate (PFBS), perfluorobutane sulfonate (PFBS), perfluorohexanoic acid and related salts (PFHxA), perfluorodecanoic acid (PFDA), and perfluorohexanesulfonic acid (PFHxS). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Data availability statement:

No new data were generated or analyzed for this systematic review/ meta-analysis.

References

  1. Agency for Toxic Substances and Disease Registry. PFAS in the US Population. 2024. https://www.atsdr.cdc.gov/pfas/health-effects/us-population.html (accessed 11.06.2024)
  2. Alsen M, Sinclair C, Cooke P, Ziadkhanpour K, Genden E, van Gerwen M, 2021. Endocrine Disrupting Chemicals and Thyroid Cancer: An Overview. Toxics 9(1), 14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ankley GT, Bennett RS, Erickson RJ, et al. , 2010. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3), 730–741. [DOI] [PubMed] [Google Scholar]
  4. Barry V, Winquist A, Steenland K, 2013. Perfluorooctanoic acid (PFOA) exposures and incident cancers among adults living near a chemical plant. Environ Health Perspect 121(11–12), 1313–1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boland MR, Davidson LM, Canelón SP, et al. , 2021. Harnessing electronic health records to study emerging environmental disasters: a proof of concept with perfluoroalkyl substances (PFAS). NPJ Digit Med 4(1), 122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyd RI, Ahmad S, Singh R, et al. , 2022. Toward a Mechanistic Understanding of Poly- and Perfluoroalkylated Substances and Cancer. Cancers (Basel). 14(12), 2919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Buck RC, Korzeniowski SH, Laganis E, Adamsky F, 2021. Identification and classification of commercially relevant per- and poly-fluoroalkyl substances (PFAS). Integr Environ Assess Manag 17(5), 1045–1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cathey AL, Nguyen VK, Colacino JA, Woodruff TJ, Reynolds P, Aung MT, 2023. Exploratory profiles of phenols, parabens, and per- and poly-fluoroalkyl substances among NHANES study participants in association with previous cancer diagnoses. J Expo Sci Environ Epidemiol 33(5), 687–698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coperchini F, Croce L, Denegri M, Pignatti P, Agozzino M, Netti GS, et al. , 2020. Adverse effects of in vitro GenX exposure on rat thyroid cell viability, DNA integrity and thyroid-related genes expression. Environ Pollut 264, 114778. [DOI] [PubMed] [Google Scholar]
  10. Coperchini F, Croce L, Ricci G, et al. , 2020. Thyroid Disrupting Effects of Old and New Generation PFAS. Front Endocrinol, 11, 612320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. https://www.covidence.org/ (accessed 28.02.2024)
  12. Davies L, Welch HG. 2006., Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295(18), 2164–2167. [DOI] [PubMed] [Google Scholar]
  13. Egger M, Davey Smith G, Schneider M, Minder C, 1997. Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109), 629–634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Environmental Protection Agency, PFOA 2024. https://www.epa.gov/system/files/documents/2024-05/final-human-health-toxicity-assessment-pfoa.pdf (accessed 11.06.2024)
  15. Environmental Protection Agency, PFOS 2024. https://www.epa.gov/system/files/documents/2024-05/final-human-health-toxicity-assessment-pfos.pdf (accessed 11.06.2024)
  16. Environmental Protection Agency, Additional Supporting Materials Final PFAS NPDWR, 2024. https://www.epa.gov/sdwa/additional-supporting-materials-final-pfas-npdwr (accessed 11.06.2024)
  17. Fromme H, Tittlemier SA, Völkel W, Wilhelm M, Twardella D, 2009. Perfluorinated compounds--exposure assessment for the general population in Western countries. Int J Hyg Environ Health 212(3), 239–270. [DOI] [PubMed] [Google Scholar]
  18. Göckener B, Weber T, Rüdel H, Bücking M, Kolossa-Gehring M, 2020. Human biomonitoring of per- and polyfluoroalkyl substances in German blood plasma samples from 1982 to 2019. Environ Int 145, 106123. [DOI] [PubMed] [Google Scholar]
  19. Higgins JP, Thompson SG, 2002. Quantifying heterogeneity in a meta-analysis. Stat Med 21(11), 1539–1558. [DOI] [PubMed] [Google Scholar]
  20. Hull SD, Deen L, Petersen KU, et al. , 2023. Time trends in per- and polyfluoroalkyl substances (PFAS) concentrations in the Danish population: A review based on published and newly analyzed data. Environ Res 237(Pt 2), 117036. [DOI] [PubMed] [Google Scholar]
  21. Ioannidis JP, Patsopoulos NA, Evangelou E, 2007. Uncertainty in heterogeneity estimates in meta-analyses. BMJ 335(7626), 914–916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kim MJ, Moon S, Oh BC, et al. , 2018. Association between perfluoroalkyl substances exposure and thyroid function in adults: A meta-analysis. PLoS One. 13(5), e0197244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kitahara CM, Sosa JA, 2016. The changing incidence of thyroid cancer. Nat Rev Endocrinol 12(11), 646–653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Knutsen HK, Alexander J, Barregård L, et al. 2018. Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food. EFSA J 16(12), e05194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li H, Yang M, Yang J, et al. , 2023. Per- and polyfluoroalkyl substances and the associated thyroid cancer risk: A case-control study in China. Chemosphere 337, 139411. [DOI] [PubMed] [Google Scholar]
  26. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM, 2017. Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974–2013. JAMA 317(13), 1338–1348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Liu M, Zhang G, Meng L, 2022. Associations between Novel and Legacy Per- and Polyfluoroalkyl Substances in Human Serum and Thyroid Cancer: A Case and Healthy Population in Shandong Province, East China. Environ Sci Technol 56(10), 6144–6151. [DOI] [PubMed] [Google Scholar]
  28. Madrigal JM, Troisi R, Surcel HM, et al. , 2024. Prediagnostic serum concentrations of per- and polyfluoroalkyl substances and risk of papillary thyroid cancer in the Finnish Maternity Cohort., Int J Cancer. 154(6), 979–991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Miranda-Filho A, Lortet-Tieulent J, Bray F, et al. , 2021. Thyroid cancer incidence trends by histology in 25 countries: a population-based study. Lancet Diabetes Endocrinol 9(4), 225–234. [DOI] [PubMed] [Google Scholar]
  30. National Institute of Environmental Health Sciences. Per- and Polyfluoroalkyl Substances (PFAS). https://www.epa.gov/pfas (accessed 12.08.2020).
  31. Page MJ, McKenzie JE, Bossuyt PM, et al. , 2021. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. PFAS Expert Health Panel Report to the Minister, Australia, 2018. https://www.health.gov.au/sites/default/files/2024-06/expert-panel-report.pdf (accessed 11.06.2024)
  33. Phosri A, Paoin K, Harada KH, 2022. Comment on “Associations between Novel and Legacy Per- and Polyfluoroalkyl Substances in Human Serum and Thyroid Cancer: A Case and Healthy Population in Shandong Province, East China”. Environ Sci Technol 56(18), 13510–13511. [DOI] [PubMed] [Google Scholar]
  34. Powers AE, Marcadis AR, Lee M, Morris LGT, Marti JL, 2019. Changes in Trends in Thyroid Cancer Incidence in the United States, 1992 to 2016. JAMA 322(24), 2440–2441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Social Science Environmental Health Research Institute. PFAS contamination site tracker; 2020. https://pfasproject.com/pfas-contamination-site-tracker/. (accessed 19.01.2023)
  36. Schrenk D, Bignami M, Bodin L, et al. , 2020. Risk to human health related to the presence of perfluoroalkyl substances in food. EFSA J 18(9), e06223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sonnenberg NK, Ojewole AE, Ojewole CO, Lucky OP, Kusi J, 2023. Trends in Serum Per-and Polyfluoroalkyl Substance (PFAS) Concentrations in Teenagers and Adults, 1999–2018 NHANES. Int J Environ Res Public Health. 20(21), 6984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Soto AM, Sonnenschein C, 2010. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol 6(7), 363–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stang A, 2010. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9), 603–605. [DOI] [PubMed] [Google Scholar]
  40. Steenland K, Fletcher T, Stein CR, et al. , 2020. Review: Evolution of evidence on PFOA and health following the assessments of the C8 Science Panel. Environ Int 145, 106125. [DOI] [PubMed] [Google Scholar]
  41. Steenland K, Winquist A, 2021. PFAS and cancer, a scoping review of the epidemiologic evidence. Environ Res 194, 110690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. van Gerwen M, Colicino E, Guan H, et al. , 2023. Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk. eBioMedicine. 97, 104831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Viechtbauer W metafor: Meta-Analysis Package for R. 2023. https://CRAN.Rproject.org/package=metafor. (accessed 14.02.2024)
  44. Wells G, Shea B, O’Connell D, et al. , 2001. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. University of Ottawa. http://www.ohri.ca/programs/clinical_epidemiology (accessed 16.12.2009) [Google Scholar]
  45. WHO. PFOS and PFOA in drinking water. http://cdn.who.int/media/docs/default-source/wash-documents/wash-chemicals/pfos-pfoa-gdwq-bd-working-draft-for-public-review-29.9.22.pdf?sfvrsn=eac28c23_3 (accessed 19.01.2023)
  46. Yan KL, Li S, Tseng CH, et al. , 2020. Rising Incidence and Incidence-Based Mortality of Thyroid Cancer in California, 2000–2017. J Clin Endocrinol Metab 105(6), dgaa121. [DOI] [PubMed] [Google Scholar]
  47. Zahm S, Bonde JP, Chiu WA, et al. , 2024. Carcinogenicity of perfluorooctanoic acid and perfluorooctanesulfonic acid. Lancet Oncol 25(1), 16–17. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No new data were generated or analyzed for this systematic review/ meta-analysis.

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