Skip to main content
NCBI home page
Journal of Environmental Health Science and Engineering logoLink to Journal of Environmental Health Science and Engineering
. 2024 Mar 21;22(2):455–469. doi: 10.1007/s40201-024-00899-w

Perfluoroalkyl and polyfluoroalkyl substances and Cancer risk: results from a dose-response Meta-analysis

Jingxuan Yang 1,#, Kui Zhang 2,#, Jingyi Shi 1,#, Zhuo Li 2, Hao Dai 2, Wenxing Yang 1,✉
PMCID: PMC11499464  PMID: 39464822

Abstract

Background

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent organic pollutants in the environment. While some studies suggest that PFASs may contribute to cancer development, the link between PFAS exposure and cancer risk remains debated.

Methods

This dose-response meta-analysis explores the relationship between PFASs and cancer. It employs odds ratio (OR) and standardized mean difference (SMD), along with their 95% confidence interval (CI), to assess the effects of PFASs on cancer risk. Relevant studies were sourced from Web of Science, PubMed, Embase, Medline, and CNKI databases. The dose-response relationship was assessed by the fixed-effects model and least-squares regression.

Results

Forty studies, involving a total of 748,188 participants, were included in this meta-analysis. Out of these, 13 studies were specifically analyzed for the dose-response relationship. Findings revealed that exposure to PFASs, especially PFDA, significantly raises the risk of genitourinary cancers, and PFDA exposure shows a dose-dependent increase in overall and breast cancer risk. Additionally, PFOS exposure is associated with an increased cancer risk, and elevated PFOA levels were significantly observed in breast cancer patients.

Conclusions

The findings suggest that PFAS exposure is a potential cancer risk factor, with the carcinogenic potential of PFDA being dose-dependent.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40201-024-00899-w.

Introduction

Cancer has been one of the leading causes of increased mortality worldwide [1]. Approximately 2.8 million people died of cancer in China in 2015 [2]. Previous studies pointed out that cancer was closely related to multiple risk factors, which were mainly behavioral and environmental factors [3, 4]. Per- and polyfluoroalkyl substances (PFASs), e.g. perfluorooctanoic acid (PFOA), perfluorooctane sulphonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), are a class of chemical contaminants existing widely and persistently in the environment and are mainly found in everyday products, workplace and food [5–8]. China is the largest global source of PFOA and PFOS due to development needs, as reported in a 2016 news article titled “The Teflon Toxin Goes to China” [9]. In general, PFASs are mainly ingested through indoor dust ingestion, dietary intake, and drinking [10–12], and continuously accumulate in the body with age, with a low clearance rate [13]. Therefore, due to the health problems caused by PFASs, they are restricted in many countries. Multiple toxicities correlated with PFASs, such as immunotoxicity, hepatotoxicity, carcinogenicity, and developmental and reproductive impairment, have been identified [14–16].

As a class of environmental pollutants, while PFOA and PFOS have been extensively studied, other PFASs, such as PFDA, have not been well characterized. Whether PFASs are carcinogenic has not been sufficiently resolved. Epidemiological studies have reported controversial findings, with some studies suggesting that PFASs are associated with cancer development [17–24], but others taking a different view [25–28]. In addition, whether the risk of cancer is dose-dependent on serum concentrations of PFASs has not been studied. Based on previous studies, we performed a dose-response meta-analysis, as presented below, aiming to clarify the previously inconclusive relationship between PFAS exposure and cancer risk.

Methods

Protocol and registration

This study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered in PRESPERO (ID: CRD42023451079).

Publication search and inclusion criteria

As of January 26, 2024, we searched for relevant literature in five databases, PubMed, Embase, Medline, Web of Science and CNKI, using the keywords listed in Table S1. The study was considered eligible if it met all the following criteria: (1) the study evaluated the association between the risk of cancer and exposure to PFASs; (2) the study provided odds ratio (OR), hazard ratio (HR), relative ratio (RR) or standardized mean difference (SMD), along with the corresponding 95% confidence interval (CI), or provided available data about standardized mortality ratio (SMR) to calculate the HR; (3) exposure to PFASs was assessed by serum concentration of PFASs; (4) for the dose-response meta-analysis, PFAS levels should be classified into at least three continuous concentration categories.

Data extraction

The data required for this paper were independently reviewed and extracted by two authors, Jingxuan Yang and Jingyi Shi. In case of disagreement, the two authors reached an agreement through discussion. The following information was recorded for each study: (1) first author; (2) year of publication; (3) region; (4) sex; (5) type of PFASs; (6) exposure category and level of PFASs in serum; (7) type of cancers; (8) number of cases; (9) number of controls; (10) the OR, RR or HR, with their 95% CI for each exposure category (Table 1).

Table 1.

Characteristics of literature included in this meta-analysis

First author Year Region Gender Study type Type of PFAS in serum Type of cancers Number of cases Number of subjects
Bonefeld-Jørgensen EC [29] 2011 Denmark female case-control study PFOA breast cancer 31 98
PFOS
Shearer JJ [20] 2021 Multiple nationalities combined case-control study PFOA renal cell carcinoma 324 324
PFOS
PFDA
PFHxS
PFNA
PFUnDA
Itoh H [25] 2021 Japan female case-control study PFOA breast cancer 401 401
PFOS
PFDA
PFHxS
PFNA
PFUnDA
Velarde MC [24] 2022 Philippines female case-control study PFOA breast cancer 66 67
PFOS
PFDA
PFHxS
PFNA
PFUnDA
Innes KE [26] 2014 US combined cross-sectional study PFOA colorectal cancer 208 47,151
PFOS
Feng Y [30] 2022 China female case-cohort study PFOA breast cancer 226 990
PFOS
PFDA
PFHxS
PFNA
Mancini FR [31] 2020 France female case-control study PFOA breast cancer 194 194
PFOS
Wen X [32] 2022 US female cohort study PFOA breast cancer 248 11,499
PFOS
Bonefeld-Jørgensen EC [33] 2014 Denmark female case-control study PFOA breast cancer 221 215
PFOS
PFDA
PFHxS
Wielsøe M [18] 2017 Denmark female case-control study PFOA breast cancer 77 81
PFOS
PFDA
PFHxS
PFNA
Vieira VM [34] 2013 US combined cross-sectional study PFOA cancers a / /
Steenland K [27] 2015 US combined cohort study PFOA cancers b / /
Barry V [17] 2013 US combined cohort study PFOA cancers c / /
Hurley S [28] 2018 US female case-control study PFOA breast cancer 902 858
PFOS
PFHxS
PFNA
Yeung LW [35] 2013 Australia combined case-control study PFOA hepatocellular carcinoma 24 25
PFOS
PFDA
PFHxS
PFNA
Cao L [21] 2022 China combined case-control study PFOA liver cancer 203 203
PFOS
PFDA
PFHxS
PFNA
Li X [36] 2022 China female case-control study PFOA breast cancer 373 657
PFOS
PFDA
PFHxS
PFNA
Goodrich JA [22] 2022 Multiple nationalities combined case-control study PFOA hepatocellular carcinoma 50 50
PFOS
PFDA
PFHxS
PFNA
Omoike OE [19] 2021 US combined cross-sectional study PFOA breast cancer/ovary cancer / /
PFOS
PFNA
PFHxS
Chang VC [37] 2023 US female case-control study PFOA breast cancer 621 621
PFOS
Liu M [23] 2022 China combined case-control study PFOA thyroid cancer 324 324
PFOS
PFHxS
PFDA
PFNA
PFUnDA
Eriksen KT [38] 2009 Denmark combined cohort study PFOA cancers d / /
PFOS
Purdue MP [39] 2023 US male case-control study PFOA testicular germ cell tumors 530 530
PFOS
PFHxS
Madrigal JM [40] 2024 Finland female case-control study PFOA papillary thyroid cancer 400 400
PFOS
PFHxS
PFDA
PFNA
Tsai MS [41] 2020 China female case-control study PFOA breast cancer 120 119
PFOS
PFHxS
PFDA
PFNA
PFUnDA
Hardell E [42] 2014 Sweden male case-control study PFOA prostate cancer 201 186
PFOS
PFHxS
PFDA
PFNA
PFUnDA
Zhang T [43] 2023 Finland/US combined case-control study PFOS cancers e 611 611
PFOA
Li H [44] 2023 China combined case-control study PFOA thyroid cancer 150 150
PFOS
PFHxS
PFDA
PFNA
PFUnDA
Alexander BH [45] 2007 US combined cohort study PFOS bladder cancer / /
Winquist A [46] 2023 US combined cohort study PFOA cancers f / /
PFOS
PFNA
PFHxS
van Gerwen M [47] 2023 US combined case-control study PFOA thyroid cancer 88 88
PFOS
PFNA
Rhee J [48] 2023 Multiple nationalities combined case-control study PFOA renal cell carcinoma 428 428
PFOS
PFHxS
PFNA
PFDA
Cathey AL [49] 2023 US female/ male cohort study PFOA reproductive cancers / /
PFOS
PFNA
Grice MM [50] 2007 US combined cohort study PFOS colon/ prostate cancer/ melanoma / /
Moon J [51] 2024 US combined cohort study PFOA cancers g / /
PFOS
PFHxS
PFNA
Frenoy P [52] 2022 France female case-control study PFOA breast cancer 194 194
PFOS
PFDA
PFNA
PFHxS
Lundin JI [53] 2009 US combined cohort study PFOA cancers h / /
Gilliland FD [54] 1993 US male cohort study PFOA cancers i / /
Girardi P [55] 2019 Italy male cohort study PFOA cancers j / /
Rhee J [56] 2023 US combined case-control study PFOA breast cancer 750 750
PFOS
PFNA
PFHxS
Open in a new tab

PFAS per- and polyfluoroalkyl substances, PFOA perfluorooctanoic acid, PFOS perfluorooctane sulphonate, PFHxS perfluorohexane sulfonate, PFNA Perfluorononanoic acid, PFDA perfluorodecanoic acid, PFUnDA perfluoroundecanoic acid

abladder cancer; breast cancer; cervix cancer; rectum cancer; kidney cancer; leukemia cancer; lung cancer; melanoma of the skin; multiple myeloma; non-Hodgkin lymphoma; ovary cancer; pancreas cancer; prostate cancer; testis cancer; thyroid cancer; thyroid cancer; uterus cancer

bbladder cancer; colorectal cancer; prostate cancer; melanoma

ckidney cancer; testes cancer; thyroid cancer

dprostate cancer; bladder cancer; pancreas cancer; liver cancer

eprostate cancer; lung cancer; colorectal cancer; ovarian cancer

fthyroid cancer; thyroid cancer; kidney cancer; pancreatic cancer; pancreatic cancer; pancreatic cancer; prostate cancer

gbladder cancer; breast cancer; cervix cancer; colon cancer; kidney cancer; leukemia cancer; lung cancer; melanoma; ovarian cancer; thyroid cancer; uterus cancer

hbiliary passages and liver primary cancer; pancreas cancer; trachea, bronchus, and lung cancer; prostate cancer; bladder and other urinary organs cancer

igastrointestinal cancer; colon cancer; pancreas cancer; respiratory cancer lung cancer; testis cancer; bladder cancer; lymphopoietic cancer

jesophagus cancer; stomach cancer; colon cancer; liver cancer; lung cancer; lymphatic and haematopoietic tissue

The sample size, mean, and standard deviation of each data set were extracted for the analysis of SMD. The association between PFAS exposure levels and cancer risk was evaluated by comparing ORs and their 95% CIs between the highest and lowest exposure categories. If the reported ORs and their 95% CIs were unadjusted for any factors, they were directly used in the analysis. While, if adjustments were made for various factors, the ORs and their 95% CIs were obtained from the model that accounted for the most factors. To further analyze the dose-dependent effect, data were extracted as follows: when the highest and lowest exposure categories were “open”, we used the critical value of the highest exposure group and 0.5 times the critical value of the lowest exposure group as the boundary. For each closed exposure category, we extracted the midpoint [57].

Statistical analysis

The ORs and their 95% CIs were used to assess the association between PFAS exposure and cancer risk. To delve deeper into the effects of various PFASs on the likelihood of different types of cancer, subgroup evaluations were carried out. The cancers under consideration were divided into seven groups according to the primary organs and systems they impact: gastrointestinal cancers, genitourinary cancers, breast cancer, thyroid cancer, hematological cancers, respiratory cancer, and skin cancer. The SMDs and their 95% CIs were estimated between groups. For dose-response analysis, we applied the two-stage approach to compute the trend from the correlated log OR estimates across levels of PFASs [58]. At first, a restricted cubic spline model, with four knots at the 5th, 35th, 65th, and 95th percentiles of the levels of PFASs, was estimated using generalized least square regression, taking the correlation within each set of published ORs into account. Then, we tested the hypothesis that the coefficient of the second or the third spline is equal to 0 with the chi-square test and obtained the P value for non-linearity. If the P value is less than 0.05, it suggests a non-linearity dose-dependent relationship; otherwise, a linear dose-response relationship is considered [59]. The heterogeneity among studies was analyzed by the Q-test and I2 statistics in the χ2 test [60]. As heterogeneity was observed in the retrieved studies, the random-effects model was used to estimate the summary OR and SMD. Sources of heterogeneity across the studies and publication bias were evaluated according to methods described in previous publications [61]. The statistical analyses were performed by STATA 12.0 software (Stata Corp., College Station, TX).

Results

Characteristics of studies

After the exclusion of 1877 duplicates, 2462 out of 4339 studies were identified for further analysis. A total of 2390 studies were excluded after screening titles and abstracts, leading to 72 studies. Upon detailed evaluation, 32 studies were further excluded due to 9 lacking original numbers of cases and controls, 18 presenting outcome indicators not meeting the extraction criteria, and 5 analyzing PFAS concentrations in water (Fig. 1). Ultimately, 40 studies involving 748,188 participants met the inclusion criteria [17–56], with 13 articles [20, 24–26, 30–33, 39, 40, 46, 48, 56] further analyzed for dose-dependent relations. Among these participants, 14,905 diagnosed with cancer, including 4905 cases of breast cancer. The selected studies are detailed in Table 1.

Fig. 1.

Fig. 1

Open in a new tab

Flowchart for identification of studies

PFASs and cancer risk

Total PFAS exposure and its relation to different categories of cancer risk

The analysis included thirty-three papers comparing the highest versus the lowest exposure categories [17–20, 23–28, 30, 31, 33, 34, 37–48, 50, 51, 53–56]. It found that PFOS exposure significantly increased total cancer risk (OR = 1.12, 95% CI = 1.00-1.25, tau2 = 0.095, n = 51, I2 = 98.6%, Fig. 2 and Table 2). PFOA exposure also showed a tendency to increase cancer risk, though not statistically significant (OR = 1.07, 95% CI = 0.99-1.17, tau2 = 0.049, n = 85, I2 = 96.4%, Fig. S1 and Table 2). No significant evidence was found for exposures to PFDA, PFHxS, PFNA, or PFUnDA (Fig. S2 and Table 2).

Fig. 2.

Fig. 2

Open in a new tab

Forest plot of the association of PFOS exposure with the risk of total cancer. ES, effect size

Table 2.

Association between PFAS exposure and the risk of cancer

Cancer type PFASf Ng Case/Total OR 95% CI I2 Ph
Total cancer PFAS 229 14,905/748,188 1.03 0.95-1.10 87.8% <0.001
PFOA 85 12,358/742,935 1.07 0.99-1.17 96.7% <0.001
PFOS 51 10,156/175,947 1.12 1.00-1.25 98.6% <0.001
PFNA 36 5812/40,432 0.98 0.84-1.15 99.4% <0.001
PFHxS 35 5724/40,344 0.95 0.69-1.33 99.9% <0.001
PFDA 11 2032/4980 0.94 0.60-1.47 81.9% <0.001
PFUnDA 11 2627/5589 0.84 0.56-1.27 80.0% 0.001
Gastrointestinal (GI) Tract Cancera PFAS 18 3125/393,112 0.80 0.65-1.00 63.4% 0.137
PFOA 10 3135/293,112 0.78 (0.64-0.95) 1.00% 0.429
PFOS 5 2384/112,196 0.75 (0.38-1.48) 88.3% <0.001
Genitourinary Cancerb PFAS 86 8272/282,217 1.28 (1.21-1.36) 93.7% 0.015
PFOA 33 8261/268,817 1.14 (0.95-1.37) 81.2% <0.001
PFOS 20 6024/169,605 1.26 (0.98-1.61) 91.4% <0.001
PFNA 14 3227/22,466 1.16 (0.91-1.47) 76.9% <0.001
PFHxS 14 2799/21,610 1.18 (0.93-1.48) 80.3% <0.001
PFDA 4 953/1891 1.45 (1.04-2.02) 0.00% 0.923
Breast Cancer PFAS 60 4905/32,099 1.04 (0.88-1.23) 99.9% 0.355
PFOA 14 3931/32,099 1.03 (0.72-1.47) 93.4% <0.001
PFOS 13 3708/24,230 1.08 (0.82-1.41) 86.3% <0.001
PFNA 11 2893/22,600 0.94 (0.77-1.16) 67.6% 0.001
PFHxS 11 2893/22,600 1.07 (0.44-2.63) 98.9% <0.001
PFDA 6 894/2342 1.14 (0.62-2.10) 81.7% <0.001
PFUnDA 5 1797/3568 0.99 (0.61-1.61) 71.4% 0.007
Thyroid Cancer PFAS 25 4079/83,622 0.59 (0.45-0.77) 87.3% 0.368
PFOA 8 4079/83,622 0.81 (0.52-1.27) 73.9% <0.001
PFOS 5 1272/6723 1.06 (0.69-1.61) 71.7% 0.007
PFNA 5 1272/6723 0.64 (0.36-1.13) 85.7% <0.001
PFHxS 4 1184/6547 0.29 (0.07-1.23) 95.5% <0.001
Hematologic Cancerc PFAS 14 1100/17,253 1.05 (0.83-1.34) 37.7% 0.047
Respiratory System Cancerd PFAS 12 800/12,869 1.41 (0.93-2.15) 43.6% 0.099
Skin Cancer e PFAS 14 1377/27,982 1.19 (0.89-1.58) 0.00% <0.001
Open in a new tab

I2 measures the heterogeneity

Boldfaced values indicate a significant difference at the 5% level

OR odds ratio, PFOA perfluorooctanoic acid, PFOS perfluorooctane sulphonate, PFHxS perfluorohexane sulfonate, PFNA Perfluorononanoic acid, PFDA perfluorodecanoic acid, PFUnDA perfluoroundecanoic acid

aColorectal cancer; liver cancer; pancreatic cancer

bPancreatic cancer; kidney cancer; prostate cancer; testicular cancer; cervical cancer; ovarian cancer; uterine cancer

cLeukemia; multiple myeloma; non-hodgkin lymphoma

dLung cancer

eMelanoma of the skin

fPFAS was not analyzed separately if the number of included references was less than 3

gNumber of comparisons

hP value of Q-test for heterogeneity test

All cancers under consideration were divided into seven groups, gastrointestinal cancers, genitourinary cancers, breast cancer, thyroid cancer, hematological cancers, respiratory cancer, and skin cancer. The subgroup analysis revealed that PFAS exposure is associated with an elevated risk of genitourinary cancers (OR = 1.28, 95% CI = 1.21-1.36, I2 = 93.7%), but does not appear to increase the risk for other cancer categories (Table 2).

Different PFAS exposures and their associated risks for breast or genitourinary cancers

The analysis incorporated thirteen studies across two categories of cancer: breast cancer [18, 19, 24, 25, 28, 30, 31, 33, 34, 37, 41, 46, 51] and genitourinary cancers [19, 20, 34, 38, 39, 42, 45, 46, 48–51, 56], comparing the outcomes of the highest versus the lowest levels of exposure. PFDA exposure has been linked to an increased risk of genitourinary cancer (OR = 1.45, 95% CI = 1.04-2.02, I2 = 0.00%, Table 2). However, for the other PFAS compounds mentioned (PFOA, PFOS, PFHxS, PFNA, and PFUnDA), along with PFDA in the context of breast cancer, there was no association found with either breast or genitourinary cancer risks (Fig. S3 and Table 2).

The SMD between groups

PFASs and total cancer

Twelve studies were included for the analysis of continuous data [18, 21–23, 28–30, 35, 36, 42, 44, 52], revealing a tendency for higher levels of PFDA in cancer patients, although not statistically significant (SMD = 0.43, 95% CI = −0.01 ~ 0.87, tau2 = 0.478, n = 10, I2 = 97.5%, Fig. 3 and Table 3). No association was found between total cancer and exposure levels of PFOA, PFOS, PFHxS, and PFNA (Fig. S4 and Table 3).

Fig. 3.

Fig. 3

Open in a new tab

Forest plots of association between PFAS levels and different cancers. (A) PFDA levels and total cancer; (B) PFOA levels and breast cancer. SMD, standardized mean difference

Table 3.

Comparison of the levels of PFASs in different population

PFAS Total Cancer Breast Cancer
Na Case/control SMD (95%CI) Pb Na Case/control SMD (95%CI) Pb
PFOA 12 2565/4239

0.18

(−0.15 ~ 0.50)

 <0.001 6 1803/3089

0.41

(0.05 ~ 0.76)

 <0.001
PFOS 12 2565/4239

0.21

(−0.10 ~ 0.53)

 <0.001 6 1803/3089

0.35

(−0.07 ~ 0.77)

 <0.001
PFDA 10 1632/3265

0.43

(−0.01 ~ 0.87)

 <0.001 4 870/2116

0.28

(−0.06 ~ 0.62)

 <0.001
PFHxS 11 2534/4124

0.23

(−0.18 ~ 0.63)

 <0.001 5 1772/2974

0.21

(−0.37 ~ 0.79)

 <0.001
PFNA 11 2503/4112

−0.25

(−0.74 ~ 0.25)

 <0.001 5 1741/2962

0.14

(−0.43 ~ 0.70)

 <0.001
Open in a new tab

Boldfaced values indicate a significant difference at the 5% level

SMD standardized mean difference, PFAS perfluoroalkyl and polyfluoroalkyl substances, PFOA perfluorooctanoic acid, PFOS perfluorooctane sulphonate, PFHxS perfluorohexane sulfonate, PFNA Perfluorononanoic acid, PFDA perfluorodecanoic acid

aNumber of comparisons

bP value of Q-test for heterogeneity test

PFASs and breast cancer

Six studies were included for the analysis of continuous data [18, 28–30, 36, 52], and an increased level of PFOA was found in breast cancer patients (SMD = 0.41, 95% CI = 0.05 ~ 0.76, tau2 = 0.183, n = 6, I2 = 96.3%; Figs. 3, and Table 3). No association was found between breast cancer and exposure levels of PFOS, PFHxS, PFDA, and PFNA (Fig. S5 and Table 3).

The dose-response analysis

PFASs and cancer risk

In the dose-response analysis, thirteen studies assessed the association between serum PFAS levels and total cancer risk [20, 24–26, 30–33, 39, 40, 46, 48, 56]. The exposure to PFOS was found to be linearly associated with total cancer risk but did not increase the risk (OR, 0.995; 95% CI, 0.992-0.999, Q = 132.84, P < 0.001, Table 4, Fig. S6). Non-linearly association with total cancer risk were observed for PFDA, PFOA, PFNA, PFHxS or PFUnDA exposures (Table 4). Notably, PFDA exposure demonstrated a J-shaped nonlinear dose-dependent association with total cancer risk, initially decreasing before increasing at a concentration of about 0.6 μg/L (Fig. 4A). Conversely, exposure to PFOA, PFNA, PFHxS, and PFUnDA did not increase total cancer risk (Fig. S6).

Table 4.

Dose-dependent associations of PFAS exposures and cancer risks

PFAS Total Cancer Breast Cancer
Na Case/control OR (95%CI) Pb Pc Na Case/control OR (95%CI) Pb Pc
PFOA 18 6569/66,210 / 0.059 0.008 7 2136/13,863

0.968

(0.942-0.995)

 0.020 0.146
PFOS 18 6914/66,546

0.995

(0.992-0.999)

 <0.001 0.200 7 2145/13,863

0.997

(0.991-1.004)

 <0.001 0.657
PFDA 5 1445/2210 / 0.007 0.010 3 693/1458 / <0.001 0.004
PFHxS 15 6255/7702 / 0.126 0.040 5 1694/2170 / 0.243 0.009
PFNA 15 6255/7702 / 0.014 0.007 5 1694/2170

0.780

(0.695-0.876)

 0.002 0.974
PFUnDA 4 1219/1219 / 0.034 0.014 / / / / /
Open in a new tab

OR odds ratio, PFAS perfluoroalkyl and polyfluoroalkyl substances, PFOA perfluorooctanoic acid, PFOS perfluorooctane sulphonate, PFHxS perfluorohexane sulfonate, PFNA Perfluorononanoic acid, PFDA perfluorodecanoic acid

aNumber of comparisons

bP value for heterogeneity test

cP value for nonlinearity

Fig. 4.

Fig. 4

Open in a new tab

Dose-response curve for the association between PFDA exposure and different cancers. (A) total cancer; (B) breast cancer. Solid line: odds ratio; dashed line: 95%CI

PFASs and breast cancer risk

A subgroup analysis for breast cancer included seven studies to assess the dose-response association between PFASs and breast cancer risk [24, 25, 30–33, 46]. The analysis revealed that exposure to PFOS, PFOA, or PFNA was linearly associated with breast cancer risk but did not result in an increased risk (OR = 0.998, 95% CI = 0.991–1.004, Q = 48.15, P < 0.001 for PFOS; OR = 0.968, 95% CI = 0.942–0.995, Q = 36.5, P = 0.013 for PFOA; and OR = 0.780, 95% CI = 0.695–0.876, Q = 33.3, P = 0.004 for PFNA; Table 4; Fig. S7). For PFDA and PFHxS, the association with breast cancer risk was non-linear (Figs. 4 and S7). PFDA exposure, in particular, showed a J-shaped nonlinear dose-dependent association with breast cancer risk, showing an initial decrease followed by an increase at a concentration of about 1.3 μg/L (Fig. 4B). There was no increase in breast cancer risk associated with PFHxS exposure (Fig. S7).

Publication bias

Begg’s test was performed to evaluate the publication bias of selected literature. Fig. S8 displays a funnel plot of PFAS exposure and associated cancer risk in the dose-response analysis. Publication bias was not observed in our analysis (P = 0.14 for total cancer, P = 0.20 for breast cancer).

Discussion

A total of 40 papers were included in this meta-analysis, performing three different types of analyses to assess the relationship between PFAS exposure and cancer risk. The findings indicate that exposure to PFASs, especially PFDA, significantly raises the risk of genitourinary cancers, and PFDA exposure shows a dose-dependent increase in overall and breast cancer risk. Additionally, PFOS exposure is associated with an increased cancer risk, and elevated PFOA levels were significantly observed in breast cancer patients. This evidence supports the theory that specific PFAS compounds may independently contribute to various types of cancer, corroborating existing literature on the topic [62]. PFAS are known to be nephrotoxic, partly due to their role in accumulating high levels of these compounds in the renal parenchyma via oxidative stress and epigenetic mechanisms impacting tubular reabsorption [63]. Beyond their direct renal effects, PFAS also disrupt immune processes and hormonal balance, potentially harming reproductive organs in both genders [64, 65]. Emerging research underscores PFAS’s role in promoting genitourinary cancers, highlighted by studies in animal models that report renal abnormalities and abnormal testicular cell proliferation post-PFAS exposure. This growing body of evidence suggests a complex interaction between PFAS exposure and the development of genitourinary cancers, necessitating further investigation.

In vitro studies have linked PFOA and PFOS to tumorigenesis by interfering with the cell cycle and DNA methylation, affecting cells’ proliferation, invasion, and migration capabilities [66–69]. Early rodent studies also suggest PFOA and PFOS may promote liver tumor activity through the activation of the Pregnane X Receptor (PXR), potentially leading to morphological changes facilitating liver cancer cell migration [68, 70–72]. Our study revealed that PFOA (highest group exposure level ≥ 71.3 μg/L) accumulates more significantly in the serum of breast cancer patients. The primary routes of this accumulation are through skin contact and intestinal absorption. Given that exposure to PFASs typically involves a mixture of substances, with PFOA and PFOS being the most common, the synergistic effect of low concentrations of a PFOS and PFOA mixture on the carcinogenesis of human breast epithelial cells is particularly concerning [73]. The impact of PFDA on cancer, compared to PFOA and PFOS, remains understudied. We recommend further in-depth molecular and cellular research on PFDA, a long-chain perfluorinated hydrocarbon less commonly used in the environment than PFOA. Although structurally similar and more toxic than PFOA [74, 75], PFDA exhibits unique effects, such as promoting cell death and damaging normal glandular follicle formation at lower doses than PFOA [62]. Environmentally relevant doses of PFDA induced DNA damage in ovarian epithelial cells and may induce cellular carcinogenesis, suggesting a potential link between PFDA and the development of associated cancers [76].

We hypothesize the following pathways through which PFDA might contribute to carcinogenesis. Initially, PFDA disrupts oocyte maturation and survival by interfering with gap junctional intercellular communication (GJIC) and the balance of calcium in oocytes [77]. GJIC, essential for maintaining regular cell growth and function, has been linked to the tumor-promoting characteristics of various carcinogens. Research indicates that PFOA and PFDA suppress GJIC in a dose-dependent manner, with PFDA exhibiting a more potent effect possibly due to differences in their peptide chain lengths [78]. Furthermore, PFDA’s interaction with certain enzymatic processes is believed to be related to cancer development. Specifically, the inhibition of UDP-glucuronosyltransferase (UGT), a significant enzyme in phase II metabolism, has been used to assess the occurrence of cancer and the potentially toxic effects of exogenous biological agents [79–81]. Notably, a study identified that PFDA more significantly inhibits various UGT isoforms among 14 examined PFASs [82]. Additionally, the inflammatory microenvironment, often linked to cancer development and metastasis [83–86], appears to be substantially influenced by PFDA. It notably stimulates the production of IL-1β and IL18, leading to disorganized epithelial structures and infiltration of inflammatory cells in gastric tissues [87]. Another aspect involves PFDA inducing oxidative stress and impeding tumor cell apoptosis, mechanisms that could potentially facilitate cancer progression [88–90]. In certain cell and animal studies, PFDA was observed to impact hepatocyte proliferation, antioxidant mechanisms, and glycolipid metabolism, primarily via the activation of peroxisome proliferator-activated receptor (PPAR-α) [91, 92]. However, some initial rodent research did not associate PFDA with an increase in liver tumor activity [93, 94], a discrepancy possibly attributable to significant variations in PPARα levels between humans and rodents, casting doubt on this mechanism’s applicability to humans [95]. These four mechanisms collectively suggest a potential link between PFDA exposure and an elevated cancer risk. Importantly, while PFDA is frequently utilized to demonstrate the toxicological properties of similar PFAS or perfluorocarboxylic acids, its precise role in tumor biology remains largely unexplored. Future research is anticipated to provide a more comprehensive understanding of PFDA’s role in cancer mechanisms.

Despite these insights, our meta-analysis has limitations. The assessment was based solely on serum PFAS concentrations, not accounting for urinary concentrations. The heterogeneity of the included studies and variations in quality and quantity also pose challenges. Furthermore, the PFAS concentrations were drawn from the general population within safe exposure ranges, which, along with factors like age, sex, occupation, and geographic location, may affect the findings. Although only PFDA showed a positive dose-related association with cancer in our study, we cannot dismiss the possibility that PFASs might increase cancer incidence at higher doses or in more targeted future studies. Future research, potentially employing modeling approaches to increase PFAS doses, may provide more definitive results.

Conclusions

In conclusion, our meta-analysis suggests that exposure to PFASs, particularly PFOS, PFOA, and PFDA, may be a risk factor for cancer. These associations, underscored by the toxicological profiles of these substances, warrant further investigation to determine causality.

Supplementary information

Supplementary file 1 (2MB, docx)

(DOCX 2046 kb)

Funding

Wenxing Yang received funding from the National Natural Science Foundation of China (No. 32271178). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Data availability

All data are incorporated into the article and its online supplementary material.

Declarations

Ethical approval

This meta-analysis did not involve direct data collection from human or animal subjects and therefore did not require ethical approval from institutional or national research ethics committees.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

The original online version of this article was revised: In this article the title was incorrectly given as "Perfluoroalkyl and polyfluoroalkyl substances and Cancer Risk: Results from A Does-response Meta-analysis" but should have been "Perfluoroalkyl and polyfluoroalkyl substances and Cancer Risk: Results from A Dose-response Meta-analysis". The word does is replaced with dose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jingxuan Yang, Kui Zhang, and Jingyi Shi contributed equally to this work.

Change history

7/17/2024

A Correction to this paper has been published: 10.1007/s40201-024-00916-y

References

  • 1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]
  • 2.Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32. 10.3322/caac.21338. [DOI] [PubMed] [Google Scholar]
  • 3.Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366(9499):1784–93. 10.1016/s0140-6736(05)67725-2. [DOI] [PubMed] [Google Scholar]
  • 4.Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet. 1997;349(9063):1436–42. 10.1016/s0140-6736(96)07495-8. [DOI] [PubMed] [Google Scholar]
  • 5.Braun JM. Early-life exposure to EDCs: role in childhood obesity and neurodevelopment. Nat Rev Endocrinol. 2017;13(3):161–73. 10.1038/nrendo.2016.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.De Silva AO, Armitage JM, Bruton TA, Dassuncao C, Heiger-Bernays W, Hu XC, Kärrman A, Kelly B, Ng C, Robuck A, et al. PFAS exposure pathways for humans and wildlife: a synthesis of current knowledge and key gaps in understanding. Environ Toxicol Chem. 2021;40(3):631–57. 10.1002/etc.4935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Domingo JL, Nadal M. Human exposure to per- and polyfluoroalkyl substances (PFAS) through drinking water: a review of the recent scientific literature. Environ Res. 2019;177:108648. 10.1016/j.envres.2019.108648. [DOI] [PubMed] [Google Scholar]
  • 8.Sen P, Qadri S, Luukkonen PK, Ragnarsdottir O, McGlinchey A, Jäntti S, Juuti A, Arola J, Schlezinger JJ, Webster TF, et al. Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease. J Hepatol. 2022;76(2):283–93. 10.1016/j.jhep.2021.09.039. [DOI] [PubMed] [Google Scholar]
  • 9.Wang Z, Cousins IT, Scheringer M, Buck RC, Hungerbühler K. Global emission inventories for C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues from 1951 to 2030, part I: production and emissions from quantifiable sources. Environ Int. 2014;70:62–75. 10.1016/j.envint.2014.04.013. [DOI] [PubMed] [Google Scholar]
  • 10.Clarke DB, Bailey VA, Routledge A, Lloyd AS, Hird S, Mortimer DN, Gem M. Dietary intake estimate for perfluorooctanesulphonic acid (PFOS) and other perfluorocompounds (PFCs) in UK retail foods following determination using standard addition LC-MS/MS. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2010;27(4):530–45. 10.1080/19440040903476590. [DOI] [PubMed] [Google Scholar]
  • 11.Domingo JL. Health risks of dietary exposure to perfluorinated compounds. Environ Int. 2012;40:187–95. 10.1016/j.envint.2011.08.001. [DOI] [PubMed] [Google Scholar]
  • 12.Schwanz TG, Llorca M, Farré M, Barceló D. Perfluoroalkyl substances assessment in drinking waters from Brazil. France and Spain Sci Total Environ. 2016;539:143–52. 10.1016/j.scitotenv.2015.08.034. [DOI] [PubMed] [Google Scholar]
  • 13.Haug LS, Thomsen C, Brantsaeter AL, Kvalem HE, Haugen M, Becher G, Alexander J, Meltzer HM, Knutsen HK. Diet and particularly seafood are major sources of perfluorinated compounds in humans. Environ Int. 2010;36(7):772–8. 10.1016/j.envint.2010.05.016. [DOI] [PubMed] [Google Scholar]
  • 14.Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J. Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci. 2007;99(2):366–94. 10.1093/toxsci/kfm128. [DOI] [PubMed] [Google Scholar]
  • 15.Wang F, Liu W, Jin Y, Dai J, Yu W, Liu X, Liu L. Transcriptional effects of prenatal and neonatal exposure to PFOS in developing rat brain. Environ Sci Technol. 2010;44(5):1847–53. 10.1021/es902799f. [DOI] [PubMed] [Google Scholar]
  • 16.Wang F, Liu W, Ma J, Yu M, Jin Y, Dai J. Prenatal and neonatal exposure to perfluorooctane sulfonic acid results in changes in miRNA expression profiles and synapse associated proteins in developing rat brains. Environ Sci Technol. 2012;46(12):6822–9. 10.1021/es3008547. [DOI] [PubMed] [Google Scholar]
  • 17.Barry V, Winquist A, Steenland K. Perfluorooctanoic acid (PFOA) exposures and incident cancers among adults living near a chemical plant. Environ Health Perspect. 2013;121(11-12):1313–8. 10.1289/ehp.1306615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wielsøe M, Kern P, Bonefeld-Jørgensen EC. Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study. Environ Health. 2017;16(1):56. 10.1186/s12940-017-0269-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Omoike OE, Pack RP, Mamudu HM, Liu Y, Wang L. A cross-sectional study of the association between perfluorinated chemical exposure and cancers related to deregulation of estrogen receptors. Environ Res. 2021;196:110329. 10.1016/j.envres.2020.110329. [DOI] [PubMed] [Google Scholar]
  • 20.Shearer JJ, Callahan CL, Calafat AM, Huang WY, Jones RR, Sabbisetti VS, Freedman ND, Sampson JN, Silverman DT, Purdue MP, et al. Serum concentrations of per- and Polyfluoroalkyl substances and risk of renal cell carcinoma. J Natl Cancer Inst. 2021;113(5):580–7. 10.1093/jnci/djaa143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Cao L, Guo Y, Chen Y, Hong J, Wu J, Hangbiao J. Per−/polyfluoroalkyl substance concentrations in human serum and their associations with liver cancer. Chemosphere. 2022;296:134083. 10.1016/j.chemosphere.2022.134083. [DOI] [PubMed] [Google Scholar]
  • 22.Goodrich JA, Walker D, Lin X, Wang H, Lim T, McConnell R, Conti DV, Chatzi L, Setiawan VW. Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort. JHEP Rep. 2022;4(10):100550. 10.1016/j.jhepr.2022.100550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Liu M, Zhang G, Meng L, Han X, Li Y, Shi Y, Li A, Turyk ME, Zhang Q, Jiang G. 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. 2022;56(10):6144–51. 10.1021/acs.est.1c02850. [DOI] [PubMed] [Google Scholar]
  • 24.Velarde MC, Chan AFO, Sajo M, Zakharevich I, Melamed J, Uy GLB, Teves JMY, Corachea AJM, Valparaiso AP, Macalindong SS, et al. Elevated levels of perfluoroalkyl substances in breast cancer patients within the greater Manila area. Chemosphere. 2022;286(Pt 1):131545. 10.1016/j.chemosphere.2021.131545. [DOI] [PubMed] [Google Scholar]
  • 25.Itoh H, Harada KH, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Yokoyama K, Zhu J, Harada Sassa M, et al. Serum perfluoroalkyl substances and breast cancer risk in Japanese women: a case-control study. Sci Total Environ. 2021;800:149316. 10.1016/j.scitotenv.2021.149316. [DOI] [PubMed] [Google Scholar]
  • 26.Innes KE, Wimsatt JH, Frisbee S, Ducatman AM. Inverse association of colorectal cancer prevalence to serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in a large Appalachian population. BMC Cancer. 2014;14:45. 10.1186/1471-2407-14-45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Steenland K, Zhao L, Winquist A. A cohort incidence study of workers exposed to perfluorooctanoic acid (PFOA). Occup Environ Med. 2015;72(5):373–80. 10.1136/oemed-2014-102364. [DOI] [PubMed] [Google Scholar]
  • 28.Hurley S, Goldberg D, Wang M, Park JS, Petreas M, Bernstein L, Anton-Culver H, Nelson DO, Reynolds P. Breast cancer risk and serum levels of per- and poly-fluoroalkyl substances: a case-control study nested in the California teachers study. Environ Health. 2018;17(1):83. 10.1186/s12940-018-0426-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Bonefeld-Jorgensen EC, Long M, Bossi R, Ayotte P, Asmund G, Krüger T, Ghisari M, Mulvad G, Kern P, Nzulumiki P, et al. Perfluorinated compounds are related to breast cancer risk in Greenlandic Inuit: a case control study. Environ Health. 2011;10:88. 10.1186/1476-069x-10-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Feng Y, Bai Y, Lu Y, Chen M, Fu M, Guan X, Cao Q, Yuan F, Jie J, Li M, et al. Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: a case-cohort study in the Dongfeng-Tongji cohort. Environ Pollut. 2022;306:119345. 10.1016/j.envpol.2022.119345. [DOI] [PubMed] [Google Scholar]
  • 31.Mancini FR, Cano-Sancho G, Gambaretti J, Marchand P, Boutron-Ruault MC, Severi G, Arveux P, Antignac JP, Kvaskoff M. Perfluorinated alkylated substances serum concentration and breast cancer risk: evidence from a nested case-control study in the French E3N cohort. Int J Cancer. 2020;146(4):917–28. 10.1002/ijc.32357. [DOI] [PubMed] [Google Scholar]
  • 32.Wen X, Wang M, Xu X, Li T. Exposure to per- and Polyfluoroalkyl substances and mortality in U.S. adults: a population-based cohort study. Environ Health Perspect. 2022;130(6):67007. 10.1289/ehp10393. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 33.Bonefeld-Jørgensen EC, Long M, Fredslund SO, Bossi R, Olsen J. Breast cancer risk after exposure to perfluorinated compounds in Danish women: a case-control study nested in the Danish National Birth Cohort. Cancer Causes Control. 2014;25(11):1439–48. 10.1007/s10552-014-0446-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Vieira VM, Hoffman K, Shin HM, Weinberg JM, Webster TF, Fletcher T. Perfluorooctanoic acid exposure and cancer outcomes in a contaminated community: a geographic analysis. Environ Health Perspect. 2013;121(3):318–23. 10.1289/ehp.1205829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Yeung LW, Guruge KS, Taniyasu S, Yamashita N, Angus PW, Herath CB. Profiles of perfluoroalkyl substances in the liver and serum of patients with liver cancer and cirrhosis in Australia. Ecotoxicol Environ Saf. 2013;96:139–46. 10.1016/j.ecoenv.2013.06.006. [DOI] [PubMed] [Google Scholar]
  • 36.Li X, Song F, Liu X, Shan A, Huang Y, Yang Z, Li H, Yang Q, Yu Y, Zheng H, et al. Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population. Environ Health. 2022;21(1):83. 10.1186/s12940-022-00895-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Chang VC, Rhee J, Berndt SI, Moore SC, Freedman ND, Jones RR, Silverman DT, Gierach GL, Hofmann JN, Purdue MP. Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: an analysis in the prostate, lung, colorectal and ovarian Cancer screening trial. Int J Cancer. 2023;153(4):775–82. 10.1002/ijc.34487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Eriksen KT, Sørensen M, McLaughlin JK, Lipworth L, Tjønneland A, Overvad K, Raaschou-Nielsen O. Perfluorooctanoate and perfluorooctanesulfonate plasma levels and risk of cancer in the general Danish population. J Natl Cancer Inst. 2009;101(8):605–9. 10.1093/jnci/djp041. [DOI] [PubMed] [Google Scholar]
  • 39.Purdue MP, Rhee J, Denic-Roberts H, McGlynn KA, Byrne C, Sampson J, Botelho JC, Calafat AM, Rusiecki J. A nested case-control study of serum per- and Polyfluoroalkyl substances and testicular germ cell tumors among U.S. air Force servicemen. Environ Health Perspect. 2023;131(7):77007. 10.1289/ehp12603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Madrigal JM, Troisi R, Surcel HM, Öhman H, Kivelä J, Kiviranta H, Rantakokko P, Koponen J, Medgyesi DN, Kitahara CM, et al. Prediagnostic serum concentrations of per- and polyfluoroalkyl substances and risk of papillary thyroid cancer in the Finnish maternity cohort. Int J Cancer. 2024;154(6):979–91. 10.1002/ijc.34776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Tsai MS, Chang SH, Kuo WH, Kuo CH, Li SY, Wang MY, Chang DY, Lu YS, Huang CS, Cheng AL, et al. A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women. Environ Int. 2020;142:105850. 10.1016/j.envint.2020.105850. [DOI] [PubMed] [Google Scholar]
  • 42.Hardell E, Kärrman A, van Bavel B, Bao J, Carlberg M, Hardell L. Case-control study on perfluorinated alkyl acids (PFAAs) and the risk of prostate cancer. Environ Int. 2014;63:35–9. 10.1016/j.envint.2013.10.005. [DOI] [PubMed] [Google Scholar]
  • 43.Zhang T, Fu S, Yu K, Albanes D, Moore SC, Purdue MP, Stolzenberg-Solomon RZ. Nested case-control studies investigating serum Perfluorooctanoate and Perfluorooctane sulfonate levels and pancreatic ductal adenocarcinoma in two cohorts. Environ Health Perspect. 2023;131(10):107702. 10.1289/ehp13208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Li H, Yang M, Yang J, Seery S, Ma C, Liu Y, Zhang X, Li A, Guo H. Per- and polyfluoroalkyl substances and the associated thyroid cancer risk: a case-control study in China. Chemosphere. 2023;337:139411. 10.1016/j.chemosphere.2023.139411. [DOI] [PubMed] [Google Scholar]
  • 45.Alexander BH, Olsen GW. Bladder cancer in perfluorooctanesulfonyl fluoride manufacturing workers. Ann Epidemiol. 2007;17(6):471–8. 10.1016/j.annepidem.2007.01.036. [DOI] [PubMed] [Google Scholar]
  • 46.Winquist A, Hodge JM, Diver WR, Rodriguez JL, Troeschel AN, Daniel J, Teras LR. Case-cohort study of the association between PFAS and selected cancers among participants in the American Cancer Society's Cancer prevention study II LifeLink cohort. Environ Health Perspect. 2023;131(12):127007. 10.1289/ehp13174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.van Gerwen M, Colicino E, Guan H, Dolios G, Nadkarni GN, Vermeulen RCH, Wolff MS, Arora M, Genden EM, Petrick LM. Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk. EBioMedicine. 2023;97:104831. 10.1016/j.ebiom.2023.104831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Rhee J, Chang VC, Cheng I, Calafat AM, Botelho JC, Shearer JJ, Sampson JN, Setiawan VW, Wilkens LR, Silverman DT, et al. Serum concentrations of per- and polyfluoroalkyl substances and risk of renal cell carcinoma in the multiethnic cohort study. Environ Int. 2023;180:108197. 10.1016/j.envint.2023.108197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Cathey AL, Nguyen VK, Colacino JA, Woodruff TJ, Reynolds P, Aung MT. 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. 2023;33(5):687–98. 10.1038/s41370-023-00601-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Grice MM, Alexander BH, Hoffbeck R, Kampa DM. Self-reported medical conditions in perfluorooctanesulfonyl fluoride manufacturing workers. J Occup Environ Med. 2007;49(7):722–9. 10.1097/JOM.0b013e3180582043. [DOI] [PubMed] [Google Scholar]
  • 51.Moon J, Mun Y. The association between per- and polyfluoroalkyl substances (PFASs) and brain, esophageal, melanomatous skin, prostate, and lung cancer using the 2003–2018 US National Health and nutrition examination survey (NHANES) datasets. Heliyon. 2024;10(2) 10.1016/j.heliyon.2024.e24337. [DOI] [PMC free article] [PubMed]
  • 52.Frenoy P, Perduca V, Cano-Sancho G, Antignac JP, Severi G, Mancini FR. Application of two statistical approaches (Bayesian kernel machine regression and principal component regression) to assess breast cancer risk in association to exposure to mixtures of brominated flame retardants and per- and polyfluorinated alkylated substances in the E3N cohort. Environ Health. 2022;21(1):27. 10.1186/s12940-022-00840-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Lundin JI, Alexander BH, Olsen GW, Church TR. Ammonium perfluorooctanoate production and occupational mortality. Epidemiology. 2009;20(6):921–8. 10.1097/EDE.0b013e3181b5f395. [DOI] [PubMed] [Google Scholar]
  • 54.Gilliland FD, Mandel JS. Mortality among employees of a perfluorooctanoic acid production plant. J Occup Med. 1993;35(9):950–4. 10.1097/00043764-199309000-00020. [DOI] [PubMed] [Google Scholar]
  • 55.Girardi P, Merler E. A mortality study on male subjects exposed to polyfluoroalkyl acids with high internal dose of perfluorooctanoic acid. Environ Res. 2019;179(Pt A):108743. 10.1016/j.envres.2019.108743. [DOI] [PubMed] [Google Scholar]
  • 56.Rhee J, Barry KH, Huang WY, Sampson JN, Hofmann JN, Silverman DT, Calafat AM, Botelho JC, Kato K, Purdue MP, et al. A prospective nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and aggressive prostate cancer risk. Environ Res. 2023;228:115718. 10.1016/j.envres.2023.115718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Filippini T, Torres D, Lopes C, Carvalho C, Moreira P, Naska A, Kasdagli MI, Malavolti M, Orsini N, Vinceti M. Cadmium exposure and risk of breast cancer: a dose-response meta-analysis of cohort studies. Environ Int. 2020;142:105879. 10.1016/j.envint.2020.105879. [DOI] [PubMed] [Google Scholar]
  • 58.Cho E, Smith-Warner SA, Ritz J, van den Brandt PA, Colditz GA, Folsom AR, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med. 2004;140(8):603–13. 10.7326/0003-4819-140-8-200404200-00007. [DOI] [PubMed] [Google Scholar]
  • 59.Godos J, Micek A, Brzostek T, Toledo E, Iacoviello L, Astrup A, Franco OH, Galvano F, Martinez-Gonzalez MA, Grosso G. Egg consumption and cardiovascular risk: a dose-response meta-analysis of prospective cohort studies. Eur J Nutr. 2021;60(4):1833–62. 10.1007/s00394-020-02345-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 61.Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101. [PubMed] [Google Scholar]
  • 62.Halsne R, Tandberg JI, Lobert VH, Østby GC, Thoen E, Ropstad E, Verhaegen S. Effects of perfluorinated alkyl acids on cellular responses of MCF-10A mammary epithelial cells in monolayers and on acini formation in vitro. Toxicol Lett. 2016;259:95–107. 10.1016/j.toxlet.2016.08.004. [DOI] [PubMed] [Google Scholar]
  • 63.Wen LL, Lin CY, Chou HC, Chang CC, Lo HY, Juan SH. Perfluorooctanesulfonate mediates renal tubular cell apoptosis through PPARgamma inactivation. PLoS One. 2016;11(5):e0155190. 10.1371/journal.pone.0155190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Di Nisio A, Rocca MS, Sabovic I, De Rocco PM, Corsini C, Guidolin D, Zanon C, Acquasaliente L, Carosso AR, De Toni L, et al. Perfluorooctanoic acid alters progesterone activity in human endometrial cells and induces reproductive alterations in young women. Chemosphere. 2020;242:125208. 10.1016/j.chemosphere.2019.125208. [DOI] [PubMed] [Google Scholar]
  • 65.Šabović I, Cosci I, De Toni L, Ferramosca A, Stornaiuolo M, Di Nisio A, Dall'Acqua S, Garolla A, Foresta C. Perfluoro-octanoic acid impairs sperm motility through the alteration of plasma membrane. J Endocrinol Investig. 2020;43(5):641–52. 10.1007/s40618-019-01152-0. [DOI] [PubMed] [Google Scholar]
  • 66.Pierozan P, Jerneren F, Karlsson O. Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. Arch Toxicol. 2018;92(5):1729–39. 10.1007/s00204-018-2181-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Liu W, Irudayaraj J. Perfluorooctanoic acid (PFOA) exposure inhibits DNA methyltransferase activities and alters constitutive heterochromatin organization. Food Chem Toxicol. 2020;141:111358. 10.1016/j.fct.2020.111358. [DOI] [PubMed] [Google Scholar]
  • 68.Butenhoff JL, Chang SC, Olsen GW, Thomford PJ. Chronic dietary toxicity and carcinogenicity study with potassium perfluorooctanesulfonate in Sprague Dawley rats. Toxicology. 2012;293(1-3):1–15. 10.1016/j.tox.2012.01.003. [DOI] [PubMed] [Google Scholar]
  • 69.Pierozan P, Cattani D, Karlsson O. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) induce epigenetic alterations and promote human breast cell carcinogenesis in vitro. Arch Toxicol. 2020;94(11):3893–906. 10.1007/s00204-020-02848-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Abdellatif AG, Préat V, Taper HS, Roberfroid M. The modulation of rat liver carcinogenesis by perfluorooctanoic acid, a peroxisome proliferator. Toxicol Appl Pharmacol. 1991;111(3):530–7. 10.1016/0041-008x(91)90257-f. [DOI] [PubMed] [Google Scholar]
  • 71.Abdellatif AG, Préat V, Vamecq J, Nilsson R, Roberfroid M. Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin. Carcinogenesis. 1990;11(11):1899–902. 10.1093/carcin/11.11.1899. [DOI] [PubMed] [Google Scholar]
  • 72.Kodama S, Negishi M. Pregnane X receptor PXR activates the GADD45beta gene, eliciting the p38 MAPK signal and cell migration. J Biol Chem. 2011;286(5):3570–8. 10.1074/jbc.M110.179812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Pierozan P, Kosnik M, Karlsson O. High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis. Environ Int. 2023;172:107746. 10.1016/j.envint.2023.107746. [DOI] [PubMed] [Google Scholar]
  • 74.Olson CT, Andersen ME. The acute toxicity of perfluorooctanoic and perfluorodecanoic acids in male rats and effects on tissue fatty acids. Toxicol Appl Pharmacol. 1983;70(3):362–72. 10.1016/0041-008x(83)90154-0. [DOI] [PubMed] [Google Scholar]
  • 75.Vanden Heuvel JP. Perfluorodecanoic acid as a useful pharmacologic tool for the study of peroxisome proliferation. Gen Pharmacol. 1996;27(7):1123–9. 10.1016/0306-3623(95)00126-3. [DOI] [PubMed] [Google Scholar]
  • 76.Qin Y, Yuan X, Cui Z, Chen W, Xu S, Chen K, Wang F, Zheng F, Ni H, Shen HM, et al. Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells. Ecotoxicol Environ Saf. 2023;265:115503. 10.1016/j.ecoenv.2023.115503. [DOI] [PubMed] [Google Scholar]
  • 77.Dominguez A, Salazar Z, Betancourt M, Ducolomb Y, Casas E, Fernandez F, Bahena I, Salomon A, Teteltitla M, Martinez R, et al. Effect of perfluorodecanoic acid on pig oocyte viability, intracellular calcium levels and gap junction intercellular communication during oocyte maturation in vitro. Toxicol in Vitro. 2019;58:224–9. 10.1016/j.tiv.2019.03.041. [DOI] [PubMed] [Google Scholar]
  • 78.Upham BL, Deocampo ND, Wurl B, Trosko JE. Inhibition of gap junctional intercellular communication by perfluorinated fatty acids is dependent on the chain length of the fluorinated tail. Int J Cancer. 1998;78(4):491–5. [DOI] [PubMed] [Google Scholar]
  • 79.Du Z, Cao YF, Li SN, Hu CM, Fu ZW, Huang CT, Sun XY, Liu YZ, Yang K, Fang ZZ. Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters. Chemosphere. 2018;197:7–13. 10.1016/j.chemosphere.2018.01.010. [DOI] [PubMed] [Google Scholar]
  • 80.Yang K, Fu ZW, Cao YF, Li SN, Du Z, Sun XY, Liu YZ, Yang K, Fang ZZ. New insights for risks of chlorophenols (CPs) exposure: inhibition of UDP-glucuronosyltransferases (UGTs). Chemosphere. 2018;206:9–16. 10.1016/j.chemosphere.2018.04.148. [DOI] [PubMed] [Google Scholar]
  • 81.Rogan EG, Badawi AF, Devanesan PD, Meza JL, Edney JA, West WW, Higginbotham SM, Cavalieri EL. Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: potential biomarkers of susceptibility to cancer. Carcinogenesis. 2003;24(4):697–702. 10.1093/carcin/bgg004. [DOI] [PubMed] [Google Scholar]
  • 82.Liu YZ, Zhang ZP, Fu ZW, Yang K, Ding N, Hu LG, Fang ZZ, Zhuo X. Per- and polyfluoroalkyl substances display structure-dependent inhibition towards UDP-glucuronosyltransferases. Environ Pollut. 2019;254(Pt B):113093. 10.1016/j.envpol.2019.113093. [DOI] [PubMed] [Google Scholar]
  • 83.Tili E, Michaille JJ, Wernicke D, Alder H, Costinean S, Volinia S, Croce CM. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci USA. 2011;108(12):4908–13. 10.1073/pnas.1101795108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell. 2012;22(5):645–55. 10.1016/j.ccr.2012.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339(6117):286–91. 10.1126/science.1232227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Bu P, Wang L, Chen KY, Srinivasan T, Murthy PK, Tung KL, Varanko AK, Chen HJ, Ai Y, King S, et al. A miR-34a-numb feedforward loop triggered by inflammation regulates asymmetric stem cell division in intestine and Colon Cancer. Cell Stem Cell. 2016;18(2):189–202. 10.1016/j.stem.2016.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Zhou X, Dong T, Fan Z, Peng Y, Zhou R, Wang X, Song N, Han M, Fan B, Jia J, et al. Perfluorodecanoic acid stimulates NLRP3 inflammasome assembly in gastric cells. Sci Rep. 2017;7:45468. 10.1038/srep45468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Xu M, Zhang T, Lv C, Niu Q, Zong W, Tang J, Liu R. Perfluorodecanoic acid-induced oxidative stress and DNA damage investigated at the cellular and molecular levels. Ecotoxicol Environ Saf. 2019;185:109699. 10.1016/j.ecoenv.2019.109699. [DOI] [PubMed] [Google Scholar]
  • 89.Dong T, Peng Y, Zhong N, Liu F, Zhang H, Xu M, Liu R, Han M, Tian X, Jia J, et al. Perfluorodecanoic acid (PFDA) promotes gastric cell proliferation via sPLA2-IIA. Oncotarget. 2017;8(31):50911–20. 10.18632/oncotarget.17284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Roque AT, Gambeloni RZ, Felitti S, Ribeiro ML, Santos JC. Inflammation-induced oxidative stress in breast cancer patients. Med Oncol. 2015;32(12):263. 10.1007/s12032-015-0709-5. [DOI] [PubMed] [Google Scholar]
  • 91.Cheng X, Klaassen CD. Critical role of PPAR-alpha in perfluorooctanoic acid- and perfluorodecanoic acid-induced downregulation of Oatp uptake transporters in mouse livers. Toxicol Sci. 2008;106(1):37–45. 10.1093/toxsci/kfn161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Cimini A, Cristiano L, Bernardo A, Farioli-Vecchioli S, Stefanini S, Cerù MP. Presence and inducibility of peroxisomes in a human glioblastoma cell line. Biochim Biophys Acta. 2000;1474(3):397–409. 10.1016/s0304-4165(00)00036-2. [DOI] [PubMed] [Google Scholar]
  • 93.Kim SC, Hong JT, Jang SJ, Kang WS, Yoo HS, Yun YP. Formation of 8-oxodeoxyguanosine in liver DNA and hepatic injury by peroxisome proliferator clofibrate and perfluorodecanoic acid in rats. J Toxicol Sci. 1998;23(2):113–9. 10.2131/jts.23.2_113. [DOI] [PubMed] [Google Scholar]
  • 94.Borges T, Peterson RE, Pitot HC, Robertson LW, Glauert HP. Effect of the peroxisome proliferator perfluorodecanoic acid on the promotion of two-stage hepatocarcinogenesis in rats. Cancer Lett. 1993;72(1-2):111–20. 10.1016/0304-3835(93)90019-6. [DOI] [PubMed] [Google Scholar]
  • 95.Klaunig JE, Babich MA, Baetcke KP, Cook JC, Corton JC, David RM, DeLuca JG, Lai DY, McKee RH, Peters JM, et al. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol. 2003;33(6):655–780. 10.1080/713608372. [DOI] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

Supplementary file 1 (2MB, docx)

(DOCX 2046 kb)

Data Availability Statement

All data are incorporated into the article and its online supplementary material.

Articles from Journal of Environmental Health Science and Engineering are provided here courtesy of Springer

RESOURCES