Table 1.
Epidemiologic studies of PFAS and cancer
| Study | Design | PFAS Studied* | Exposure Assessment | Measured or estimated PFAS serum concentrations† | Cancer types | Population | Size | Control for confounding | Main findings* | Notes on study design, methods and findings |
|---|---|---|---|---|---|---|---|---|---|---|
| Cohort Studies and Case-Cohort Studies (N=16) | ||||||||||
| Occupational Cohorts | ||||||||||
| Occupational Cohort, Decatur, Alabama, USA | ||||||||||
| Alexander et al. 2003 | Occupational cohort mortality study | Primarily PFOS | Job history, categorized as no exposure, low potential exposure and high potential exposure (based on knowledge of major job-specific serum levels), some analyses also included years in each category | From study of random sample of workers (Olsen et al., 2003) Geometric mean (GM) and range of serum concentrations: Chemical plant workers (n=126, “low exposure” and “high exposure”)- PFOS 941 (91–10,600) ng/ml; PFOA 899 (21–6,160) ng/ml; Film plant workers (n=60, “no exposure”)- PFOS 136 (15–946) ng/ml; PFOA 49 (6–298) ng/ml |
Reported on several cancer categories including all malignant neoplasms; all digestive organs and peritoneum; esophagus; large intestine; biliary passages and liver; all respiratory system; bronchus, trachea and lung; breast; urinary organs; bladder and other urinary; malignant melanoma; and lymphatic and hematopoietic | Workers with at least 1 year of cumulative employment during 1961–1997 at a manufacturing site producing PFOS | 2083 cohort members, followed through 1998, 145 deaths, including 39 cancer deaths (highest number of deaths for a specific reported cancer type was 15 for cancers of the bronchus, trachea and lung) | Calculated standardized mortality ratios (SMRs) for comparison with state or regional mortality rates standardized by age, gender, and calendar period | Risk of bladder cancer among plant workers (3 deaths) compared with Alabama population: SMR and 95% confidence interval (CI) 4.81 (0.99–14.06), all bladder cancer deaths among high-exposed workers | -No quantitative exposure assessment -Dose-response analysis not possible because all bladder cancer deaths were in highest exposure group. |
| Olsen et al. 2004 | Retrospective occupational cohort study of episodes of care of workers | Primarily PFOS | Job history, categorized as working at exposed (chemical) plant or working at non-exposed (film) plant; some analyses were restricted to long-term workers | From study of random sample of workers (Olsen et al., 2003) Geometric mean (GM) and range of serum concentrations: Chemical plant workers (n=126, “low exposure” and “high exposure”)- PFOS 941 (91–10,600) ng/ml; PFOA 899 (21–6,160) ng/ml; Film plant workers (n=60, “no exposure”)- PFOS 136 (15–946) ng/ml; PFOA 49 (6–298) ng/ml |
Reported on several cancer categories including colon, liver, rectum, lower respiratory tract, malignant melanoma, bladder, prostate and thyroid; also reported on some benign neoplasms | Workers as of 1/1/1993 with at least 1 year of employment at a manufacturing site producing PFOS (same site as Alexander et al. 2003) | 652 employees at a plant that produced PFOS and 659 employees at a non-exposed plant (film plant), followed during 1993–1998 (highest number of episodes of care for a specific cancer type in PFOS plant workers was 5 (for melanoma and prostate cancer) | Compared each group of workers with other 3M workers using indirect standardization by age in 3 categories (<40, 40–49 and ≥50 years) and sex | Comparison used the ratio of two indirect standardized ratios (referred to as “risk ratio episodes of care (RREpC))”. Comparable episodes of care were observed for most diseases between PFOS-exposed and non-exposed workers, notable associations for malignancies [RREpC (95% CI)] included: colon cancer (n=4 among exposed workers) 5.4 (0.5->100), prostate cancer (n=5 among exposed workers) 7.7 (0.9->100) and melanoma (n=5 among exposed workers) 12 (1.0->100). | -Full time employees who retired were eligible for care after retirement and were included in the study. -No dose-response analysis. |
| Alexander and Olsen, 2007 | Retrospective occupational cohort study via survey of occupational cohort (medical records confirmation sought for self-reported cancers) and death certificate matching. | Primarily PFOS | Job history, categorized as no exposure, low potential exposure and high potential exposure (based on knowledge of major job-specific serum levels), some analyses also included a cumulative exposure measure that considered weighted years in each category | From study of random sample of workers (Olsen et al., 2003) Geometric mean (GM) and range of serum concentrations: Chemical plant workers (n=126, “low exposure” and “high exposure”)- PFOS 941 (91–10,600) ng/ml; PFOA 899 (21–6,160) ng/ml; Film plant workers (n=60, “no exposure”)- PFOS 136 (15–946) ng/ml; PFOA 49 (6–298) ng/ml |
Bladder cancer only | Workers with at least 1 year of cumulative employment at a manufacturing site producing PFOS (same site as Alexander et al. 2003) | 1588 in analysis (included 188 who had died and 1400 who had not died and responded to the survey), follow up through 2002 (total of 11 bladder cancer cases) | Calculated standardized incidence ratios (SIR) with the U.S. population (SEER data) as the reference population, standardized by age, gender and calendar period. Rate ratios (RRs) for internal comparisons were adjusted for age and gender | Bladder cancer incidence compared with SEER reference population [SIR (95% CIs)]: group with ever high exposure (6 cases) 1.74 (0.64–3.79); group with ever low exposure (7 cases) 2.26 (0.91–4.67) In internal comparison, bladder cancer incidence RRs (95% CIs) from lowest to highest exposure groups (total of 11 cases in all groups): 1.0, 0.83 (0.15–4.65), 1.92 (0.30–12.06), 1.52 (0.21–10.99) |
-Data limited to self-reported cancers that were not disconfirmed on validation and cancers identified on death certificates, numbers low -Exposure classification was limited -Response rate to survey among surviving cohort members was 74% overall and 67% in the most highly exposed group. - Although work histories started in 1961, the follow-up period for the incidence analysis started in 1970 because SEER reference data were only available for 1970–1999. -Internal comparisons were limited by the small number of cases. -Some suggestion of dose-response pattern but not monotonic. |
| Grice et al. 2007 | Retrospective follow-up study via survey of occupational cohort (medical records confirmation sought for self-reported cancers). | Primarily PFOS | Job history, categorized as no exposure, low potential exposure and high potential exposure (based on knowledge of major job-specific serum levels), some analyses also included a cumulative exposure measure that considered weighted years in each category | From study of random sample of workers (Olsen et al., 2003) Geometric mean (GM) and range of serum concentrations: Chemical plant workers (n=126, “low exposure” and “high exposure”)- PFOS 941 (91–10,600) ng/ml; PFOA 899 (21–6,160) ng/ml; Film plant workers (n=60, “no exposure”)- PFOS 136 (15–946) ng/ml; PFOA 49 (6–298) ng/ml |
Reported on several cancer types including breast, colon, liver, melanoma, prostate and thyroid | Workers with at least 1 year of cumulative employment at a manufacturing site producing PFOS (same site as Alexander et al. 2003) | 1400 survey respondents out of 1895 surviving current and former employees, plus death certificate information for 188 decedents, follow up through 2002 (highest number of cases for an analyzed cancer type was 54 for prostate cancer) | Calculated odds ratios for each exposure group relative to the never exposed group adjusted for age and gender | Only the 3 types of cancer with a substantial number of cases were analyzed. -For PFOS exposure, classified as ever low or high, low or high ≥1 year, or high >1 year, respectively; ORs (95% CIs) compared with never exposed group: colon cancer (total of 44 cases of which 22 were self-reported) 1.21 (0.51–2.87), 1.37 (0.57–3.30), 1.69 (0.68–4.17); prostate cancer (total of 54 cases of which 29 were self-reported) 1.34 (0.62–2.91), 1.36 (0.61–3.02), 1.08 (0.44–2.69) |
-Analysis used self-reported cancers and cancers recorded on death certificates (except for melanoma for which only validated cases were used), numbers low -Exposure classification was limited -Response rate to survey among surviving cohort members was 74% overall and 67% in the most highly exposed group. -Some suggestion of dose-response pattern for colon cancer and prostate cancer (not monotonic for prostate cancer). |
| Occupational cohort, Parkersburg, West Virginia, USA | ||||||||||
| Leonard et al, 2008 | Occupational cohort mortality study | PFOA | Workers at an exposed plant were compared to the general population and to a regional worker population | Sample of 1025 volunteers among active employees in 2004 (Sakr et al., 2007) - Serum PFOA concentrations: range 5–9,550 ng/ml; median 494 among current PFOA workers, and 114–195 among other categories of workers | Reported on 29 cancer categories | Workers with any history of working during 1948–2002 at a plant that used PFOA | 6,027 workers, mortality follow up through 2002; 806 deaths including 234 cancer deaths (highest number of deaths for a specific cancer type was 66 for lung cancer) | SMRs calculated relative to 3 reference populations (U.S. population, West Virginia population and DuPont regional worker population) standardized by sex, 5-year age category and 5-year time period | In analyses of SMRs relative to regional worker population [SMR (95% CI)]: kidney cancer mortality (12 deaths) 1.8 (0.9,3.2); laryngeal cancer mortality (3 deaths) 1.9 (0.4–5.7); thyroid and other endocrine cancer mortality (3 deaths) 6.3 (1.3–18.4); bone cancer mortality (2 deaths) 6.5 (0.8–23.4) |
-No analysis by exposure level, small numbers of cancers -Analyses of SMRs in comparison with the U.S. or West Virginia populations were likely affected by healthy worker bias, analyses in comparison with the regional worker population reduced that bias. |
| Steenland and Woskie, 2012 | Occupational cohort mortality study | PFOA | Workers at an exposed plant were compared to the general population and to a regional worker population; also estimated cumulative serum concentration (ppm-years) using work histories and a job-exposure matrix based on models using historical measured serum concentrations to estimate annual serum concentrations by job category/group | Estimated average annual serum PFOA concentration: mean 350 ng/ml, median 230 ng/ml | Reported on several cancer categories including all cancers, liver, pancreas, lung, breast, prostate, testis, kidney, bladder, mesothelioma, non-Hodgkin’s lymphoma and leukemia | Workers with any history of working during 1948–2002 at a plant that used PFOA and who had exposure estimates and dates of birth (subset of population in Leonard et al. 2008) | 5,791 workers, mortality follow- up through 2008; 1084 deaths, including 304 cancer deaths (highest number of deaths for a specific cancer type was 84 for lung cancer) | SMRs calculated using NIOSH Life Table Analysis System, details of standardization variables and categories not specified | In analyses relative to a regional worker population [SMRs (95% CIs) for quartiles 1–4 of estimated cumulative exposure]: -Mesothelioma death (6 deaths) 0, 0, 1.73 (0.04–9.65), 6.27 (2.04–14.63), trend p-value 0.02 with no lag; and 0, 0, 3.08 (0.37–11.12), 4.66 (1.27–11.93), trend p-value=0.15 with 10-year lag -Kidney cancer death (12 deaths) 1.07 (0.02–3.62), 1.37 (0.28–3.99), 0 (0.00–1.42), 2.66 (1.15,5.24), trend p-value 0.02 with no lag; and 1.05 (0.13–3.79), 0.87 (0.11–3.15), 0.44 (0.01–2.44), and 2.82 (1.13–5.81), trend p-value=0.02, with 10-year lag |
-Cumulative serum levels estimated based on occupation and a large number of measured levels (Woskie et al. 2012) -Association between estimated PFOA exposure and mesothelioma was likely due to confounding by other occupational exposures, such as asbestos exposure. -Evidence of dose-response relationship for mesothelioma and kidney cancer, although not monotonic for kidney cancer |
| Consonni et al. 2013 | Occupational cohort mortality study | PFOA | Compared plant workers to general population, also estimated time-varying cumulative exposure (in arbitrary relative unit-years based on occupational histories and a job-exposure matrix) | PFOA serum concentrations or estimates were not provided (the main focus of the study was tetrafluoro-ethylene exposure) | Reported on 22 cancer categories | Workers in 6 plants (the largest of which was the Dupont plant in West Virginia, United States.; other plants were in New Jersey, United States; Germany; Italy; the Netherlands; and the United Kingdom) | 4,773 male tetrafluoro-ethylene (TFE) workers exposed to TFE through 2002 were included in the analysis for PFOA; mortality follow up through 2001–2008 (varying by work site) (highest number of deaths for a specific cancer type across all exposure groups in the PFOA analysis was 59 for lung cancer) | Calculated SMRs relative to national reference rates for males only, standardized by 5-year age categories and 5-year calendar periods | SMRs (95% CIs) for low, medium and high PFOA exposure groups (excluding never exposed group) (from web table 3): liver cancer mortality (7 deaths among exposed) 0.70 (0.02–3.87), 1.25 (0.15–4.52), 2.14 (0.58–5.49), trend p-value 0.24; kidney cancer mortality (10 deaths among exposed) 1.57 (0.32–4.59), 1.50 (0.31–4.39), 2.00 (0.54–5.12), trend p-value 0.28; pancreatic cancer mortality (10 deaths among exposed) 0, 1.30 (0.35–3.33), 1.84 (0.67–4.00), trend p-value 0.34; leukemia mortality (11 deaths among exposed) 1.64 (0.45–4.20), 1.35 (0.28–3.94), 1.85 (0.50–4.74), trend p-value 0.58 |
-Focus was on TFE exposure estimated by job-exposure matrix, authors could not effectively separate PFOA exposure from TFE exposure for most cancers (PFOA was used to polymerize TFE). Stratification by levels of TFE and PFOA exposure simultaneously led to small counts and many strata with no cases (web table 4). SMRs could be calculated across PFOA exposure levels for kidney cancer among the group with medium TFE exposure [SMR (95% CI)]: low PFOA 3.20 (0.08–17.83); medium PFOA 2.15 (0.44–6.29), high PFOA 9.58 (1.16–34.56). Similar comparisons were not possible for other cancer types. -SMRs used national reference rates -No clear trends across exposure groups but some suggestion of a trend for liver cancer and kidney cancer |
| Steenland et al. 2015 | Occupational cohort incidence study (medical records confirmation sought for self-reported cancers) | PFOA | Modeled time-varying lifetime serum cumulative concentration (sum of estimated annual serum concentrations up to a given year), created by combining occupational estimates based on a work history and a job-exposure matrix (as in Steenland and Woskie, 2012) and residential exposure (from a multistage model estimating serum concentrations based on drinking water exposures). | Measured serum PFOA concentration in 2005–2006 (n=1881): mean 325 ng/ml, median 113 ng/ml | Reported on cancers with at least 20 cases, including bladder, colorectal, prostate and melanoma | Workers with any history of working during 1948–2002 at a plant that used PFOA and who had an interview or proxy interview and exposure estimates (subset of population in Leonard et al. 2008) | 3,713 workers, incidence follow-up through final interview (during 2008–2011), 335 cancer cases with medical records validation (highest number of cases in the analysis for a specific cancer type for which results were reported was 129 for prostate cancer) | Cox regression models with age as time scale, controlled for gender, race (Caucasian/non-Caucasian), education (4 categories), body mass index (4 categories) and time-varying smoking (current, former, never) and alcohol consumption (current, former, never) | Results reported only for sites with more than 20 cases (bladder, colorectal, prostate, melanoma)-rate ratios (RRs) and 95% CIs for quartiles 2–5 of estimated cumulative serum concentration relative to quartile 1: -Prostate cancer (129 cases) 1.92 (0.56–6.58), 1.89 (0.57–6.34), 2.15 (0.64–7.26), trend p-value=0.10 with 10-year lag -Bladder cancer (29 cases) 0.55 (0.12–2.61), 0.47 (0.10–2.21), 0.31 (0.06–1.54), trend p-value=0.03 with 10-year lag |
-Serum levels estimated based on occupation and a large number of measured levels (Woskie et al. 2012) as well as estimated residential exposures (Shin, et al, 2011b) -Interviews available for 79% of workers who had not died and 48% of workers who had died -No clear trends across exposure levels for prostate cancer, decreasing trend in RRs across exposure levels for bladder cancer -Negative trend for bladder cancer contrasts with bladder cancer findings from earlier studies on same cohort [SMR=1.30 (0.52–2.69) for bladder cancer mortality in Leonard, et. al, 2008; SMRs >1 for quartiles 1 and 2 relative to regional worker cohort in Steenland and Woskie, 2012] |
| Occupational cohort, Cottage Grove, MN, USA | ||||||||||
| Gilliland and Mandel, 1993 | Occupational cohort mortality study | Primarily PFOA | Job history, categorized as exposed (at least 1 month in chemical division) or unexposed; some analyses used months worked in chemical division | No measurements or estimates of PFOA serum concentrations are provided. Information available from a separate study of 122 plant workers voluntarily tested who did not take cholesterol-reducing medication (Olsen and Zobel, 2007)(n=122)- serum concentrations [median (range)]: PFOA- 950 (10–92,030) ng/ml; PFOS 450 (30–4790) ng/ml | Reported on several cancer categories including all cancer, gastrointestinal, respiratory, breast, genital, and lymphopoietic among women; and all cancer, all gastrointestinal, colon, pancreas, all respiratory, lung, prostate, testis, bladder, and lymphopoietic among men | Workers employed for at least 6 months during 1947–1983 at a plant producing PFOA | 3,573 workers, mortality follow-up through 1989, 398 deaths including 120 total cancer deaths (highest number of deaths for a specific cancer type analyzed was 29 for male lung cancer) | Calculated “stratified SMRs” relative to U.S. population and Minnesota population for sexes separately, standardized by 5-year age category, and calendar period; calculated RRs for internal comparisons using proportional hazard models with time from first employment as the time scale, controlling for age and year at first employment and duration of employment, stratified by gender | -SMRs relative to Minnesota population for men employed in the chemical division [SMR (95% CI)]: prostate cancer mortality (4 deaths among exposed) 2.03 (0.55–4.59); pancreatic cancer (4 deaths among exposed) 1.96 (0.53–5.01); testicular cancer (1 death among exposed) 2.28 (0.03–12.66) -Internal comparison using proportional hazards models [RR (95% CI)]: prostate cancer mortality (6 deaths): RR per 1-year increase in time in chemical division 1.13 (1.01–1.27), p=0.03 |
-Workers categorized as exposed or non-exposed based on job histories (exposed if 1 or more months in chemical division), also did analyses by number of months in chemical division -SMRs were calculated using a U.S. referent population for females and a Minnesota reference population for males -No clear dose-response relationships although SMRs relative to the MN population were higher for men employed in chemical division than for all male employees for prostate, pancreatic and testicular cancer mortality. |
| Lundin et al. 2009 | Occupational cohort mortality study | Primarily PFOA | Job history, categorized as definite exposure, probable exposure and no exposure and by time in definite exposure job (≥6 months vs. <6 months); also estimated cumulative exposure based on duration of employment and a job exposure matrix with relative exposure weights | See above from Olsen and Zobel, 2007. In addition, Lundin, et al provide median serum concentrations for job categories based on serum PFOA concentrations measured on 131 employees in 2000: Definite exposure jobs- median 2600–5200 ng/ml, probable exposure jobs-median 300–1500 ng/ml | Reported on several cancer categories including all cancers; biliary passages and liver; pancreas; trachea, bronchus and lung; prostate; and bladder and other urinary organs | Workers employed for at least 365 days during 1947–1997 at a plant producing PFOA (overlaps with population in Gilliland and Mandel, 1993) | 3,993 workers, mortality follow-up through 2002, 807 deaths including 246 cancer deaths (highest number of deaths for a specific cancer type reported was 75 for cancer of the trachea, bronchus and lung) | Calculated SMRs relative to Minnesota population, standardized by age, sex and calendar period; Calculated hazard ratios (HRs) for internal comparisons using Cox regression models with time from entry into the cohort as the time scale, controlling for sex and year of birth (also considered wage type and smoking) | -SMR (95% CI) relative to Minnesota population for prostate cancer: 2.1 (0.4–6.1) in ever definite exposure group (3 deaths), 0.9 (0.4–1.8) in the ever probable/never definite exposure group (9 cases) and 0.4 (0.1–0.9) in the never exposed group (4 cases) -Internal comparisons for prostate cancer (16 cases) [HR (95% CI)]: moderate/high vs. low exposure by job classification 3.2 (1.0–10.3); group with highest vs. lowest cumulative exposure 3.7 (1.3–10.4) |
-Small number of specific cancers (e.g., 3 liver, 13 pancreas), few sites reported -Some SMRs calculated relative to Minnesota population -Internal analyses (for liver, pancreas and prostate cancers) used exposure categorized by job classification and cumulative exposure estimated based on job histories and exposure weights for specific job categories -Some evidence for dose-response relationship for prostate cancer by job classification category [HR and 95% CI relative to low exposure jobs: 3.0 (0.9–9.7) for moderate exposure jobs (10 deaths) and 6.6 (1.1–37.7) for high exposure jobs (2 deaths)] |
| Raleigh et al. 2014 | Occupational cohort mortality and incidence study | Primarily PFOA | Compared exposed and unexposed plants and estimated time-weighted average inhalation exposure using job history and a task-based job exposure matrix (incorporated industrial hygiene monitoring data, information from workers and hygiene professionals, and annual production levels) | Provided results for 148 participants in a biomonitoring program in 2000: serum PFOA concentration- overall GM=815 ng/ml; among those who worked only in PFOA-related areas (n=50) GM=2,538 ng/ml; among those with some work on PFOA areas (n=38) GM=979 ng/ml; among those who never worked in PFOA areas (n=60) GM=282 ng/ml | Reported on several cancer categories including all cancers, liver, pancreas, prostate, kidney, breast, and bladder | Workers employed for at least 365 days during 1947–2002 at a plant producing PFOA (overlaps with populations in Gilliland and Mandel, 1993 and Lundin et al. 2009) plus workers employed for at least 365 days before 1999 at a plant not producing PFOA | 9,027 workers (4,668 at exposed plant and 4,359 at unexposed plant); mortality follow up through 2008, cancer incidence for 1988-“end of follow up” (end date not specified); 1,145 deaths at exposed plant and 1,824 at unexposed plant (at exposed plant- highest number of deaths for a specific reported cancer type was 24 for prostate cancer, highest number of incident cases for a specific cancer type was 188 for prostate cancer) | Calculated SMRs relative to the Minnesota population, standardized by age, sex and calendar period, for comparisons with workers at unexposed plant, used Cox regression models with age as the time scale, controlling for year of birth and sex | -No markedly elevated SMRs for any cancer site relative to Minnesota population -In comparison with unexposed plant [HRs (95% CIs) relative to unexposed workers]: bladder cancer mortality (8 total deaths) 1st and 2nd exposure quartiles 1.03 (0.27–3.96), 3rd and 4th exposure quartiles 1.96 (0.63–6.15); bladder cancer incidence (40 total cases) 1st exposure quartile 0.81 (0.36–1.81), 2nd exposure quartile 0.78 (0.033–1.85), 3rd exposure quartile 1.5 (0.8–2.81), 4th exposure quartile 1.66 (0.86–3.18) |
-Mortality analysis started in 1960 and incidence analysis started in 1988 (Exposures first occurred in 1947) -SMRs calculated relative to Minnesota population -Improved exposure assessment with estimation of past cumulative inhalation exposure -Some evidence of dose-response relationship for bladder cancer but not monotonic for bladder cancer incidence. |
| Occupational cohort, Vento Region, Italy | ||||||||||
| Girardi and Merler 2019 | Occupational cohort mortality study | Primarily PFOA | Compared plant workers to regional populations, categorized workers by probability of exposure (ever exposed plant workers, never exposed plant workers and office workers), and estimated time-dependent cumulative serum concentrations (based on work history and historical measured serum concentrations) | Serum concentrations available for 120 workers during 2000–2013 [GM (range)]: PFOA 4,048 (19–91,900) ng/ml; PFOS 148.8 (10–3,386) ng/ml | Reported on several cancer categories including all malignant neoplasms, esophagus, stomach, colon, liver, lung, malignant neoplasms of lymphatic and hematopoietic tissue, and non-Hodgkin lymphoma | Male workers employed for at least 6 months at a PFOA production plant or an unexposed workplace during 1960–2008, and with available information on date of birth, birthplace, residence and period of employment | 462 male employees at exposed plant, 1383 at unexposed workplace; follow-up during 1970–2018; 107 deaths among exposed plant workers, 218 deaths among unexposed workplace workers (highest number of deaths for a specific reported cancer type among exposed workers was 7 for both liver cancer and malignant neoplasms of lymphatic and hematopoietic tissue) |
Calculated SMRs relative to regional mortality rates, standardized by gender, 5-year age groups and 5-year calendar periods. For comparison with a cohort of workers at another factory, calculated mortality risk ratios using Poisson regression controlling for age at risk (continuous) and 10-year calendar period | -Among workers at exposed plant, SMRs (95% CIs) relative to regional population: Liver cancer mortality (7 deaths) 2.32 (1.11–4.87), mortality due to malignant neoplasms of lymphatic and hematopoietic tissue (7 deaths) 2.26 (1.08–4.73) -RRs (95% CIs) in comparison with worker reference group: liver cancer mortality 6.69 (1.71–26.2), mortality due to malignant neoplasms of lymphatic and hematopoietic tissue 3.20 (1.09–8.94) |
-High exposure cohort, limited by small numbers of deaths, exposures to other PFAS but mostly PFOA. -Workers classified as “ever at PFAS department, “Never at PFAS department (but not exclusively working in offices), and “Offices”, also estimated cumulative exposure based on work histories and some measured serum levels. -SMRs calculated relative to regional general population -Evidence of dose- response trend with increasing estimated exposure for liver cancer and malignant neoplasms of lymphatic and hematopoietic tissue relative to both the regional population and the unexposed worker cohort |
| Community Cohorts | ||||||||||
| Eriksen et al. 2009 | Cohort incidence study (case-cohort study design) | PFOA and PFOS | Measured concentrations in stored serum collected at cohort recruitment | Serum concentrations [median (5th-95th percentiles)]: PFOA- among men 6.8 (3.1–14.0) ng/ml in cancer patients and 6.9 (3.2–13.3) ng/ml in subcohort comparison group; among women 6.0 (2.6–11.0) mg/ml in cancer patients and 5.4 (2.2–11.6) ng/ml in subcohort comparison group. PFOS- among men 35.1 (17.4–60.9) ng/ml in cancer patients and 35.0 (16.8–62.4) ng/ml in subcohort comparison group; among women 32.1 (14.0–58.1) ng/ml and 29.3 (14.2–55.6) ng/ml in subcohhort comparison group. |
Cancers of the prostate, bladder, pancreas and liver | General population, large cohort enrolled during 1993–1997, aged 50–65 years, matched with Danish Cancer Registry and Danish Pathology Data Bank through 2006 | Overall cohort of 57,053 people- analysis included incident cancer cases: 713 prostate, 332 bladder, 128 pancreas, and 67 liver; comparison sub-cohort of 772 selected from overall cohort | Calculated incidence rate ratios using Cox proportional hazards models stratified by sex with age as the time scale, controlling for cancer type -specific variables (prostate cancer: years of school attendance, body mass index, fat intake, and fruit and vegetable intake; bladder cancer: smoking status, intensity and duration, years of school attendance and occupation associated with bladder cancer; pancreatic cancer: smoking status, intensity and duration, fat intake, and fruit and vegetable intake; liver cancer: smoking status, years of school attendance, alcohol intake and occupation associated with liver cancer) | PFOA: No marked associations for any cancer type, RRs (95% CIs) for quartiles 2,3 and 4 relative to quartile 1: prostate cancer (713 total cases) 1.09 (0.78–1.53), 0.94 (0.67–1.32), 1.18 (0.84–1.65); pancreatic cancer (128 total cases) 0.88 (0.49–1.57), 1.33 (0.74–2.38), 1.55 (0.85–2.80) PFOS: No marked associations for any cancer type, RRs (95% CIs for quartiles 2,3 and 4 relative to quartile 1: prostate cancer (713 cases) 1.35 (0.97–1.87), 1.31 (0.94–1.82), 1.38 (0.99–1.93) |
-Serum collected at time of enrollment -Cohort was enrolled at ages 50–65 -Suggestion of dose-response trends for prostate and pancreatic cancers but not monotonic. |
| Bonefeld-Jorgensen et al. 2014 | Cohort incidence study (case-cohort study design) | PFHxS, PFNA, PFOA, PFOS, PFOSA, and sums of PFAS groups | Measured concentrations in stored serum collected at baseline | Mean serum concentrations among controls: PFHxS 1.2 ng/ml, PFNA 0.5 ng/ml, PFOA 5.2 ng/ml, PFOS 30.6 ng/ml, PFOSA 3.5 ng/ml |
Breast cancer only | Nested in cohort of pregnant women formed in 1996–2002 in Denmark, matched with Danish National Patient Registry through 2010 | Overall cohort of about 100,000 pregnancies, 250 cases of breast cancer, 233 controls selected from overall cohort, frequency matched on age and parity | Controls were frequency matched to cases on age and parity. Unconditional logistic regression models were used to calculate relative risks controlling for age, pre-pregnancy body mass index, gravidity, oral contraceptive use, age at menarche, smoking during pregnancy, alcohol intake, maternal education and physical activity | PFOA: No association between baseline serum PFOA and later development breast cancer PFOS: No association between baseline serum PFOS and later development of breast cancer. Other PFAS: RRs (95% CIs for associations with breast cancer for quintiles 2–5 relative to quintile 1: PFHxS 0.64 (0.34–1.18), 0.70 (0.38–1.29), 0.38 (0.20–0.70), 0.61 (0.33–1.12); PFOSA 1.38 (0.75–2.52), 0.91 (0.49–1.66), 1.11 (0.60–2.05), 1.89 (1.01–3.54) |
-Serum collected at baseline in 1996–2002, during first and second trimester of pregnancy -No clear dose-response relationships. |
| Barry et al. 2013 | Cohort incidence study (primarily retrospective, medical records confirmation sought for self-reported cancers). | PFOA | Modeled time-varying lifetime serum cumulative concentration (sum of estimated annual serum concentrations up to a given year), created by combining occupational estimates based on a work history and a job-exposure matrix (as in Steenland and Woskie, 2012) and residential exposure (from a multistage model estimating serum concentrations based on drinking water exposures). | Measured PFOA serum concentrations [median (range)] in 2005–2006: community 24.2 (0.25–4,752) ng/ml), workers 112.7 (0.25–22,412) ng/ml; Estimated annual PFOA serum concentrations [median (range)] across all years: community 19.4 (2.8–9,217) ng/ml, workers 174.4 (5.2–3,683) ng/ml | Reported on 21 cancer types | People aged 20 years and older who lived, worked or attended school for at least 1 year in a community with high PFOA exposure (near a chemical plant), recruited from participants in a prior survey (from 2005–2006) that had included approximately 81% of current residents, followed retrospectively from the later of age 20 or 1952 until the last completed survey (2008–2011) Also included chemical plant workers who completed surveys or had a proxy survey (subset of cohort in Leonard et al, 2008) | 32,254 people in analysis (28,541 community, 3,713 workers), 2507 cancer cases validated by medical records review, 21 cancer sites (highest number of validated cases in the analysis for a specific reported cancer type was 559 for breast cancer) | Calculated hazards ratios using proportional hazards models with age as the time scale, controlling for time-varying smoking, time-varying alcohol consumption, sex, education and 5-year birth period. | Hazard ratios and 95% CIs for quartiles 2–4 relative to quartile 1 (no lag): For combined community and worker cohorts: testicular cancer (17 cases) 1.04 (0.26–4.22), 1.91 (0.47–7.75), 3.17 (0.75–13.45), trend p-value=0.04; kidney cancer (105 cases) 1.23 (0.70–2.17), 1.48 (0.84–2.60), 1.58 (0.88–2.84), trend p-value=0.18; thyroid cancer (86 cases) 1.54 (0.77–3.12), 1.48 (0.74–2.93), 1.73 (0.85–3.54),trend p-value =0.25. For community cohort only: testicular cancer (15 cases) 0.80 (0.16–3.97), 3.07 (0.61–15.36), 5.80 (0.97–34.58), trend p-value=0.05; kidney cancer (87 cases) 1.34 (0.71–2.52), 1.95 (1.03–3.70), 2.04 (1.07–3.88), trend p-value=0.20; thyroid cancer (78 cases) 1.54 (0.73–3.26), 1.71 (0.81–3.59), 1.40 (0.66–2.97),trend p-value =0.46. |
-Community cohort included only people who were alive at time of 2005–2006 survey -Estimated annual individual cumulative serum concentration based on fate-transport model using plant emissions (Shin et al. 2011a, 2011b), correlation coefficient 0.67 with measured levels in 2005–2006 -Dose-response trend observed for testicular cancer and kidney cancer, possible trend for thyroid cancer but not monotonic. |
| Fry and Power 2017 | Cohort mortality study- cancer mortality after the time of the NAHNES examination was determined through the NCHS 2011 Public-use Linked Mortality Files |
PFHxS, PFNA, PFOA, PFOS | Measured concentrations in serum collected through the U.S. National Health and Nutrition Examination Survey (NHANES) | Median concentrations for PFOA and PFOS reported in the paper (Table 2) are not consistent with NHANES data from 2003–2006. Values for GM serum concentrations among NHANES participants aged ≥60 years from Kato et al., 2011: PFHxS 2003–2004 GM=2.04 ng/ml, 2005–2006 GM=1.88 ng/ml; PFNA 2003–2004 GM=0.85 ng/ml, 2005–2006 GM=1.24 ng/ml; PFOA 2003–2004 GM=3.65 ng/ml, 2005–2006 GM=4.65 ng/ml; PFOS 2003–2004 GM=23.2 ng/ml, 2005–2006 GM=23.4 ng/ml |
All cancer mortality combined | Participants in the 2003–2006 U.S. NHANES cycles who were aged ≥60 years at the time of examination, followed for a median of 5.5 years | 1043 NHANES participants in analysis (4.5% died with a cancer cause of death during follow-up) | Calculated hazard ratios using Cox proportional hazards models with unspecified time scale, controlling for age, gender, race/ethnicity, education and smoking (in sensitivity analyses, also considered control for body mass index, family poverty income ratio and alcohol use) | No evidence of an association between serum PFAS concentrations and all-cancer mortality, HR (95% CI) for one standard deviation increase: PFHxS 1.06 (0.73–1.54), PFNA 0.89 (0.72–1.09), PFOA 0.94 (0.80–1.11), PFOS 1.01 (0.86–1.19) | -Serum collected at baseline (at NHANES examination) -Included only NHANES participants aged ≥60 years |
| Case-control studies (N=10) | ||||||||||
| Studies nested in Cohorts (N=4) | ||||||||||
| Study of California Teachers | ||||||||||
| Hurley et al. 2018 | Nested case control study (did not state that they used density sampling) | MeFOSAA, PFHxS, PFNA, PFOA, PFOS, PFUnDA | Measured concentrations in serum collected from cases after diagnosis and from controls at the time of study enrollment | Serum concentrations [median (range)]: MeFOSAA- Cases 0.15 (0.01–4.00) ng/ml, Controls 0.17 (0.01–8.37) ng/ml; PFHxS- Cases 1.52 (0.01–40.70) ng/ml, Controls 1.61 (0.01–21.80); PFNA- Cases 0.85 (0.02–7.31) ng/ml, Controls 0.85 (0.02–10.40) ng/ml; PFOA- Cases 2.35 (0.04–39.10) ng/ml, Controls 2.48 (0.10–20.20) ng/ml; PFOS- Cases 6.70 (0.05–39.40) ng/ml, Controls 6.95 (0.05–99.80) ng/ml; PFUnDA- Cases 0.12 (0.01–1.03) ng/ml, Controls 0.13 (0.01–1.31) ng/ml |
Breast cancer only | California teachers cohort (initially enrolled during 1995–1996), participants who had provided a blood sample and completed a questionnaire for a separate breast cancer case-control study during 2011–2015, excluding those whose blood sample was drawn prior to October 2011 or in the last two months of the prior case-control study. | 902 breast cancer cases (diagnosed during 2006–2014, identified through California Cancer Registry linkage); 858 controls from the overall cohort, frequency matched by age, race/ethnicity, and region of residence | Controls frequency matched to cases by age at baseline, race/ethnicity, and region of residence. Calculated odds ratios using unconditional logistic regression, controlling for age at baseline, race/ethnicity, region of residence, date of blood draw, date of blood draw squared, season of blood draw, total smoking pack years, body mass index, family history of breast cancer, age at first full-term pregnancy, menopausal status at blood draw and pork consumption. | No association with case status for PFOA, PFOS or other or any of the other examined types of PFAS | -Serum collected mean of 35 months (range 9 months-8.5 years) after diagnosis (during 2011–2015) |
| French E3N study | ||||||||||
| Mancini et al. 2020 | Nested case control study (with density sampling of controls) | PFOA, PFOS | Measured concentrations in stored serum collected from cases and controls at baseline | Serum concentrations [median (range)]: PFOA 6.64 (1.29–21.39) ng/ml, PFOS 17.51 (5.83–85.26) ng/ml |
Breast cancer only | Nested within cohort of 98,995 women enrolled in 1990, 25,000 with blood samples collected during 1994–1999 | Random sample of 194 incident post-menopausal breast cancer cases (identified through self-report, national health insurance files, or death certificates) diagnosed through 2013 with pre-diagnosis blood samples and dietary data; 194 controls sampled from those free of breast cancer at the time of diagnosis of corresponding case and with blood samples, matched by age, menopausal status and BMI at blood collection and year of blood collection (density sampling) |
Controls matched with cases by age, menopausal status at blood collection (all post-menopausal), body mass index (< 25 or ≥25 kg/m²), and year of blood collection. Calculated odds ratios using conditional logistic regression (conditioned on matching factors), adjusted for total serum lipids, body mass index (continuous), smoking status, physical activity, education level, history of benign breast disease, family history of breast cancer, parity, age at first full-term pregnancy, breastfeeding duration, age at menarche, age at menopause, current use of menopausal hormone therapy, use of oral contraceptives, adherence to healthy and Western and Mediterranean diet patterns | -In fully adjusted model, OR (95% CI, total n) for association with breast cancer for quartiles 2–4 respectively, compared with quartile 1: PFOA 1.69 (0.89–3.21, n=118), 0.88 (0.43–1.80, n=91), 0.92 (0.43–1.98, n=94), trend p-value 0.43; PFOS 1.94 (1.00–3.78, n=109, 2.03 (1.02–4.04, n=99), 1.72 (0.88–3.36, n=100), trend p-value 0.25. -For association between case status and PFOS exposure for estrogen receptor positive tumors (ORs and 95% CIs) for quartiles 2–4 respectively, compared with quartile 1: PFOA- no clear association; PFOS- 1.85 (0.90–3.82), 2.22 (1.05–4.69), 2.33 (1.11–4.90), trend p-value 0.04) -For association with progesterone receptor positive tumors (ORs and 95% CIs) for quartiles 2–4 respectively, compared with quartile 1: PFOA- no clear association; PFOS- 1.84 (0.82–4.14), 2.47 (1.07–5.65), 2.76 (1.21–6.30), trend p-value 0.02. |
-Serum collected at baseline before case diagnosis. -No clear evidence of dose-response relationship in overall analysis, some evidence of a dose-response relationship for PFOS for estrogen- and progesterone-receptor positive tumors. |
| Child and Health Development Pregnancy Cohort | ||||||||||
| Cohn et al. 2020 | Nested case-control study of maternal serum PFAS levels and breast cancer in daughters (appears to have used density sampling) | EtFOSAA, PFHxS, PFOA, PFOS | Measured concentrations in stored serum collected from mothers of cases and controls at baseline | Maternal serum concentrations [median (25th-75th percentiles)]: EtFOSAA- Cases 0.3 (0.1–0.6) ng/ml, Controls 0.3 (0.1–0.5) ng/ml; PFHxS- Cases 2.0 (1.0–3.6) ng/ml, Controls 2.3 (1.0–3.5) ng/ml; PFOA- Cases 0.4 (0.3–0.6) ng/ml, Controls 0.4 (0.2–0.6) ng/ml; PFOS- Cases 30.5 (14.1–55.8) ng/ml, Controls 32.1 (14.9–58.2) ng/ml |
Breast cancer only | Nested within Child Health and Development Studies pregnancy cohort in California with baseline maternal blood samples (collected during 1959–1967), total cohort size 20,754 pregnancies; 9,300 live-born female offspring | 102 breast cancer cases (identified through self-report, cancer registry matching and death certificates) diagnosed by age 52 in daughters; 310 controls (selected at random from daughters not known to have been diagnosed with breast cancer at the age of diagnosis of the case) matched by birth year and trimester of maternal blood draw | Controls matched with cases by birth year and trimester of maternal blood draw. Calculated odds ratios using age-matched conditional logistic regression, stratified by total maternal cholesterol (in light of apparent interaction), and adjusted for maternal age, race, overweight in early pregnancy, parity, maternal history of breast cancer, maternal serum DDE and DDT concentrations, and whether the daughter was breastfed. | No associations between breast cancer and maternal serum PFOA or PFHxS concentrations. PFOS and EtFOSAA were included in same model (because PFOS is a metabolite of EtFOSAA). The authors present results from a model with linear terms for log2 transformed EtFOSAA, PFOS and cholesterol concentrations and the EtFOSAA-cholesterol interaction. From this model, among daughters of mothers with total cholesterol at the median of its highest quartile, ORs (95% CIs) for an increment from the median of the first PFAS quartile to the median of the 4th PFAS quartile: maternal PFOS 0.3 (0.1–0.9), maternal EtFOSAA 3.6 (1.1–11.6) | -Serum collected from mothers at baseline before case diagnosis in daughters. -Multiple comparisons examined, including interactions of PFASs with cholesterol -Stratification by cholesterol might be problematic because cholesterol might be affected by the exposure -Dose-response relationships cannot be assessed. |
| Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial | ||||||||||
| Shearer et al. 2020 | Nested case control study (with density sampling of controls) | EtFOSAA, MeFOSAA, PFDA, PFHxS, PFNA, PFOA, PFOS, PFUnDA | Measured concentrations in stored serum collected from cases and controls at baseline | Serum Concentration quartile end points among controls (Q1, Q2, Q3, Q4): EtFOSAA 0.7, 1.2, 2.4, 60.4 ng/ml; MeFOSAA 0.9, 1.4, 2.1, 8.2 ng/ml; PFDA quartile cut points not provided, maximum 2.1 ng/ml; PFHxS 2.2, 3.4, 5.5, 37.4 ng/ml; PFNA 0.5, 0.7, 1.0, 4.9 ng/ml; PFOA 4.0, 5.5, 7.3, 27.2 ng/ml; PFOS 26.3, 38.4, 49.9, 154.2; PFUnDA quartile cut points not provided, maximum 1.7 ng/ml |
Kidney cancer [renal cell carcinoma (RCC)] only | Nested within cohort of participants in screening arm of PLCO trial (overall trial ~150,000 adults aged 55–74 years enrolled in 1993–2001) | 324 RCC cases (identified through the overall study, methods of case identification not specified) with serum PFAS measure-ments; 324 controls who were at risk for RCC at the time of diagnosis of the matched case, individually matched on age, sex, race/ethnicity, study center, and study year of blood draw | Controls matched with cases on age at enrollment, sex, race/ethnicity, study center and study year of blood draw. Calculated odds ratios using conditional logistic regression (conditioned on matched sets), controlling for eGFR, body mass index, smoking status, history of hypertension, prior freeze-thaw cycles and calendar year of blood draw. | In conditional logistic regression models ORs (95% CIs) comparing quartiles 2–4 to quartile 1 in single-pollutant models: PFOA 1.47 (0.77–2.80), 1.24 (0.64–2.41), 2.63 (1.33–5.20), trend p-value 0.007; PFOS 1.67 (0.84–3.30), 0.92 (0.45–1.88), 2.51 (1.28–4.92), trend p-value 0.009; PFHxS 1.41 (0.75–2.64), 1.14 (0.59–2.20), 2.07 (1.06–4.04), trend p-value 0.04. ORs (95% CIs) comparing PFOA quartiles 2–4 to quartile 1 in models controlling for PFOS and PFHxS: 1.41 (0.69–2.90), 1.12 (0.52–2.42), 2.19 (0.86–5.61), trend p-value 0.13 |
-Serum collected at baseline before case diagnosis. -Evidence of dose-response relationship for PFOA, PFOS and PFHxS in single-PFAS models, some evidence for dose-response relationship (although not monotonic) for PFOA in models controlling for PFOS and PFHxS. -Association with PFOA remained in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed ≥8 years after phlebotomy. |
| Non-nested studies (N=6) | ||||||||||
| Study of cancer in Greece | ||||||||||
| Vassiliadou et al. 2010 | Case-control study | PFOA, PFOS | Measured concentrations in serum collected from cancer patients (presumably after diagnosis), and from other patients at the time of a clinic visit | Serum concentrations across males and females in 3 groups: PFOA medians 1.70–3.14 ng/ml, maximums 3.26–10.21 ng/ml; PFOS medians 7.03–13.69 ng/ml, maximums 16.63–40.36 ng/ml |
Group of patients with cancers of various types (not specified) | Convenience sample, clinical care populations in Greece, all samples collected during 2009 | 40 hospitalized cancer patients from hospital in Athens; 86 and 56 healthy controls from two clinics (from Argolida and Athens respectively) | Compared PFAS serum concentrations between groups for men and women separately. No other control for confounding. | No differences between cancer patients and controls for either PFOA or PFOS serum concentrations | -Serum collected from patients presumably after diagnosis. -Patient groups were from different areas of Greece. -No specific types of cancers were studied. |
| Greenland Inuit Studies | ||||||||||
| Bonefeld-Jorgensen et al. 2011 | Case-control study | PFOA, PFOS, and sums of PFAS groups | Measured concentrations in serum collected from cases at the time of diagnosis and from controls at the time of study enrollment | Serum concentrations [median (range)]: PFOA- Cases 2.5 (0.2–7.2) ng/ml, Controls 1.6 (0.2–7.6) ng/ml; PFOS- Cases 45.6 (11.6–124) ng/ml, Controls 21.9 (1.5–172) ng/ml |
Breast cancer only | General population Inuit, Greenland, enrolled during 2000–2003 | 31 hospital-based breast cancer cases; 115 controls from two previous cross-sectional studies, frequency matched to cases by age and district (only 98 cases and 31 control included in comparison of PFAS means, 69 controls and 7–15 cases included in fully adjusted logistic regression models for various PFAS measures) | Cases and controls frequency matched on age and district. Compared ln-transformed PFAS serum concentrations between cases and controls using ANCOVA analysis adjusted for age, body mass index, number of pregnancies and smoking. Calculated odds ratios using unconditional logistic regression, controlling for “identified confounders”- considered age, body mass index, number of full-term pregnancies, breastfeeding, menopausal status and serum cotinine but variables actually included in final models are not listed | Breast cancer cases (n=31) had significantly higher levels of PFOA, PFOS, and sums of perfluorosulfonated acids and perfluorinated carboxylated acids in their serum at time of diagnosis compared to controls (n=115) (presented only p-values for this comparison, no adjusted effect measure). Adjusted OR (95% CI), per unspecified increase in serum PFAS concentration in fully adjusted models: PFOA (69 controls and 7 cases) 1.20 (0.77–1.88); PFOS (69 controls and 9 cases) 1.03 (1.001–1.07); sum of PFOS, PFHxS and PFOSA 1.03 (1.00–1.05); sum of PFHpA, PFOA, PFNA, PFDA, PFUnDA and PFTrA 1.07 (0.96–1.18) | -Serum collected at time of diagnosis, multiple comparisons, small population -Adjusted logistic regression analysis excluded a large number of cases and controls (presumably because of missing data) -Matched cases and controls on district but did not control for district in analysis. -Only analyses of continuous variables presented, so difficult to assess dose-response pattern. |
| Wielsoe et al. 2017 | Case-control study | PFDA, PFDoDA, PFHpA, PFHxS, PFNA, PFOA, PFOS, PFUnDA, and sums of PFAS groups | Measured concentrations in serum collected from cases at the time of diagnosis and from controls at the time of study enrollment | Serum concentrations [median (range)]: PFDA- Cases, 1.30 (0.20–11.10) Controls 1.01 (0.05–6.41); PFDoDA- Cases 0.40 (0.15–5.71), Controls 0.21 (0.15–6.49); PFHpA- Cases 0.11 (0.03–1.55), Controls 0.08 (0.03–0.59); PFHxS- Cases 2.52 (0.19–23.40), Controls 1.14 (0.16–13.90); PFNA- Cases 3.28 (0.30–38.60), Controls 1.83 (0.25–12.50); PFOA- Cases 2.08 (0.20–9.52) ng/ml, Controls 1.48 (0.20–6.29) ng/ml; PFOS- Cases 35.50 (4.23–187.0) ng/ml, Controls 18.2 (1.70–133.0) ng/ml; PFUnDA- Cases 2.23 (0.20–24.90), Controls 2.02 (0.03–20.0) |
Breast cancer only | General population, Inuit, Greenland (population partially overlapping with Bonefeld-Jorgensen et al. 2011), enrolled during 2000–2003 and 2011–2014 | 77 hospital-based breast cancer cases; 81 controls with PFAS measurements from two previous cross-sectional studies (2000–2003) or hospital-based patients with non-malignant conditions (2011–2014), frequency matched on age and geographic area (fewer in adjusted analyses) | Cases and controls were matched on age and geographic area, Compared ln-transformed PFAS serum concentrations between cases and controls using ANCOVA analysis adjusted for age. Calculated odds ratios using unconditional logistic regression, controlling for “identified confounders”- considered age, body mass index, breastfeeding, parity and serum cotinine but variables actually included in final models are not listed | Serum PFAS levels were significantly higher in breast cancer cases than controls in age-adjusted analysis for PFHxS, PFOS, the sum of perfluorinated sulfonic acids, and the sum of all PFAS types considered. ORs (95% CI) for 2nd and 3rd tertiles relative to first tertile in adjusted analyses: PFDA 2.14 (0.94–4.91), 2.36 (1.04–5.36); PFHxS 1.13 (0.48–2.66),2.69 (1.23–5.88); PFOA 1.86 (0.80–4.31), 2.64 (1.17–5.97); PFOS 3.13 (1.20–8.15), 5.50 (2.19–13.84) | -Serum collected at time of diagnosis -Some controls were patients hospitalized for non-malignant conditions. -Matched cases and controls on geographic area but did not control for geographic area in analysis. -Some evidence of dose-response relationships. |
| West Virginia-Ohio Study | ||||||||||
| Vieira et al. 2013 | Case-control study (two studies)- compared incident cases of cancer in persons aged 15 years and older at 18 cancer sites with controls which consisted of all other cancers except kidney, pancreatic, testicular, and liver. | PFOA | For 13 counties in Ohio and West Virginia: Categorization by water district, comparing water districts with various levels of historic water contamination For 5 counties in Ohio only: did analyses by modeled time-varying annual or cumulative serum concentration (sum of estimated annual serum concentrations up to a given year), created based on residence at diagnosis (assuming residence at that address for the prior 10 years) using environmental and pharmacokinetic models (Shin 2011 a and b) | Serum PFOA concentrations in cross sectional study of >69,000 residents in the area: median 28.2 ng/ml, range 0.2–22,412 ng/ml | Reported on 18 cancer types | 13 high-exposure and low exposure counties in Ohio and West Virginia, near plant that used PFOA- one study in Ohio only and one in both Ohio and West Virginia; incident cancers during 1996–2005 | Analysis included a total of 7,869 cancer cases (all types) in Ohio and 17,238 cancer cases (all types) from West Virginia, cancer-specific total number of cases ranged from 61 for liver and testicular cancer in the Ohio-only analysis to 4926 for lung cancer in the analysis for Ohio and West Virginia | Calculated odds ratios using logistic regression controlling for age, sex, diagnosis year, smoking status, and insurance provider in both analyses; also controlled for race (white/non-white) in Ohio-only analysis | Based on individually estimated annual serum levels in Ohio only, ORs (95% CIs, number of cases) for comparison with other cancer types for high and very high estimated PFOA exposure groups, respectively: kidney cancer 2.0 (1.3–3.2, n=22), 2.0 (1.0–3.9, n=9); testicular cancer 0.3 (0.0–2.7, n=1), 2.8 (0.8, 9.2, n=6); non-Hodgkin lymphoma 1.1 (0.7–1.19, n=17), 1.8 (1.0–3.4, n=11); ovarian cancer 1.4 (0.7–2.9), n=8), 2.1 (0.8–5.5, n=5); prostate cancer 0.8 (0.5–1.1, n=47), 1.5 (0.9–2.5, n=31); female breast cancer 0.7 (0.5, 1.0, n=45), 1.4 (0.9, 2.3, n=29). -For analysis of combined Ohio and West Virginia cases, OR (95% CI, n) for comparison with other cancer types for the highest exposure water district (Little Hocking): testicular cancer 5.1 (1.6–15.6, n=8); ovarian cancer 1.8 (0.7–4.4) n=5); kidney cancer 1.7 (0.9–3.3, n=10); non-Hodgkin lymphoma 1.6 (0.9–2.8, n=14); prostate cancer 1.4 (0.9–2.3, n=36) |
-Exposure estimated water district contamination for the combined Ohio and West Virginia analysis -Modeled annual and cumulative exposure assigned to individuals in Ohio, ten-year latency and residence assumed. -Some overlap of cases with Barry et al. (2013) community cohort. -Small numbers of cases for some cancers. No detailed residence data for West Virginia Cases. -Controls were cases of other cancers, which might not be representative of the source population. -No clear evidence of dose-response relationships |
| Swedish Study | ||||||||||
| Hardell et al. 2014 | Case-control study | PFDA, PFHxS, PFNA, PFOA, PFOS, PFUnDA | Measured concentrations in serum collected from cases after diagnosis and from controls at the time of study enrollment | Serum concentrations [median (range)]: PFDA- Cases 0.30 (0.03–1.2) ng/ml, Controls 0.27 (0.02–1.0) ng/ml; PFHxS- Cases 0.91 (0.09–16) ng/ml, Controls 0.87 (0.15–3.0) ng/ml; PFNA- Cases 0.61 (0.05–4.6) ng/ml, Controls 0.57 (0.09–2.1) ng/ml; PFOA- Cases 2.0 (0.32–15) ng/ml, Controls 1.9 (0.35–8.4) ng/ml; PFOS- Cases 9.0 (1.4–69) ng/ml, Controls 8.3 (1.7–49) ng/ml; PFUnDA- Cases 0.26 (0.02–1.3) ng/ml, Controls 0.25 (0.02–1.5) ng/ml |
Prostate cancer only | General population, Sweden, enrolled during 2007–2011 | 201 hospital-based cases, 186 population controls selected from population registry (matched on age and county), fewer cases (105–118) and controls (87–93) in logistic regression analyses for the various types of PFAS | Controls matched with cases on age and geographic area (cases from hospital in Ӧrebro county and controls from same county), calculated odds ratios using unconditional logistic regression controlling for age, body mass index, and year of sampling. | PFOA and PFOS: No difference in PFOA or PFOS serum levels between cases and controls in overall analysis. In examination of interaction between heredity and PFAS, OR (95% CI) for comparison with the group with no first degree relatives with prostate cancer and PFAS levels below the median: group with first degree relatives with prostate cancer and PFAS levels above the median- PFDA 2.6 (1.1–6.1), PFHxS 4.4 (1.7–12), PFNA 2.1 (0.9–4.8), PFOA 2.6 (1.2–6.0), PFOS 2.7 (1.04–6.8), and PFUnDA 2.6 (1.1–5.9); no associations for the group with no first degree relatives with prostate cancer and PFAS levels above the median, or the group with first degree relatives with prostate cancer and PFAS levels below the median. | -Serum collected after diagnosis of cases (same year as diagnosis to 3 years after diagnosis) -Did not assess dose-response relationship. |
| Taiwanese Study | ||||||||||
| Tsai et al. 2020 | Case-control study | PFDA, PFDoDA PFHxS, PFNA, PFOA, PFOS, PFTrDA, PFUnDA | Measured concentrations in serum collected from cases after diagnosis but before treatment, and from controls at the time of study enrollment | Across all participants, geometric mean serum concentrations: PFDA 0.77 ng/ml, PFDoDA 0.24 ng/ml, PFHxS 0.64 ng/ml, PFNA 0.99 ng/ml, PFOA 1.77 ng/ml, PFOS 4.77 ng/ml, PFTrDA 0.59 ng/ml PFUnDA 2.14 ng/ml |
Breast cancer only | Patients at National Taiwan University Hospital and controls from hospital and community recruited through posters and flyers (cases and controls enrolled during 2014–2016) | 120 case patients and 119 control participants – not matched | Calculated odds ratios using logistic regression controlling for pregnancy history, oral contraceptive use, abortion, body mass index, education level, menopause, and stratified by age category (≤50 years and > 50 years). | No associations with case status for any of the types of PFAS in overall analyses. Among cases (n=60) and controls (n=60) aged ≤50 years, adjusted ORs (95% CIs) per unit increase in natural log transformed PFAS concentration: PFHxS 1.59 (0.99–2.57), PFOS 2.34 (1.02–5.38), PFUnDA 1.66 (0.85–3.24); In analyses stratified by tumor estrogen receptor status, positive associations for PFHxS, and PFOS only among estrogen receptor positive cases in patients aged ≤50 years; negative associations for PFDA and PFNA among estrogen receptor negative cases in patients aged ≤50 years. |
-Blood samples collected after diagnosis of breast cancer in cases but before start of treatment. -Dose-response pattern could not be assessed. |
| Cross-sectional study (N=1) | ||||||||||
| Innes et al. 2014 | Cross-sectional prevalence study | PFOA and PFOS | Measured concentrations in serum collected at the same time as ascertainment of a history of colorectal cancer | Serum concentrations [median (range)]: PFOA 27.9 (<0.5–22,412) ng/ml; PFOS 20.2 (<0.5–759.2) ng/ml |
Colorectal cancer only | Highly exposed general population in mid-Ohio valley, aged ≥21 years who completed a survey during 2005–2006, had not received a diagnosis of cancer other than colon cancer, and had complete information on covariates of interest. | Total of 47,359 adults (208 with validated diagnosis of colorectal cancer; 47,151 cancer-free) | Calculated odds ratios using logistic regression controlling for age, sex, race/ethnicity, marital status, years of education, family income, employment status, regular exercise, vegetarian diet, smoking, current alcohol consumption, menopausal status, use of hormone replacement therapy, body mass index, reported physician diagnosis of other conditions (heart, kidney, liver thyroid immune or connective tissue disease; stroke; hypertension; dyslipidemia; diabetes; chronic obstructive pulmonary disease; or asthma), and current treatment for hypertension or hyperlipidemia. Some models also controlled for physician diagnosis of rheumatoid arthritis, osteoarthritis, or fibromyalgia; gastrointestinal symptoms; anemia; and serum concentrations of folate, cholesterol, c-reactive protein, uric acid, estradiol and other PFAS. | In models adjusted for age, inverse association between PFOS and PFOA serum levels and colorectal cancer case status- ORs (95% CIs) for 2nd-4th quartiles compared with 1st quartile: PFOA 0.50 (0.33–0.77), 0.53 (0.36–0.78), 0.64 (0.45–0.92), trend p-value <0.01; PFOS 0.39 (0.26–0.57), 0.33 (0.23–0.48), 0.27 (0.19–0.39), trend p-value <0.01; similar results in models adjusted for other variables | -Serum PFAS concentration measured after diagnosis -Use of prevalent cases -Control for factors that might be caused by PFAS or by colorectal cancer could be problematic. |
| Ecologic study (N=1) | ||||||||||
| Mastrantonio et al. 2018 | Ecologic mortality study | Not specified | Compared areas with known PFAS contamination in drinking water with areas without PFAS contamination in drinking water | Not provided for the population in this study. A separate biomonitoring study (Ingelido et al., 2018) of 257 adults in contaminated areas of the Vento Region of Italy showed median serum concentrations of 13.77 ng/ml for PFOA, 8.69 ng/ml for PFOS, and 2.98 ng/ml for PFHxS. | Reported on several cancer types including liver, kidney, bladder, pancreas, leukemia, non-Hodgkin’s lymphoma, breast, prostate, testis, and ovary | Population in Vento Region of Italy, excluding three province chief towns, comparing mortality during 1980–2013 (excluding 2004–2005) in municipalities with PFAS concentrations above specified levels during 2013–2015 and in municipalities not found to have ground water contamination in 2013–2014. | Total number of deaths in contaminated areas was 41,841 (21,149 in men and 20,692 in women) | Calculated mortality rates standardized to the Italian population by age group, stratified by sex, and calculated rate ratios; compared deprivation index and smoking prevalence in contaminated areas and uncontaminated areas to assess potential for confounding by those factors. | Rate Ratios (95% CIs) comparing contaminated areas to uncontaminated areas: Among women: kidney cancer deaths 1.32 (1.06–1.65), 103 deaths in contaminated areas; bladder cancer deaths 1.15 (0.86–1.55), 57 deaths in contaminated areas; breast cancer deaths 1.11 (1.02–1.20), 809 deaths in contaminated areas; leukemia deaths 1.12 (0.94–1.33), 166 deaths in contaminated areas; ovarian cancer deaths 1.08 (0.92–1.26), 201 deaths in contaminated areas. -Among men: testicular cancer deaths 1.86 (0.81–4.27), 8 deaths in contaminated areas; leukemia deaths 1.16 (0.99–1.35), 210 deaths in contaminated areas; bladder cancer deaths 1.12 (0.97–1.30), 225 deaths in contaminated areas; pancreatic cancer 1.11 (0.99–1.25), 361 deaths on contaminated areas; kidney cancer deaths 1.07 (0.90–1.28), 155 deaths in contaminated areas. |
-Compared PFAS contaminated areas with uncontaminated areas, but did not do analyses by PFAS level or specific PFAS type -No analysis of dose-response relationship |
*
EtFOSAA = N-ethyl-perfluorooctane sulfonamide acetic acid; MeFOSAA=2-(N-Methyl-perfluorooctane sulfonamido) acetic acid; PFDA = perfluorodecanoic acid; PFDoDA=perfluorododecanoic acid; PFOA = perfluorooctanoic acid; PFHpA=perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonate; PFNA = perfluorononanoic acid; PFOS = perfluorooctane sulfonate; PFOSA= perfluorooctanesulfonamide; PFTrDA =perfluorotridecanoic acid; PFUnDA = perfluoroundecanoic acid
†
Serum concentration information from the paper cited is presented if available. If information is not available from the paper, information from other references pertaining to the same cohort or study area is presented. If summary information about serum concentrations is available for the overall study population, that information is presented. Otherwise, if information is available only for sub-groups, information is presented by sub-group.