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

Abstract

Background: Previous epidemiological studies found associations between exposure to per- and polyfluoroalkyl substances (PFAS) and some cancer types. Many studies considered highly exposed populations, so relevance to less-exposed populations can be uncertain. Additionally, many studies considered only cancer site, not histology.

Objectives: We conducted a case-cohort study within the American Cancer Society's prospective Cancer Prevention Study II (CPS-II) LifeLink cohort to examine associations between PFAS exposure and risk of selected cancers, considering histologic subtypes.

Methods: Serum specimens were collected from cohort participants during the period 1998-2001. This study included a subcohort (500 men, 499 women) randomly selected from participants without prior cancer diagnoses at serum collection, and all participants with incident (after serum collection) first cancers of the breast (females only, $n=786$), bladder ($n=401$), kidney ($n=158$), pancreas ($n=172$), prostate (males only, $n=\mathrm{1,610}$) or hematologic system ($n=635$). PFAS concentrations [perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] were measured in stored serum. We assessed associations between PFAS concentrations and incident cancers, by site and histologic subtype, using multivariable Cox proportional hazards models stratified by sex and controlling for age and year at blood draw, education, race/ethnicity, smoking, and alcohol use.

Results: Serum PFOA concentrations were positively associated with renal cell carcinoma of the kidney among women [hazard ratio (HR) and 95% confidence interval (CI) per PFOA doubling: 1.54 (95% CI: 1.05, 2.26)] but not men. Among men, we observed a positive association between PFHxS concentrations and chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL, HR and 95% CI per PFHxS doubling: 1.34 (95% CI: 1.02, 1.75)]. We observed some heterogeneity of associations by histologic subtype within sites.

Discussion: This study supports the previously observed association between PFOA and renal cell carcinoma among women and suggests an association between PFHxS and CLL/SLL among men. Consideration of histologic subtypes might be important in future studies of PFAS-cancer associations. https://doi.org/10.1289/EHP13174.

Figure 1.

Hazard ratios and 95% confidence intervals for overall cancer sites per doubling of PFAS concentrations (using ${\log }_2\text{-transformed}$ measures) by sex and type of PFAS, case–cohort study of association between PFAS and selected cancers among participants in the Cancer Prevention II LifeLink cohort, 1998–2015. All models had separate baseline hazards by sex or were restricted to one sex. The primary models controlled for year of serum sample collection (single-year categories), age at serum collection ($<60$, 60–64, 65–69, 70–74, 75–79, $\ge 80$ y), race (non-Hispanic White, other), education (high school graduate or less, vocational/trade school or some college, college graduate, graduate school), smoking status (current smoker, former smoker, ever smoked but unknown if current or former, never smoked), and alcohol consumption (nondrinker, $<1$ drink/wk, 1–6 drinks/wk, 1 drink/d, $\ge 2$ drinks/d). The overall number of cancers (both sexes) included in the models were as follows: bladder, 396; kidney, 156; pancreas, 171; hematologic malignancies (Heme), 626. See Table S9 for numerical data. Note: PFAS, per- and polyfluoroalkyl substances; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate.

Figure 2.

Hazard ratios and 95% confidence intervals for overall cancer sites (dark circles) and histologic subtypes (light circles) for bladder and kidney cancers per doubling of PFAS concentrations (using ${\log }_2\text{-transformed}$ measures) by sex and type of PFAS, case–cohort study of association between PFAS and selected cancers among participants in the Cancer Prevention II LifeLink cohort, 1998–2015. All models had separate baseline hazards by sex or were restricted to one sex. The primary models controlled for year of serum sample collection (single-year categories), age at serum collection ($<60$, 60–64, 65–69, 70–74, 75–79, $\ge 80$ y), race (non-Hispanic White, other), education (high school graduate or less, vocational/trade school or some college, college graduate, graduate school), smoking status (current smoker, former smoker, ever smoked but unknown if current or former, never smoked), and alcohol consumption (nondrinker, $<1$ drink/wk, 1–6 drinks/wk, 1 drink/d, $\ge 2$ drinks/d). The overall number of cancers (both sexes) included in the models were as follows: bladder, 396; TCC-B, 385; TCC-BK, 432; kidney, 156; RCC, 107. See Tables S9 and S10 for numerical data. Note: PFAS, per- and polyfluoroalkyl substances; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; RCC, renal cell carcinoma; TCC-B, transitional cell carcinoma of the bladder; TCC-BK, transitional cell carcinoma of the bladder or kidney.

Figure 3.

Hazard ratios and 95% confidence intervals for overall hematologic malignancies (dark circles) and histologic subtypes (light circles) for hematologic subtypes per doubling of PFAS concentrations (using ${\log }_2\text{-transformed}$ measures) by sex and type of PFAS, case–cohort study of association between PFAS and selected cancers among participants in the Cancer Prevention II LifeLink cohort, 1998–2015. All models had separate baseline hazards by sex or were restricted to one sex. The primary models controlled for year of serum sample collection (single-year categories), age at serum collection ($<60$, 60–64, 65–69, 70–74, 75–79, $\ge 80$ y), race (non-Hispanic White, other), education (high school graduate or less, vocational/trade school or some college, college graduate, graduate school), smoking status (current smoker, former smoker, ever smoked but unknown if current or former, never smoked), and alcohol consumption (nondrinker, $<1$ drink/wk, 1–6 drinks/wk, 1 drink/d, $\ge 2$ drinks/d). The overall number of cancers (both sexes) included in the models were as follows: Heme, 626; MYELO, 80; LYMPH, 540; B-NHL, 483; DLBCL, 123; CLL/SLL, 140; MM, 99. See Tables S9 and S10 for numerical data. Note: B-NHL, B-cell non-Hodgkin leukemia/lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma/mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; Heme, hematologic malignancies; LYMPH, lymphoid malignancies; MM, multiple myeloma; MYELO, myeloid malignancies; PFAS, per- and polyfluoroalkyl substances; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate.