Perfluoroalkyl substances and risk of kidney cancer in US men and women

Abstract PFAS are a class of man-made organofluorine compounds whose presence in the environment is an emerging, worldwide public health concern and a priority in environmental and human health research. Many PFAS are environmentally persistent, bioaccumulative, and have long half-lives in humans. Of particular concern is that environmental exposure to PFAS may increase the risk of kidney cancer, whose incidence has shown unexplained sustained and rapid increases in the US during the past decades. Several lines of emerging evidence strongly support that PFAS exposures may increase the risk of kidney cancer among humans: First, the kidney is a target organ of PFAS, which cause serious damage to the kidney at the levels commonly experienced by US population; Second, PFAS exposures have been associated with kidney damage that is known to increase kidney cancer risk; Third, a recent population-based case-control study of 324 RCC cases and 324 controls from NCI supports the findings of early occupational mortality studies that PFAS exposure increases kidney cancer risk. Much larger prospective studies of diverse, non-occupationally exposed populations are urgently needed to either confirm or refute these preliminary findings. Here, we propose a prospective nested case-control study to test the association between PFAS exposure and renal cell carcinoma (RCC, more than 85% of all cases of kidney cancer). We will utilize the extensive resources from five large and well-characterized US prospective cohorts: The Southern Community Cohort Study; Hispanic Community Health Study/Study of Latinos Cohort; Nurses’ Health Study; Health Professionals Follow-Up Study; and Physicians' Health Study. We will measure pre-diagnostic plasma levels of 40 PFAS from ~650 incident RCC cases and their individually matched controls (~1,300 controls in 1:2 ratio). Specifically, we will examine the following hypotheses: 1. Environmental exposure to PFAS increases the risk of RCC. In particular, environmental exposure to PFOA, PFOS and PFHxS increases RCC risk; 2. Risk of RCC associated with environmental PFAS exposure varies by mixture patterns, and varies by PFAS chemical structure, branched vs linear isomers, and short vs. long chain length; and 3. Established baseline risk factors of RCC (hypertension, obesity, diabetes and smoking) moderate the relationship between PFAS exposure and risk of RCC. In exploratory aims, we will test if the risk of RCC associated with individual PFAS exposures varies by histologic type of RCC or by race, and thus may contribute to racial disparities in kidney cancer risk. This proposed study fills a critical knowledge gap and represents the first large prospective cohort study to investigate the alleged association between PFAS exposure and kidney cancer risk in the US among diverse cohorts of non-occupationally exposed individuals. The results of the study will inform the medical and public health communities about the potential health effects of PFAS exposure and can help regulators make sound, science-based decisions.