PFAS and cancer, a scoping review of the epidemiologic evidence

Abstract

Background

The number of studies addressing per- and polyfluoroalkyl substances (PFAS) and cancer is increasing. Many communities have had water contaminated by PFAS, and cancer is one of the important community concerns related to PFAS exposure.

Objectives

We critically reviewed the evidence relating to PFAS and cancer from an epidemiologic standpoint to highlight directions for future research that would be the most likely to meaningfully increase knowledge.

Methods

We conducted a search in PubMed for studies of cancer and PFAS (through 9/20/2020). We identified epidemiologic studies that provided a quantitative estimate for some measure of the association between PFAS and cancer. Here, we review that literature, including several aspects of epidemiologic study design that impact the usefulness of study results.

Results

We identified 16 cohort (or case-cohort) studies, 10 case-control studies (4 nested within cohorts and 6 non-nested), 1 cross sectional study and 1 ecologic study. The cancer sites with the most evidence of an association with PFAS are testicular and kidney cancer. There are also some suggestions in a few studies of an association with prostate cancer, but the data are inconsistent.

Discussion

Each study's design has strengths and limitations. Weaknesses in study design and methods can, in some cases, lead to questionable associations, but in other cases can make it more difficult to detect true associations, if they are present. Overall, the evidence for an association between cancer and PFAS remains sparse. A variety of studies with different strengths and weaknesses can be helpful to clarify associations between PFAS and cancer. Long term follow-up of large-sized cohorts with large exposure contrasts are most likely to be informative.

Introduction

There is growing concern regarding the health effects of per- and polyfluoroalkyl substances (PFAS), as an ever-increasing number of sites of local contamination are being discovered in many countries [e.g., the United States (https://www.atsdr.cdc.gov/pfas/atsdr_sites_involvement.html, https://www.ewg.org/interactive-maps/2019_pfas_contamination/); Sweden (Andersson et al., 2019); Italy (Girardi and Merler, 2019; Ingelido et al., 2018, 2020); Germany (Skutlarek et al., 2006; Hölzer et al., 2008); China (Li et al., 2019)]. Since the phasing out of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) by major producers and users, serum concentrations of PFOA and PFOS in the general population have decreased in the United States (decrease of 50% for PFOA and 75% for PFOS during 2003–2014 in the general U.S. adult population (Jain, 2018; Kato et al., 2011)) and in Europe (EFSA CONTAM panel, 2020, Appendix B; Land et al., 2018). However, serum concentrations of other types of PFAS (such as perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA)) have increased or remained stable in various parts of Europe (EFSA CONTAM panel, 2018; Appendix B) and serum concentrations of PFOA and PFOS have increased in some areas of China (Land et al., 2018; Bao et al., 2017). During 2003–2014, >98% of adult U.S. residents had detectable serum levels of PFOA, PFOS, PFHxS, and PFNA (Jain, 2018); and several types of PFAS were detected in most adults studied in several areas in Europe during 2007–2016 (EFSA CONTAM Panel EFSA Panel on Contaminants in the Food Chain et al., 2018, EFSA CONTAM Panel EFSA Panel on Contaminants in the Food Chain et al., 2020). The primary sources of human PFAS exposure are thought to include drinking water, indoor dust and air, and food (including contamination from food packing) (Sunderland et al., 2019). During 2013–2015 in the United States, PFAS concentrations above the minimum reporting levels were found in 194 of 4864 tested public water supplies. An estimated 6 million people served by 66 public water systems were exposed via their drinking water to levels of PFOA and PFOS above currently EPA-recommended levels of 70 ng/L (for PFOA and PFOS individually or combined) (Hu et al., 2016). Various types of PFAS have also been found in drinking water samples collected during 2013–2015 in several European locations [e.g., among samples from the Netherlands, France and Spain (PFOS detected in 5–38% of samples and PFOA detected in 21–35% (Zafeiraki et al., 2015; Schwanz et al., 2016)] and Brazil [e.g., detection of PFOS in 100% of samples and of PFOA in 33% of samples (Schwanz et al., 2016)]; and in drinking water samples collected during 2017 in 79 cities in China (all samples had detectable levels of at least one type of PFAS) (Li et al., 2019).

Cancer is one of the health effects of interest in relation to PFAS exposures. Part of the reason for concern about PFAS and cancer is that, in rats, administration of PFOA has been associated with development of testicular Leydig cell adenomas, pancreatic acinar cell adenomas, and hepatocellular adenomas or carcinomas, and with promotion of hepatocellular carcinoma development after treatment with N-nitrosodiethylamine (IARC, 2017); and PFOS administration has been associated with development of hepatocellular adenomas and thyroid follicular cell adenomas (Lau et al., 2007; Chang et al., 2014). Studies in rainbow trout found evidence that PFOA promoted development of liver tumors after initiation by aflatoxin B or N-methyl-N′-nitro-N-nitrsoguanidine (IARC, 2017). A recent study by the National Toxicology Program (NTP), that included rats with both prenatal and postnatal exposure to PFOA, found PFOA exposure to be associated with development of benign and malignant liver and pancreatic tumors in male rats and with increased pancreatic tumors in female rats, with no clear difference between rats with both prenatal and postnatal exposure and those exposed only postnatally. That report concluded that there was clear evidence of carcinogenicity in male rats and some evidence of carcinogenicity in female rats (National Toxicology Program, 2020). However, in some instances the mechanism by which PFOA is thought to cause tumors in rats (PPARα activation) does not appear as relevant in humans (ATSDR, 2018, p. 446 (Cancer Mechanisms)). In addition, the testicular tumors observed in rats were Leydig tumors, which are very rare in humans (Kennedy et al., 2004).

In light of the uncertain relevance of studies of PFAS and cancer in rodents to human cancers, epidemiologic studies of PFAS and cancer can provide valuable additional information. There have been a relatively large number of studies of human cancer and PFAS. Our purpose here is to review that evidence critically from an epidemiologic standpoint, to identify the types of study designs that have been used, along with their strengths and weaknesses, and to try to highlight directions for future research that would be the most likely to meaningfully increase knowledge. We used the approach of a scoping review for this assessment (Tricco et al., 2018) because we sought to summarize the information available from studies with a wide variety of study designs for a variety of types of PFAS and cancer types. Several previous reviews focused on PFAS and cancer have been published (e.g., IARC, 2017; ATSDR, 2018; EFSA CONTAM Panel, 2018; Chang et al., 2014; Arrieta-Cortes, 2017), and some have commented on study design issues. However, we sought to provide an up-to-date review with a more in-depth consideration of features of study design.