Liver cancer is one of the most rapidly increasing cancers over the past decades in the United States. The
causes for this long-term increase are unclear, but could stem from exposures to possibly carcinogenic
environmental contaminants. One likely source is per- and polyfluoroalkyl substances (PFAS), a group of
synthetic chemicals that are highly persistent and accumulate in human liver tissue. Emerging, converging
evidence from laboratory animals and occupational mortality studies strongly support the role of PFAS in liver
carcinogenesis. However, these studies are limited by small sample sizes, restriction to occupational
exposure, and studying single types of PFAS. Hence, we propose the first comprehensive prospective pooled
cohort study in non-occupational settings to examine real-world human exposure to PFAS (of multiple types
and mixtures) in relation to liver cancer incidence. Our long-term goal is to identify novel risk factors for liver
cancer to reduce liver cancer burden. Moreover, liver cancer incidence is higher in African Americans and
Hispanics compared with whites, but the causes of these disparities remain unclear. Furthermore, more liver
cancer cases in the United States are not caused by chronic hepatitis B virus (HBV) and C virus (HCV)
infections, but risk factors for non-viral liver cancer remain poorly understood. The objective of this proposal is
to comprehensively assess the relationship between mixture exposure to PFAS and liver cancer risk overall,
by racial/ethnic groups, and by HBV/HCV status. To do so, we propose this first comprehensive study to
date of exposures to PFAS and liver cancer risk through a pooling project that leverages extensive resources
from six well-characterized cohort studies. This pooling project includes a racially/ethnically diverse population
followed for up to 32 years, along with pre-diagnosis plasma samples and validated covariate data. Our
specific aims are to characterize the associations between plasma levels of PFAS and risk of developing liver
cancer in this pooled nested case-control study with measured HBV/HCV status data (Aim 1); and assess the
extent to which certain PFAS mixture patterns act synergistically to increase liver cancer risk (Aim 2). In
exploratory aims, we will quantify the aforementioned associations by major liver cancer subtypes, and further
estimate the associations between plasma PFAS levels and survival among patients with liver cancer. This
proposal is innovative in addressing an important, yet understudied research area of PFAS and liver cancer
through integrating cutting-edge technologies of PFAS assays and advanced methods of mixture analyses into
longitudinal cohort studies. The contribution is significant because this research will generate new insights into
the etiology of liver cancer, enable design of new prevention/intervention strategies and actions that reduce
liver cancer morbidity and mortality and related disparities. These findings will also provide new information on
health effects of PFAS for practitioners and regulatory agencies to make solid decisions, regulations, and
action plans to improve public health.
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