PFAS and cholesterol in epidemiological studies: causality, biomarkers, mixtures and relative potency

Abstract

Concern continues about adverse effects, including raised cholesterol, associated with perfluorinated substances (PFAS) in general and perfluoro-octanoic acid (PFOA) in particular, and whether all associations are truly causal. There have been numerous epidemiological studies of blood concentrations (usually cross-sectional studies of serum concentrations) of PFOA and cholesterol. In addition to the usual sources of potential confounding, using serum PFOA as the exposure raises the possibility of confounding by physiology, for example, enterohepatic recirculation and correlated absorption of both PFAS and bile acids or cholesterol. Mechanistic toxicology studies of the pharmacodynamics of PFOA and cholesterol may shed light on the plausibility of these various causal and artefactual contributions to the associations, but the large and complex C8 dataset offers the possibility of assessing directly the strength of the epidemiological evidence in favour of this association being causal.District level measures of exposure offer a way of addressing exposure response immune from confounding by physiology, acting as instrumental variables for exposure. For 40,000 adults 18+ in the C8 study population, there was a strong and significant association of cholesterol, in relation to serum PFOA, adjusting for sex, age, race and other measured potential confounders. New results using the instrumental variable approach by water district contamination level showed a similar, significant dose response, and the concordance of the two approaches strongly supports a causal interpretation of the association. Comparison of slopes suggests that about half of the association with PFOA in single pollutant models is explained by confounding. A similar change in slope is achieved in cross sectional analyses by adding adjustment for other PFASs in the blood. Slopes for each PFAS in multi-pollutant models thus allow the estimation of relative potency which is helpful for risk assessment in populations with mixed PFAS exposure.