Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms.

Serum concentrations of cholesterol are positively correlated with exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans. The associated change in cholesterol is small across a broad range of exposure to PFOA and PFOS. Animal studies generally have not indicated a mechanism that would account for the association in humans. The extent to which the relationship is causal is an open question. Nonetheless, the association is of particular importance because increased serum cholesterol has been considered as an endpoint to derive a point of departure in at least one recent risk assessment. To gain insight into potential mechanisms for the association, both causal and non-causal, an expert workshop was held Oct 31 and Nov 1, 2019 to discuss relevant data and propose new studies. In this report, we summarize the relevant background data, the discussion among the attendees, and their recommendations for further research.

Use of anatomical and kinetic models in the evaluation of human food additive safety.

Toxicological testing in animals is relied upon as a surrogate for clinical testing of most food additives. Both animal and human clinical test results are generally available for direct additives when high levels of exposure are expected. Limited animal studies or in vitro test results may be the only sources of toxicological data available when low levels of exposure (microg/person/day) are expected and where no effects of the additive on the food itself are desired. Safety assessment of such materials for humans requires mathematical extrapolation from any effects observed in test animals to arrive at acceptable daily intakes (ADIs) for humans. Models of anatomy may be used to estimate tissue and organ weights where that information is missing and necessary for evaluation of a data set. The effect of growth on target tissue exposure during critical phases of organ development can be more accurately assessed when models of growth and known physiological changes are combined with pharmacokinetic results for test species. Kinetic models, when combined with limited chemical property, kinetic, and distribution data, can often be used to predict steady-state plasma and tissue levels of a test material over the range of doses employed in chronic studies to aid in interpretation of effects that are often nonlinear with respect to delivered dose. A better understanding of the reasons for nonlinearity of effects in animals improves our confidence in extrapolation to humans.