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Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms
Citation:
Andersen, M., C. Corton, B. Hagenbuch, U. Apte, T. Fletcher, W. Roth, B. Staels, G. Vega, H. Clewell 3rd, M. Longnecker, AND Chris Lau. Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 459:152845, (2021). https://doi.org/10.1016/j.tox.2021.152845
Impact/Purpose:
Background/Overview: Per- and polyfluoroalkyl substances (PFAS) are organic chemicals with wide industrial and consumer uses. They are found ubiquitously at low levels in the environment and detectable in humans and wildlife. The toxicity profile of some of these chemicals have been described previously by ORD investigators using in vitro and in vivo (rodent) models, and toxicity assessment for selected PFAS is currently being developed. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are two prototypic PFAS that have been studied extensively with laboratory animal models and epidemiological surveys. One of the confounding epidemiological observations is a consistent positive association between serum concentrations of cholesterol and exposure to PFOS and PFOA in humans, although a reduction of serum cholesterol and triglycerides are typically observed in rodents exposed to high doses of these two PFAS. To gain insight into potential mechanisms for the positive association seen in humans, both causal and non-causal, an expert workshop was held to discuss relevant data and propose new studies. Dr. Chris Lau (CPHEA) and Dr. Chris Corton (CCTE) were invited to join this panel of experts. This report summarizes the relevant background data, highlights of the discussion among the workshop participants, and their recommendations for further research. Relevancy to EPA Program/Regional Research Needs/Priorities: ORD is currently reviewing the toxicity profiles of six “legacy” PFAS that may share the same toxicity profiles and mechanisms of toxicity as PFOS and PFOA. Information gleaned from the workshop discussion may be applicable to many chemicals within this class of pollutants. Name(s) of Program Office Reviewer(s) of Earlier Drafts: None. Program Office/Regional Office Co-Authors: None Study Description: The review provides a brief background of PFOS and PFOA and examined four scenarios that may explain the association of serum cholesterol and chemical exposure found in humans. Future investigations that may help to elucidate the causality of the epidemiological findings are proposed. Major Observations and Results: Despite an intense deliberation among the experts, a clear-cut mechanistic hypothesis to support the human association could not be discerned, although a number of studies were proposed to lend clarity to this confounding observation. Impact/Potential Implications of the Findings: Information summarized in this review provides a state-of-science understanding of the association between serum cholesterol and PFOS/PFOA exposure in human populations. Findings Advancing Existing Scientific Knowledge: This review will spur future research to fill data gaps and resolve uncertainties, to facilitate human health risk assessment of these persistent environmental pollutants. Publication Information (journal, book chapter/book) and Estimated Timelines: Once cleared, this manuscript will be submitted to Toxicology for publication consideration. Although the time for peer review and manuscript processing varies considerably from one journal to another, the manuscript likely will appear on-line within 3 to 4 months. Contact: Christopher Lau. Reproductive and Developmental Toxicology Branch, Public Health and Integrative Toxicology Division, Center for Public Health and Environmental Assessment, lau.christopher@epa.gov, (919) 541-5097.
Description:
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.
URLs/Downloads:
DOI: Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms