A comparative toxicological and epidemiological evaluation of dioxins and PFAS chemicals

Regulatory frameworks, informed by robust and transparent scientific evidence, can significantly benefit society when thoughtful and measured regulation is promulgated. However, regulations founded on incomplete or misinterpreted science often result in unintended consequences. As was the case with the polychlorinated dibenzodioxin and polychlorinated dibenzofuran (PCDD/PCDF) chemicals, for the past 50 years, there has been a lack of scientific consensus on the adverse health effects of per- and polyfluoroalkyl substances (PFAS) in humans at current blood concentrations (about 4 ppb TEQ) or even concentrations 10-300-fold higher (40-1200 ppb TEQ). Despite their distinctly different chemical structures, the dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and perfluorooctanoic acid (PFOA)/perfluorooctanesulfonic acid (PFOS), share notable similarities: environmental persistence, biological recalcitrance, slightly unpredictable acute toxicity, a lack of genotoxicity, and suggestive data on adverse health effects in humans; across a wide range of doses. Both substances display varying degrees of acute toxicity across species, and both have been associated with the onset of wasting syndrome in certain animals at fairly high doses, but wasting syndrome is not seen in humans. Although there is moderate to high acute toxicity in multiple animal species for both families of chemicals, there is low acute toxicity in humans. In humans, both compounds interact with fatty acid metabolism. The evidence indicates that both are either weakly genotoxic or non-genotoxic. The dioxins can cause cancer in a variety of animal species, but even in humans exposed to high doses, no increased cancer risk is apparent. PFAS chemicals are similar; weakly carcinogenic in animals and, perhaps, lacking carcinogenic potency in humans. However, unlike with dioxins, high human exposure to PFAS has only occurred in the workplace; thus, few data from highly exposed human populations are available to rigorously evaluate the human cancer risk or other potential effects at elevated doses. Similar to the widespread presence of dioxins reported in the 1970s-1980s, PFAS chemicals are now globally ubiquitous, with detectable concentrations in nearly every individual, fish, and wildlife species. As awareness has increased over time, pressure to prevent the release or manufacture of PFOA and PFOS has decreased the blood concentrations in Americans by 10-fold over the past 15 years, paralleling trends observed with the dioxins when global concerns surfaced. The dioxins were regulated in a heavy-handed manner despite scientific uncertainty regarding their human health risks over a range of exposure levels, as well as a lack of consensus on dose-response relationships, thresholds for adverse effects, and human relevance of high-dose animal studies. The regulatory actions that occurred with the dioxins ultimately resulted in substantial economic and societal costs, even in the face of much uncertainty. This paper examines the parallels between the development of scientific understanding of the health hazards and the eventual regulation of dioxins and PFAS chemicals. For both families of chemicals, the precautionary principle was followed by most agencies rather than solid scientific data during the rulemaking process.