Characterizing the chronic oral reproductive toxicity of per-and polyfluoroalkyl substances (PFAS) and their mixtures to terrestrial ecological receptors to inform ecotoxicological risk assessment of PFAS-impacted ecosystems

Per‐ and poly‐fluoroalkyl substances (PFAS) are a broad class of environmentally persistent chemicals that include thousands of potentially toxic synthetic organic molecules. Terrestrial toxicology data are particularly lacking in order to derive the toxicological reference values (TRVs) necessary to complete a comprehensive ecotoxicological risk assessment (ERA) of PFAS-impacted environments. This is partly due to the existence of PFAS as mixtures in the environment, which complicates logistical dose-response modeling and the establishment of threshold values that are used to characterize the chronic oral toxicity of PFAS solutions to ecological receptors. Characterizing the chronic toxicity of PFAS is necessary because of the global presence of PFAS in nearly every environmental compartment previously tested over the past two decades, now coupled with the adverse health effects reported in the epidemiological and toxicological literature regarding chronic PFAS exposure. To derive TRVs and complete comprehensive ERAs of PFAS-impacted ecosystems for wildlife inhabiting the area, species- and tissue-specific chronic toxicity values (CTVs) are required. Therefore, we set out to provide these necessary CTVs using a representative upland gamebird species for our model organism. To complete this goal, we performed four traditional avian reproductive toxicology studies according to current guidelines. We examined reproduction, growth, and survival endpoints using a combination of hypothesis testing and logistical dose-response modeling for a single avian species (Colinus Virginianus) chronically orally exposed via drinking water during reproduction to perfluorooctane sulfonate (PFOS), perfluorohexanoic acid (PFHxA), a binary PFOS and perfluorohexane sulfonate (PFHxS) mixture, and a binary PFOS and PFHxA mixture. We further quantified and reported the PFAS residues from liver tissue and eggs from the test animals chronically exposed to the PFAS treatment levels that produced the no-observable-adverse-effect-level (NOAEL) and/or lowest-observable-adverse-effect-level (LOAEL) thresholds in the model organism during the chronic exposures.
Both NOAEL and LOAEL thresholds were established for each exposure based on observed chronic toxicity in several variables relative to the controls (e.g., reduced female weight gain, decreased offspring weight and growth rate at 21-days post-hatch, decreased successful liberation from the shell once pipped, increased infertility, reduced juvenile survival, decreased hatching success, and earlier arrested embryonic development). Based on these observed adverse health effects to avian receptors, the tissue-and species-specific PFAS LOAEL CTVs were estimated for oral exposure concentration, average daily intake (ADI), adult and juvenile liver tissue, and whole-egg homogenates. For single chemical avian exposure to PFOS, the estimated oral exposure concentration, ADI, adult liver-tissue, juvenile liver tissue, and a whole-egg homogenate LOAEL CTVs were 18.7 ng/mL, 2.45 × 10−3 mg/kg body weight/d, 21.4 ng/g wet wt, 23.7 ng/g wet wt, and 92.4 ng/g wet wt, respectively. For binary chemical avian exposure to a 1.2:1 PFOS:PFHxS mixture, the estimated oral exposure concentration, ADI, adult liver-tissue, juvenile liver tissue, and a whole-egg homogenate LOAEL CTVs were 22.9 ng/mL, 3.10 × 10−3 mg/kg body weight/d, 46.9 ng ∑PFAS/g wet wt, 22.7 ng ∑PFAS/g wet wt, and 81.3 ng ∑PFAS/g wet wt, respectively. For single chemical and binary chemical avian exposure to either PFHxA or 2.1-2.8:1 PFOS:PFHxA mixture solutions, the estimated oral exposure concentration, ADI, and whole-egg homogenates LOAEL CTVs were 0.10 and 0.06 ng/mL, 1.49x10-5 and 8.19x10-6 mg x kg bw-1 x d-1, and 0.092 and 0.890 ng/g wet wt, respectively. PFHxA and PFOS were not detected in the adult or juvenile liver tissues as a result of chronic oral exposure to PFHxA or the PFOS:PFHxA mixture at the treatment levels that produced the LOAEL CTVs. The CTVs estimated herein for NBQ presently exposed via drinking water are comparatively much lower than the current avian TRV estimated for PFOS derived from birds that were exposed via feed. Thus, the current avian PFOS TRV may not be fully protective of wild avian populations at PFAS‐impacted sites, suggesting the need for updated avian PFAS TRVs. Relationships between test chemicals (PFOS or PFHxA) and test substances (PFOS:PFHxS or PFOS:PFHxA) showed that PFOS may have possible interacting effects in avian receptors when mixed with either PFHxS or PFHxA and likely has differing mechanisms of toxicity depending on chemical co‐occurrence and dose. Comparison between like studies showed that PFHxA exposure was much more toxic to reproducing quail than PFOS exposure when each were administered singly as well as when the two were mixed vs when PFOS was mixed with another sulfonate as evidenced by the lower CTVs produced by exposure to PFHxA and the PFOS:PFHxA mixture vs PFOS and a PFOS and PFHxS mixture. This defies our assumptions regarding the relative toxicity and bioaccumulation potential of certain PFAS (i.e., longer vs shorter chained PFAS and sulfonated vs carboxylated PFAS). The results among all health parameters presently studied demonstrate that reaction(s) occur among the individual PFAS present in a PFAS mixture to alter the potential toxicity of the individual PFAS present in that mixture to exposed birds, indicating that mixtures play an important role in avian PFAS toxicity. Therefore, chronic oral PFAS toxicity to avian receptors represented as the sum of the individual toxicities of the measured PFAS may not necessarily be the best method for assessing chronic PFAS mixture exposure risk to avian receptors at PFAS-impacted sites. The mixture exposure CTVs presently estimated mirrored the single chemical exposure CTVs demonstrating that the toxicity of PFAS mixtures tends to mirror the toxicity of the single chemical within the mixture exhibiting the lowest CTV. Thus, ERAs completed using sum PFAS may severely underestimate health risk to avian receptors inhabiting PFAS-impacted ecosystems and could likely benefit from reassessment. The single-species avian PFAS LOAEL CTVs provided herein are representative of possible population-level adverse health effects, can be modified with the use of uncertainty factors to derive class-wide avian TRVs for site-specific ERAs, and are immediately useful for assessing reproductive health risk to wild avian receptors at PFAS-impacted sites.

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