The toxicity of Perfluorohexanoic acid

Description

Perfluorohexanoic Acid (PFHxA) and its related salts are members of the group of per and polyfluoroalkyl substances (PFAS). Concerns about PFHxA and other PFAS stem from the resistance of these compounds to hydrolysis, photolysis, and biodegradation, which leads to their persistence in the environment. PFAS are not naturally occurring in the environment; they are man-made compounds used widely over the past several decades in consumer products and industrial applications because of their resistance to heat, oil, stains, grease, and water[1-2]. In 2017, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) proposed a human health chronic oral toxicity value (0.32 mg/kg-day) for PFHxA that is more than four orders of magnitude greater (i.e., less toxic) than the oral toxicity value derived by the U.S. Environmental Protection Agency (USEPA) for the drinking water health advisory for PFOA (0.00002 mg/kg-day).

Oral toxicity

Two studies investigating the acute oral toxicity of PFHxA were identified. First, Loveless et al. dosed fasted female Crl: CD(SD) rats with a single oral (gavage) dose of sodium perfluorohexanoate (NaPFHx) at 175, 550, 1,750, or 5000 mg/kg BW. Rats were monitored for clinical signs of toxicity for up to 14 days. No mortality was observed in the 175 or 550 mg/kg treatment groups; one of four rats died on the day of dosing in the 1750 mg/kg treatment group, and all rats in the 5000 mg/kg treatment group died within 1 day after dosing. Clinical signs of toxicity occurred at the highest dose groups. They included abnormal gait, ataxia, dehydration, high or low posture, lethargy, oral and nasal discharge, and wet or stained fur observed in many surviving rats. Loveless et al. do not report the severity, dose dependency, or day these effects were observed[3].

Research indicates that the acute oral LD50 for rats ranges from>1750 to <5000 mg/kg. USEPA (2016a) identified studies that reported an LD50 for rats in the range of 250–1000 mg/kg for PFOA. Comparatively, the acute oral toxicity of PFOA is 3- to 20-fold greater than that of PFHxA.

In vitro toxicity

The acute toxicity of PFAAs, including PFHxA, has also been tested in vitro. PFHxA is acutely irritating. Several studies have shown that toxicity is dependent on chain length. Using human colon carcinoma cells (HCT116), Kleszczyński et al. demonstrated that 24-h EC50 values (based on cell viability measured using the MTT assay) decrease with chain length (PFHxA [4154 μM] > PFHpA [1386 μM] > PFOA [937 μM] > PFNA [708 μM] > PFDA [283 μM] > PFDoDa [136 μM]). Similarly, Mulkiewicz et al. reported chain-length-dependent reductions in cell viability EC50 values in promyelocytic leukemia rat cells (IPC-81), rat glioma cells (C6), and Vibrio fischeri. PFHxA was less toxic (EC50 values 3–12 fold larger) than PFOA in every cell line tested. Finally, Buhrke et al. demonstrated that PFHxA is less cytotoxic than PFOA (IC50s = 344 and 47 μM, respectively) and is a less potent inducer of cell proliferation in human hepatocarcinoma cells (HepG2). USEPA and NIH ran PFHxA through their Tox21 high-throughput bioassays. These in vitro results demonstrate that PFHxA is 3–12-fold less toxic than PFOA in acute exposure to cultured cell lines.

References

[1] Lilong Jiang. “Comprehensive multi-omics approaches reveal the hepatotoxic mechanism of perfluorohexanoic acid (PFHxA) in mice.” Science of the Total Environment (2021): 148160.

[2] James E Klaunig. “Evaluation of the chronic toxicity and carcinogenicity of perfluorohexanoic acid (PFHxA) in Sprague-Dawley rats.” Toxicologic Pathology 43 2 (2015): 209–20.

[3] Anthony L. Luz . “Perfluorohexanoic acid toxicity, part I: Development of a chronic human health toxicity value for use in risk assessment.” Regulatory Toxicology and Pharmacology 103 (2019): Pages 41-55.

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