Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B₆C₃F₁/N mice when administered by oral gavage for 28 days

Abstract

Poly-and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF 3 (CF 2 ) 8 COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague-Dawley rats were exposed to 0-2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B 6 C 3 F 1 /N mice were exposed once/week to 0-5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26-89%) was observed following exposure to !0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig þ and NK þ cells were decreased (17.6-27%). At ! 1.25 mg PFDA/kg/week the numbers of splenic CD3 þ , CD4 þ , CD8 þ , and Mac3 þ cells were decreased (10.5-39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24-39%) at !0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral-and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.ARTICLE HISTORY

Risk to human health related to the presence of perfluoroalkyl substances in food

“…Frawley et al. () reported on the effects of PFDA on the immune system (see also Section 3.3.3.2.1 on effects following repeated exposure), when applied to female rats and mice for a period of 28 days. Female Harlan Sprague‐Dawley rats were exposed to 0, 0.125, 0.25, 0.5, 1 or 2 mg PFDA/kg bw per day by oral gavage for 28 days.…”

NTP Technical Report on the Toxicity Studies of Perfluoroalkyl Sulfonates (Perfluorobutane Sulfonic Acid, Perfluorohexane Sulfonate Potassium Salt, and Perfluorooctane Sulfonic Acid) Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

“…This study is part of a larger NTP program to evaluate PFAS chemicals, which has included an assessment of the contribution of perinatal exposure to PFOA chronic toxicity and carcinogenicity in rats 80 ; evaluation of the toxicokinetics of seven PFAS chemicals after a single dose in rats 32 ; and in vitro class evaluations of potential neurotoxicity 81 , mitochondrial toxicity 82 , and immunotoxicity 83; 84 with a follow-up in vivo immune toxicity study on perfluorodecanoic acid 85 .…”

NTP Technical Report on the Toxicity Studies of Perfluoroalkyl Carboxylates (Perfluorohexanoic Acid, Perfluorooctanoic Acid, Perfluorononanoic Acid, and Perfluorodecanoic Acid) Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

“…This study is part of a larger NTP program to evaluate PFAS chemicals, which has included an assessment of the contribution of perinatal exposure to PFOA chronic toxicity and carcinogenicity in rats 101 ; evaluation of the toxicokinetics of seven PFAS chemicals after a single dose in rats 25 ; and in vitro class evaluations of potential neurotoxicity, mitochondrial toxicity 102 , and immunotoxicity 103; 104 with a follow-up in vivo immune toxicity study on perfluorodecanoic acid 105 .…”