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PEFLUOROOCTANOIC ACID-INDUCED IMMUNOMODULATION IN C57BL/6 FEMALE MICE
Citation:
DEWITT, J., C. B. COPELAND, AND R. W. LUEBKE. PEFLUOROOCTANOIC ACID-INDUCED IMMUNOMODULATION IN C57BL/6 FEMALE MICE. Presented at Toxicokinetics and Mode-of-Action Workshop, Arlington, VA, February 14 - 16, 2007.
Description:
Perfluorooctanoic acid (PFOA), used in fluoropolymer production, is environmentally persistent, present in human and wildlife populations worldwide, and associated with myriad health effects in laboratory animals. A preliminary risk assessment by the US EPA identified immunosuppression as an endpoint of concern, citing reports of splenic and thymic atrophy and reduced antibody synthesis in adult mice fed 30 mg PFOA/kg body weight (BW) for 15d (Yang et al., 2001, 2002). The level of Agency concern and lack of corroborating studies warranted a more thorough dose-response assessment. C57BL/6 female mice were given 0, 3.75, 7.5, 15, or 30 mg PFOA/kg BW in drinking water for 15d in two separate studies. Mice were immunized with SRBC on d11 of dosing and sera for evaluation of IgM titers was collected 1d post-dosing (PD). Booster immunizations with SRBC were given 10d PD and sera for evaluation of IgG titers was collected 15d PD. Mice were sensitized to BSA on d11 of dosing, challenged with BSA 3d PD, and footpad swelling measured 4d PD. The dose-response curves of the two studies were compared at each endpoint, and as the effective doses (ED50s) did not differ statistically, the results of the two studies were combined. IgM titers were suppressed at all PFOA doses; IgG titers were elevated at the two lower doses, suggesting recovery and rebound. DTH responses were not altered by PFOA exposure. At 1d PD, 15 and 30 mg PFOA/kg decreased body weights and relative spleen and thymus weights. All doses of PFOA increased relative liver weights. By 15d PD, body, spleen and thymus weights were normalizing but liver weights remained elevated. These data indicate that 15d of PFOA exposure suppresses IgM titers but that humoral function recovers within 15d PD. Similar recovery was observed in spleen and thymus weights 15d PD. DTH responses appear less sensitive than humoral responses. Although we failed to identify a NOAEL for the immune functions evaluated, our LOAEL for IgM titers (3.75 mg PFOA/kg) was nearly 10-fold lower than the LOAEL of 30 mg PFOA/kg reported by Yang et al. (2002). [This abstract does not reflect EPA policy and was supported by UNC/EPA Cooperative Training Agreement CT829472.]