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dc.contributor.authorHenderson, William Matthew
dc.description.abstractPerfluorinated chemicals (PFCs) are anthropogenic and currently, there are no known natural sources of long-chain perfluorinated carboxylic acids (PFCAs) such as perfluorooctanoic acid (PFOA) or perfluorononanoic acid (PFNA) in the environment. The most plausible explanation for global dissemination is that stable acids like PFOA and PFNA are formed as metabolism and/or degradation products of several structurally-related homologues in the atmosphere, specifically 8-2 fluorotelomer alcohol (8-2 FTOH). An appropriate animal model is needed to fully elucidate the mechanisms of 8-2 FTOH metabolism and distribution in mammals. The objectives of this study were to 1) develop a method to simultaneously quantify known volatile and non-volatile metabolites of 8-2 FTOH, 2) determine the metabolism and distribution of 8-2 FTOH in adult male, female and pregnant CD-1 mice, and 3) determine the developmental effects to fetal and neonatal mice following in utero and post-natal exposure to 8-2 FTOH. Initially, a GC/MS method was developed and tested based on selected ion monitoring ofperfluorinated alkyl parent chain fragment ions (131, 169, 231 and 331 m/z). The method instrument detection limits are between 7.1 and 24.5 ng/mL extract, and the method quantification limits are below 50 ng/mL or ng/g in all matrices. In order to determine the pharmacokinetics of 8-2 FTOH metabolism, CD-1 mice received a gavage dose (10-30 mg 8-2 FTOH/kg BW) in a propylene glycol/water (1:1) vehicle on day 0 and timed-pregnant mice were dosed (30 mg 8-2 FTOH/kg BW) on gestational day (GD) 8. Animals were serially sacrificed and tissues excised for analysis via GC/MS. 8-2 FTOH was rapidly metabolized and no longer present by 48 hrs post-treatment (PT) and the estimated half-life (t1/2) of 8-2 FTOH in serum of male and female mice was 6.2 and 5.8 hrs, respectively. In male mice, maximal PFOA concentrations in serum (992±38 ng/mL) and liver (902±27 ng/g) were at 12 hrs PT and decreased temporally for up to 120 hrs. The maximum concentrations in serum and liver of female (768±25 ng/mL and 699±38 ng/g) and pregnant mice (789±41 ng/mL and 673±23 ng/g) also occurred by 24 hrs PT. Using least-squares regression, the t1/2 in male mice was 15.1 d and was comparable to female mice (14.9 d). However, during gestation (GD 8-18), the calculated t1/2 was 31.3 d, but values after parturition were similar to non-pregnant females (12.9 d). PFOA appears in the developing fetus as early as 24 hrs PT and exposure of neonates to metabolites of 8-2 FTOH can occur both pre- and post-natally following a single oral maternal dose on GD8. Estimated PFOA t1/2 in liver was 8.2, 9.2 and 28.4 d for male, female and pregnant mice, respectively. In conclusion, 8-2 FTOH is rapidly metabolized to PFOA in adult male, female and pregnant mice. Sex-mediated elimination is absent, but pregnant mice retain PFOA approximately 2x longer in serum than non-pregnant females suggesting that physiologic changes during pregnancy increase PFOA retention. Furthermore, maternal-fetal transfer of the
dc.subjectperfluorinated compounds
dc.subjectperfluorooctanoic acid
dc.subjectperfluorononanoic acid
dc.subjectfluorotelomer alcohols
dc.subject8-2 FTOH
dc.subjectdevelopmental toxicity
dc.subjectin utero exposure
dc.subjectCD-1 mouse
dc.titleComparative metabolism and distribution of 8-2 fluorotelomer alcohol (FTOH) in male, female and pregnant mice
dc.description.departmentEnvironmental Health Science
dc.description.advisorMary Alice Smith
dc.description.committeeMary Alice Smith
dc.description.committeeEric J. Weber
dc.description.committeeRandall O. Manning
dc.description.committeeRonald T. Riley
dc.description.committeeErin K. Lipp

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