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P47—Retrospective exposure estimation for perfluorooctanoic acid (PFOA) for participants in the C8 health project
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Abstracts / Reproductive Toxicology 33 (2012) 1–29
controls received water. Like PFOS and PFOA, PFNA did not affect maternal weight gain, number of implantations, fetal viability or fetal weight in both species. Maternal hepatomegaly and minor delays in anatomical development of the fetus were noted both in rats and mice. Mouse pups were born alive and survival in the 1 and 3 mg/kg PFNA groups was not different from that in controls. In contrast, 80% of 5 mg/kg PFNA exposed mice neonates died within the first 10 days of life, whereas no neonatal death was observed in the rat. However, PFNA-induced neonatal death differed somewhat from that induced by PFOS or PFOA, in that PFNA-exposed pups survived a few days longer than those exposed to PFOS or PFOA, which typically died within the first 2–3 days of postnatal life. In rat pups exposed to 5 mg/kg PFNA had significantly lower birth weight than controls (16%), which remained lower than controls through early postnatal development. Surviving mice neonates exposed to PFNA exhibited dose-dependent deficits in growth and development (eye-opening, onset of puberty). In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neonatal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPAR␣) genes and molecular signals by PFNA that resembled the response of PFOA. Our results indicate developmental toxicity of PFNA comparable to that of PFOA, suggesting these effects are common to perfluoroalkyl acids that persist in the body. This abstract does not necessarily reflect U.S. EPA policy. doi:10.1016/j.reprotox.2011.11.080 P47—Retrospective exposure estimation for perfluorooctanoic acid (PFOA) for participants in the C8 health project Hyeong-Moo Shin 1,∗ , Verónica Vieira 2 , P. Barry Ryan 3 , Russell etwiler 1 , Brett Sanders 1 , Kyle Steenland 3,4 , Scott Bartell 1 1
University of California-Irvine, Irvine, CA, United States Boston University, Boston, MA, United States 3 Emory University, Atlanta, GA, United States 4 C8 Science Panel, Atlanta, GA, United States 2
Background/aims: The primary source of perfluorooctanoic acid in the environment of eastern Ohio and western West Virginia is believed to be the DuPont Washington Works facility. Percolation of aerially deposited perfluorooctanoic acid downwards through the soil and pumping by industrial and municipal wells near the contaminated Ohio River is thought to explain elevated well water concentrations observed in six municipal water districts and human serum concentrations measured in recent years. Our objective is to estimate historical perfluorooctanoic acid exposures and historical serum concentrations experienced by each of the participants in the C8 Health Project who consented to share their residential histories, excluding those who reported ever depending on bottled water, those who had missing residential histories during any of the 16 years prior to the serum samples, and those who identified past or present DuPont employment. Methods: We linked several environmental fate and transport models including AERMOD, PRZM3, BREZO, MODFLOW, and MT3D to simultaneously model PFOA air dispersion, transit through the unsaturated soil zone, surface water transport, and groundwater flow and transport. Annual PFOA exposure rates were estimated for each individual based on predicted calibrated water concentrations and predicted air concentrations, individual residential histories, and default assumptions from the EPA Exposure Factors Handbook. Individual exposure estimates were coupled with a onecompartment pharmacokinetic model to estimate time-dependent serum concentrations for 31,517 participants.
Results: Prior to calibration, predicted water concentrations were within 2.1 times the observed mean water concentrations for all six municipal water districts. Using calibrated water concentrations, predicted and observed median serum concentrations in 2005–2006 are 12.1 and 24.5 ppb, respectively (Spearman’s rho = 0.66). Conclusion: Our linked fate and transport and toxicokinetic models predict recently observed municipal water concentrations reasonably well and only slightly under-predict observed serum concentrations. These models will be used to produce individualized retrospective exposure estimates for a variety of epidemiologic studies being conducted in this region. doi:10.1016/j.reprotox.2011.11.081 P48—Developmental toxicity of perfluorononanoic acid in the wild-type and PPAR-alpha knockout mouse after gestational exposure C.J. Wolf 1,∗ , R.D. Zehr 2 , J.E. Schmid 2 , C. Lau 1 , B.D. Abbott 1 1
Toxicology Assessment Division, Research Triangle Park, NC, United States 2 Research Core Unit, NHEERL, ORD, USEPA, Research Triangle Park, NC, United States
Perfluorononanoic acid (PFNA) is a perfluoroalkyl acid detected in the environment and in tissues of humans and wildlife, and its concentration in human serum has increased in the past few years. PFNA negatively affects development and survival of CD1 mice and activates peroxisome proliferator-activated receptor-alpha (PPAR␣) in vitro. Our objective was to characterize the developmental effects and serum levels of PFNA in 129S1/SvlmJ wild type (WT) and PPAR␣-knockout (KO) mice after gestational exposure, and determine the dependence of PFNA toxicity on PPAR␣. Sperm positive WT and KO females were dosed orally with water (vehicle control; 0.01 ml/g), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GD) 1–18 (day of plug = GD 0). Dams and pups were monitored daily and euthanized at postnatal day 21 (pups) or 42 days post-coitus (adults). Serum was collected from adults and from 2 pups per litter. Dam weight gain during gestation, uterine implantation and pup birth weight were not affected by treatment in either strain. The number of live pups at term and the survival of offspring to weaning were drastically reduced in WT 1.1 and 2 mg/kg groups (p < 0.05, p < 0.001). Pup eye opening was delayed by 2 days and postnatal pup weight was reduced in WT at 2 mg/kg. None of these endpoints was affected in the KO. Relative liver weight at weaning in both dams and pups was increased in all treated WT groups (p < 0.001), but only in the highest dose group in KO dams and pups (p < 0.001). PFNA was present in the serum of all mice in a dose-dependent manner and levels were higher in treated animals compared to controls (p < 0.0001). Serum levels of PFNA were generally higher in pups than in dams. In dams, serum levels of PFNA were higher in WT than in KO. In pups, PFNA levels were higher in KO compared to WT (p < 0.0001), despite no adverse developmental effects in KO. These results suggest that effects of PFNA on pup development, survival to weaning, and liver weight in dams and pups are dependent on PPAR␣. This abstract does not necessarily reflect USEPA policy. doi:10.1016/j.reprotox.2011.11.082
Abstracts / Reproductive Toxicology 33 (2012) 1–29
controls received water. Like PFOS and PFOA, PFNA did not affect maternal weight gain, number of implantations, fetal viability or fetal weight in both species. Maternal hepatomegaly and minor delays in anatomical development of the fetus were noted both in rats and mice. Mouse pups were born alive and survival in the 1 and 3 mg/kg PFNA groups was not different from that in controls. In contrast, 80% of 5 mg/kg PFNA exposed mice neonates died within the first 10 days of life, whereas no neonatal death was observed in the rat. However, PFNA-induced neonatal death differed somewhat from that induced by PFOS or PFOA, in that PFNA-exposed pups survived a few days longer than those exposed to PFOS or PFOA, which typically died within the first 2–3 days of postnatal life. In rat pups exposed to 5 mg/kg PFNA had significantly lower birth weight than controls (16%), which remained lower than controls through early postnatal development. Surviving mice neonates exposed to PFNA exhibited dose-dependent deficits in growth and development (eye-opening, onset of puberty). In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neonatal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPAR␣) genes and molecular signals by PFNA that resembled the response of PFOA. Our results indicate developmental toxicity of PFNA comparable to that of PFOA, suggesting these effects are common to perfluoroalkyl acids that persist in the body. This abstract does not necessarily reflect U.S. EPA policy. doi:10.1016/j.reprotox.2011.11.080 P47—Retrospective exposure estimation for perfluorooctanoic acid (PFOA) for participants in the C8 health project Hyeong-Moo Shin 1,∗ , Verónica Vieira 2 , P. Barry Ryan 3 , Russell etwiler 1 , Brett Sanders 1 , Kyle Steenland 3,4 , Scott Bartell 1 1
University of California-Irvine, Irvine, CA, United States Boston University, Boston, MA, United States 3 Emory University, Atlanta, GA, United States 4 C8 Science Panel, Atlanta, GA, United States 2
Background/aims: The primary source of perfluorooctanoic acid in the environment of eastern Ohio and western West Virginia is believed to be the DuPont Washington Works facility. Percolation of aerially deposited perfluorooctanoic acid downwards through the soil and pumping by industrial and municipal wells near the contaminated Ohio River is thought to explain elevated well water concentrations observed in six municipal water districts and human serum concentrations measured in recent years. Our objective is to estimate historical perfluorooctanoic acid exposures and historical serum concentrations experienced by each of the participants in the C8 Health Project who consented to share their residential histories, excluding those who reported ever depending on bottled water, those who had missing residential histories during any of the 16 years prior to the serum samples, and those who identified past or present DuPont employment. Methods: We linked several environmental fate and transport models including AERMOD, PRZM3, BREZO, MODFLOW, and MT3D to simultaneously model PFOA air dispersion, transit through the unsaturated soil zone, surface water transport, and groundwater flow and transport. Annual PFOA exposure rates were estimated for each individual based on predicted calibrated water concentrations and predicted air concentrations, individual residential histories, and default assumptions from the EPA Exposure Factors Handbook. Individual exposure estimates were coupled with a onecompartment pharmacokinetic model to estimate time-dependent serum concentrations for 31,517 participants.
Results: Prior to calibration, predicted water concentrations were within 2.1 times the observed mean water concentrations for all six municipal water districts. Using calibrated water concentrations, predicted and observed median serum concentrations in 2005–2006 are 12.1 and 24.5 ppb, respectively (Spearman’s rho = 0.66). Conclusion: Our linked fate and transport and toxicokinetic models predict recently observed municipal water concentrations reasonably well and only slightly under-predict observed serum concentrations. These models will be used to produce individualized retrospective exposure estimates for a variety of epidemiologic studies being conducted in this region. doi:10.1016/j.reprotox.2011.11.081 P48—Developmental toxicity of perfluorononanoic acid in the wild-type and PPAR-alpha knockout mouse after gestational exposure C.J. Wolf 1,∗ , R.D. Zehr 2 , J.E. Schmid 2 , C. Lau 1 , B.D. Abbott 1 1
Toxicology Assessment Division, Research Triangle Park, NC, United States 2 Research Core Unit, NHEERL, ORD, USEPA, Research Triangle Park, NC, United States
Perfluorononanoic acid (PFNA) is a perfluoroalkyl acid detected in the environment and in tissues of humans and wildlife, and its concentration in human serum has increased in the past few years. PFNA negatively affects development and survival of CD1 mice and activates peroxisome proliferator-activated receptor-alpha (PPAR␣) in vitro. Our objective was to characterize the developmental effects and serum levels of PFNA in 129S1/SvlmJ wild type (WT) and PPAR␣-knockout (KO) mice after gestational exposure, and determine the dependence of PFNA toxicity on PPAR␣. Sperm positive WT and KO females were dosed orally with water (vehicle control; 0.01 ml/g), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GD) 1–18 (day of plug = GD 0). Dams and pups were monitored daily and euthanized at postnatal day 21 (pups) or 42 days post-coitus (adults). Serum was collected from adults and from 2 pups per litter. Dam weight gain during gestation, uterine implantation and pup birth weight were not affected by treatment in either strain. The number of live pups at term and the survival of offspring to weaning were drastically reduced in WT 1.1 and 2 mg/kg groups (p < 0.05, p < 0.001). Pup eye opening was delayed by 2 days and postnatal pup weight was reduced in WT at 2 mg/kg. None of these endpoints was affected in the KO. Relative liver weight at weaning in both dams and pups was increased in all treated WT groups (p < 0.001), but only in the highest dose group in KO dams and pups (p < 0.001). PFNA was present in the serum of all mice in a dose-dependent manner and levels were higher in treated animals compared to controls (p < 0.0001). Serum levels of PFNA were generally higher in pups than in dams. In dams, serum levels of PFNA were higher in WT than in KO. In pups, PFNA levels were higher in KO compared to WT (p < 0.0001), despite no adverse developmental effects in KO. These results suggest that effects of PFNA on pup development, survival to weaning, and liver weight in dams and pups are dependent on PPAR␣. This abstract does not necessarily reflect USEPA policy. doi:10.1016/j.reprotox.2011.11.082