Evaluation of placental and lactational pharmacokinetics of PFOA and PFOS in the pregnant, lactating, fetal and neonatal rat using a physiologically based pharmacokinetic model.

Perfluoroalkyl carboxylates and sulfonates (PFAAs) have many consumer and industrial applications. Developmental toxicity studies in animals have raised concern about potential developmental effects of PFOA and PFOS in humans. We have developed PBPK models for PFAAs in the rat to help define a relationship between external dose, internal tissue concentrations, and observed adverse effects, and to understand how physiological changes that occur during gestation and lactation affect tissue distribution of PFAAs in the mother, fetus, and neonate. The models developed here expand upon a PBPK model for PFAAs in the adult female rat, and are consistent with available PK data. These models, along with the adult rat PFAA models, published in the companion paper, will help address concerns about possible health effects due to PFAA exposure in the fetus and neonate and will be useful in comparing PK across life stages.

[1]  C. Lau,et al.  Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  Konrad Hungerbühler,et al.  Estimating Consumer Exposure to PFOS and PFOA , 2008, Risk analysis : an official publication of the Society for Risk Analysis.

[3]  A. Koizumi,et al.  Human organic anion transporter hOAT4 is a transporter of perfluorooctanoic acid. , 2009, Basic & clinical pharmacology & toxicology.

[4]  G. Koren,et al.  Designing pregnancy centered medications: drugs which do not cross the human placenta. , 2006, Placenta.

[5]  C. Lau,et al.  Effects of prenatal perfluorooctane sulfonate (PFOS) exposure on lung maturation in the perinatal rat. , 2005, Birth defects research. Part B, Developmental and reproductive toxicology.

[6]  Harvey J Clewell,et al.  Evaluating placental transfer and tissue concentrations of manganese in the pregnant rat and fetuses after inhalation exposures with a PBPK model. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  Anne E. Loccisano,et al.  Comparison and evaluation of pharmacokinetics of PFOA and PFOS in the adult rat using a physiologically based pharmacokinetic model. , 2012, Reproductive toxicology.

[8]  R. G. York,et al.  Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: dose-response, and biochemical and pharamacokinetic parameters. , 2005, Toxicology.

[9]  W. Liu,et al.  Prenatal and postnatal impact of perfluorooctane sulfonate (PFOS) on rat development: a cross-foster study on chemical burden and thyroid hormone system. , 2009, Environmental science & technology.

[10]  J. Holson,et al.  Blood flow during pregnancy in the rat: II. Dynamics of and litter variability in uterine flow. , 1982, Teratology.

[11]  Geary W Olsen,et al.  Comparison of human whole blood, plasma, and serum matrices for the determination of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other fluorochemicals. , 2007, Environmental research.

[12]  D. Mattie,et al.  Predicting age-appropriate pharmacokinetics of six volatile organic compounds in the rat utilizing physiologically based pharmacokinetic modeling. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[13]  Rebecca A Clewell,et al.  Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  Gerald L Kennedy,et al.  Comparative responses of rats and mice exposed to linear/branched, linear, or branched ammonium perfluorooctanoate (APFO). , 2006, Toxicology.

[15]  W. Slusser,et al.  Effect of malnutrition during pregnancy on the development of the mammary glands of rats. , 1981, The Journal of nutrition.

[16]  M. Andersen,et al.  Lactational transfer of manganese in rats: predicting manganese tissue concentration in the dam and pups from inhalation exposure with a pharmacokinetic model. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  R. G. York,et al.  Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. , 2005, Toxicology.

[18]  A. Calafat,et al.  Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  A. Calafat,et al.  Automated solid-phase extraction and measurement of perfluorinated organic acids and amides in human serum and milk. , 2004, Environmental science & technology.

[20]  H. Kusuhara,et al.  Gender Difference in the Urinary Excretion of Organic Anions in Rats , 2002, Journal of Pharmacology and Experimental Therapeutics.

[21]  G Levy,et al.  Serum protein binding of drugs during and after pregnancy in rats. , 1980, The Journal of pharmacology and experimental therapeutics.

[22]  Harvey J Clewell,et al.  Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. , 2011, Regulatory toxicology and pharmacology : RTP.

[23]  M. Horster,et al.  Filtration fraction and extraction of PAH during neonatal period in the rat. , 1970, The American journal of physiology.

[24]  D. H. Taylor,et al.  Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. , 1990, Toxicology and applied pharmacology.

[25]  C. Lau,et al.  Perfluoroalkyl acids: a review of monitoring and toxicological findings. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  Gerald L Kennedy,et al.  Perfluorooctanoate: Placental and lactational transport pharmacokinetics in rats. , 2005, Toxicology.

[27]  F. Lorscheider,et al.  Rat alpha-fetoprotein: isolation, radioimmunoassay and fetal-maternal distribution during pregnancy. , 1976, Journal of reproduction and fertility.

[28]  J. V. Vanden Heuvel,et al.  Lack of evidence for perfluorodecanoyl- or perfluorooctanoyl-coenzyme A formation in male and female rats. , 1992, Journal of biochemical toxicology.

[29]  N. Kudo,et al.  Rat Organic Anion Transporter 3 and Organic Anion Transporting Polypeptide 1 Mediate Perfluorooctanoic Acid Transport , 2007 .

[30]  J. Garcia Changes in blood, plasma and red cell volume in the male rat, as a function of age. , 1957, The American journal of physiology.

[31]  B. Lake Species differences in the hepatic effects of inducers of CYP2B and CYP4A subfamily forms: relationship to rodent liver tumour formation , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[32]  A. Schecter,et al.  Polybrominated Diphenyl Ethers (PBDEs) and Hexabromocyclodecane (HBCD) in Composite U.S. Food Samples , 2009, Environmental health perspectives.

[33]  Rebecca A Clewell,et al.  Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmacokinetic modeling. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  K. Teo,et al.  Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples. , 2008, Environmental research.

[35]  H. Barton,et al.  Predicting maternal rat and pup exposures: how different are they? , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  Harvey J Clewell,et al.  Time dependencies in perfluorooctylacids disposition in rat and monkeys: a kinetic analysis. , 2008, Toxicology letters.

[37]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[38]  D. Richardson,et al.  The utilization of protein and energy during lactation in the rat, with particular regard to the use of fat accumulated in pregnancy , 1982, British Journal of Nutrition.

[39]  Dowell Rt,et al.  Maternal hemodynamics and uteroplacental blood flow throughout gestation in conscious rats. , 1997 .

[40]  C. Lau,et al.  Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR alpha) in the mouse. , 2009, Reproductive toxicology.

[41]  Harvey J Clewell,et al.  Pharmacokinetic modeling of saturable, renal resorption of perfluoroalkylacids in monkeys--probing the determinants of long plasma half-lives. , 2006, Toxicology.

[42]  Melvin E Andersen,et al.  Tissue exposures to free and glucuronidated monobutylyphthalate in the pregnant and fetal rat following exposure to di-n-butylphthalate: evaluation with a PBPK model. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  C. Lau,et al.  The developmental toxicity of perfluoroalkyl acids and their derivatives. , 2004, Toxicology and applied pharmacology.

[44]  Xing Han,et al.  Organic anion transporting polypeptide (Oatp) 1a1-mediated perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal elimination of perfluorocarboxylates in rats. , 2009, Toxicology letters.

[45]  C. Lau,et al.  Effects of perfluorooctanoic acid exposure during pregnancy in the mouse. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[46]  S. Fenton,et al.  Analysis of PFOA in dosed CD-1 mice. Part 2. Disposition of PFOA in tissues and fluids from pregnant and lactating mice and their pups. , 2009, Reproductive toxicology.

[47]  M. Stanton,et al.  Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[48]  A. Rudolph,et al.  Effects of cord compression on fetal blood flow distribution and O2 delivery. , 1987, The American journal of physiology.

[49]  A. Bergman,et al.  A temporal trend study (1972-2008) of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in pooled human milk samples from Stockholm, Sweden. , 2011, Environment international.

[50]  J. Taylor,et al.  Changes in rat alpha 1-fetoprotein and albumin mRNA levels during fetal and neonatal development. , 1980, The Journal of biological chemistry.

[51]  Jørn Olsen,et al.  Perfluorinated Chemicals and Fetal Growth: A Study within the Danish National Birth Cohort , 2007, Environmental health perspectives.

[52]  J. Kim,et al.  Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta* , 2000, The Journal of Biological Chemistry.

[53]  Sikov Mr,et al.  Prenatal growth of the rat. , 1970 .

[54]  D. Stump,et al.  Gestational and lactational exposure to potassium perfluorooctanesulfonate (K+PFOS) in rats: developmental neurotoxicity. , 2009, Reproductive toxicology.

[55]  Xing Han,et al.  Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[56]  Rolf U Halden,et al.  Determinants of fetal exposure to polyfluoroalkyl compounds in Baltimore, Maryland. , 2007, Environmental science & technology.

[57]  John W. Froehlich,et al.  Half-Life of Serum Elimination of Perfluorooctanesulfonate,Perfluorohexanesulfonate, and Perfluorooctanoate in Retired Fluorochemical Production Workers , 2007, Environmental health perspectives.

[58]  H. Schneider Placental transport function. , 1991, Reproduction, fertility, and development.

[59]  J. Johnson,et al.  Cholestyramine-enhanced fecal elimination of carbon-14 in rats after administration of ammonium [14C]perfluorooctanoate or potassium [14C]perfluorooctanesulfonate. , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[60]  C. Lau,et al.  Perfluorooctanoic acid induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[61]  A. Calafat,et al.  Developmental toxicity of perfluorooctanoic acid in the CD-1 mouse after cross-foster and restricted gestational exposures. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[62]  G. W. Jepson,et al.  Binding of perfluorooctanoic acid to rat and human plasma proteins. , 2003, Chemical research in toxicology.

[63]  J. V. Vanden Heuvel,et al.  Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats. , 1991, Journal of biochemical toxicology.

[64]  Y. Kanai,et al.  Roles of organic anion transporters in the renal excretion of perfluorooctanoic acid. , 2008, Basic & clinical pharmacology & toxicology.

[65]  J. Atherton Glomerular filtration rate and salt and water reabsorption during pregnancy in the conscious rat. , 1983, The Journal of physiology.

[66]  Yoichi Kawashima,et al.  Toxicity and toxicokinetics of perfluorooctanoic acid in humans and animals. , 2003, The Journal of toxicological sciences.

[67]  S. Choudhuri,et al.  Gender-specific and developmental influences on the expression of rat organic anion transporters. , 2002, The Journal of pharmacology and experimental therapeutics.

[68]  N. Kudo,et al.  Sex hormone-regulated renal transport of perfluorooctanoic acid. , 2002, Chemico-biological interactions.

[69]  Wenyue Hu,et al.  Binding of perfluorinated fatty acids to serum proteins , 2003, Environmental toxicology and chemistry.

[70]  S. Henning Postnatal development: coordination of feeding, digestion, and metabolism. , 1981, The American journal of physiology.

[71]  B. Shirley The food intake of rats during pregnancy and lactation. , 1984, Laboratory animal science.

[72]  Harvey J Clewell,et al.  Exposure assessment and risk characterization for perfluorooctanoate in selected consumer articles. , 2005, Environmental science & technology.

[73]  J L Linzell,et al.  The time course of cardiovascular changes in lactation in the rat , 1973, The Journal of physiology.

[74]  F. Gonzalez,et al.  PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. , 2008, Toxicology.

[75]  R. Setzer,et al.  Pharmacokinetic modeling of perfluorooctanoic acid during gestation and lactation in the mouse. , 2009, Reproductive toxicology.

[76]  K. Conrad Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. , 1984, Kidney international.

[77]  L. Shaw,et al.  Community Exposure to Perfluorooctanoate: Relationships Between Serum Concentrations and Exposure Sources , 2006, Journal of occupational and environmental medicine.

[78]  A. Aperia,et al.  Distal tubular sodium reabsorption in the developing rat kidney. , 1981, The American journal of physiology.

[79]  M. Beckmann,et al.  Transplacental exposure of neonates to perfluorooctanesulfonate and perfluorooctanoate: a pilot study , 2007, International archives of occupational and environmental health.

[80]  P. Hinderliter,et al.  Age effect on perfluorooctanoate (PFOA) plasma concentration in post-weaning rats following oral gavage with ammonium perfluorooctanoate (APFO). , 2006, Toxicology.

[81]  Marie Aune,et al.  Exposure of Perfluorinated Chemicals through Lactation: Levels of Matched Human Milk and Serum and a Temporal Trend, 1996–2004, in Sweden , 2006, Environmental health perspectives.

[82]  Nathan M. Bass,et al.  Interactions of flurochemicals with rat liver fatty acid-binding protein , 2002 .

[83]  C. Klaassen,et al.  Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1-3; Slc22a6-8) mRNA levels. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[84]  G. Olsen,et al.  Perfluoroalkyl chemicals and human fetal development: an epidemiologic review with clinical and toxicological perspectives. , 2009, Reproductive toxicology.

[85]  R H Ophaug,et al.  Metabolic Handling of Perfluorooctanoic Acid in Rats , 1980, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[86]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[87]  D. Ehresman,et al.  Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[88]  J. Goedbloed Embryonic and postnatal growth of rat and mouse. V. Prenatal growth of organs and tissues, general principles: allometric growth, absence of growth, and the genetic regulation of the growth process. , 1976, Acta anatomica.

[89]  Yoichi Kawashima,et al.  Tissue distribution and hepatic subcellular distribution of perfluorooctanoic acid at low dose are different from those at high dose in rats. , 2007, Biological & pharmaceutical bulletin.

[90]  P. Rosso Changes in the transfer of nutrients across the placenta during normal gestation in the rat. , 1975, American journal of obstetrics and gynecology.

[91]  Melvin E Andersen,et al.  Perfluoroalkyl acids and related chemistries--toxicokinetics and modes of action. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[92]  R. Luthy,et al.  Binding of perfluorocarboxylates to serum albumin: a comparison of analytical methods. , 2010, Analytical chemistry.

[93]  D. Stump,et al.  Gestational and lactational exposure to potassium perfluorooctanesulfonate (K+PFOS) in rats: toxicokinetics, thyroid hormone status, and related gene expression. , 2009, Reproductive toxicology.

[94]  A. Calafat,et al.  Polyfluoroalkyl Chemicals in the U.S. Population: Data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 and Comparisons with NHANES 1999–2000 , 2007, Environmental health perspectives.

[95]  M S Christian,et al.  Rat and rabbit oral developmental toxicology studies with two perfluorinated compounds. , 2001, International journal of toxicology.

[96]  C. Klaassen,et al.  The presence of xenobiotic transporters in rat placenta. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[97]  A. Calafat,et al.  Polyfluoroalkyl chemicals in the serum and milk of breastfeeding women. , 2009, Reproductive toxicology.

[98]  S. Mabury,et al.  Disposition of perfluorinated acid isomers in sprague‐dawley rats; Part 1: Single dose , 2009, Environmental toxicology and chemistry.

[99]  G. Olsen,et al.  Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[100]  J. Wambaugh,et al.  Modeling single and repeated dose pharmacokinetics of PFOA in mice. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[101]  J. Fisher,et al.  Organ Growth Functions in Maturing Male Sprague-Dawley Rats , 2007, Journal of toxicology and environmental health. Part A.

[102]  W. Liu,et al.  Transcriptional effects of prenatal and neonatal exposure to PFOS in developing rat brain. , 2010, Environmental science & technology.

[103]  E J O'Flaherty,et al.  A physiologically based kinetic model of rat and mouse gestation: disposition of a weak acid. , 1992, Toxicology and applied pharmacology.