Abstract
Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5–10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra-liquid chromatography coupled tandem mass spectrometry (UPLC–MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 µg/kg/day (male) and 0.159 µg/kg/day (female) and external doses of 0.007 µg/kg/day (male) and 0.006 µg/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure.
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Abbreviations
- AUC0−∞ :
-
Area under the concentration–time curve from zero to infinity
- CL:
-
Clearance
- C max :
-
Maximum plasma concentration
- C ss :
-
Steady-state concentration
- F r :
-
Free fraction in plasma
- IV:
-
Intravenous
- K p :
-
Tissue-to-plasma partition coefficient
- K st :
-
Rate constant to storage compartment
- K t :
-
Transporter affinity constant
- K u :
-
Urinary elimination rate constant
- MOE:
-
Margin of exposure
- NOAEL:
-
No-observed-adverse-effect level
- PBPK:
-
Physiologically based pharmacokinetic model
- PFASs:
-
Perfluoroalkyl and polyfluoroalkyl substances
- PFHxS:
-
Perfluorohexanesulfonate
- PFOA:
-
Perfluorooctanoic acid
- PFOS:
-
Perfluorooctane sulfonate
- PK:
-
Pharmacokinetic
- POD:
-
Points of departure
- RfD:
-
Reference dose
- t 1/2 :
-
The elimination half-life
- T m :
-
Transporter maximum
- UF:
-
Uncertainty factor
- UFA :
-
Uncertainty factor for interspecies extrapolation from rats to humans
- UFH :
-
Uncertainty factor for inter-individual variability in humans
- UFS :
-
Uncertainty factor for subchronic to chronic extrapolation
- UPLC-MS/MS:
-
Ultra-liquid chromatography coupled tandem mass spectrometry
- V d :
-
Volume of distribution
References
Andersen ME, Clewell HJ 3rd, Tan YM, Butenhoff JL, Olsen GW (2006) Pharmacokinetic modeling of saturable, renal resorption of perfluoroalkylacids in monkeys–probing the determinants of long plasma half-lives. Toxicology 227(1–2):156–164. https://doi.org/10.1016/j.tox.2006.08.004
ATSDR (2015) Agency for Toxic Substances and Disease Registry, minimal risk levels (MRLs). http://www.atsdr.cdc.gov/mrls/pdfs/atsdr_mrls.pdf
Borg D, Lund BO, Lindquist NG, Hakansson H (2013) Cumulative health risk assessment of 17 perfluoroalkylated and polyfluoroalkylated substances (PFASs) in the Swedish population. Environ Int 59:112–123. https://doi.org/10.1016/j.envint.2013.05.009
Butenhoff JL, Chang SC, Ehresman DJ, York RG (2009) Evaluation of potential reproductive and developmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats. Reprod Toxicol 27(3–4):331–341. https://doi.org/10.1016/j.reprotox.2009.01.004
Cho CR, Lam NH, Cho BM, Kannan K, Cho HS (2015) Concentration and correlations of perfluoroalkyl substances in whole blood among subjects from three different geographical areas in Korea. Sci Total Environ 512–513:397–405. https://doi.org/10.1016/j.scitotenv.2015.01.070
Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10(7):1093–1095
Dong Z, Bahar MM, Jit J et al (2017) Issues raised by the reference doses for perfluorooctane sulfonate and perfluorooctanoic acid. Environ Int 105:86–94. https://doi.org/10.1016/j.envint.2017.05.006
Dourson ML, Stara JF (1983) Regulatory history and experimental support of uncertainty (safety) factors. Regul Toxicol Pharmacol 3(3):224–238
EPA (2006) Approaches for the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment. National Center for Environmental Assessment, Washington, DC; EPA/600/R-05/043F. Available from: National Technical Information Service, Springfield, VA, and online at http://epa.gov/ncea. https://doi.org/10.7748/ns.14.36.26.s40
Eriksson U, Mueller JF, Toms LL, Hobson P, Karrman A (2017) Temporal trends of PFSAs, PFCAs and selected precursors in Australian serum from 2002 to 2013. Environ Pollut 220(Pt A):168–177. https://doi.org/10.1016/j.envpol.2016.09.036
FDA (2013) The guidance for industry: bioanalytical method validation. Department of Health and Human Services, U.S. Food and Drug Administration. https://doi.org/10.7748/ns.14.36.26.s40
Gleason JA, Post GB, Fagliano JA (2015) Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the US population (NHANES), 2007–2010. Environ Res 136:8–14. https://doi.org/10.1016/j.envres.2014.10.004
Han X, Snow TA, Kemper RA, Jepson GW (2003) Binding of perfluorooctanoic acid to rat and human plasma proteins. Chem Res Toxicol 16(6):775–781. https://doi.org/10.1021/tx034005w
Han X, Nabb DL, Russell MH, Kennedy GL, Rickard RW (2012) Renal elimination of perfluorocarboxylates (PFCAs). Chem Res Toxicol 25(1):35–46. https://doi.org/10.1021/tx200363w
Harada KH, Hashida S, Kaneko T et al (2007) Biliary excretion and cerebrospinal fluid partition of perfluorooctanoate and perfluorooctane sulfonate in humans. Environ Toxicol Pharmacol 24(2):134–139. https://doi.org/10.1016/j.etap.2007.04.003
Hu TM, Hayton WL (2001) Allometric scaling of xenobiotic clearance: uncertainty versus universality. AAPS PharmSci 3(4):E29. https://doi.org/10.1208/ps030429
Igari Y, Sugiyama Y, Sawada Y, Iga T, Hanano M (1983) Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model. J Pharmacokinet Biopharm 11(6):577–593
Jing P, Rodgers PJ, Amemiya S (2009) High lipophilicity of perfluoroalkyl carboxylate and sulfonate: implications for their membrane permeability. J Am Chem Soc 131(6):2290–2296. https://doi.org/10.1021/ja807961s
Jones PD, Hu W, De Coen W, Newsted JL, Giesy JP (2003) Binding of perfluorinated fatty acids to serum proteins. Environ Toxicol Chem 22(11):2639–2649
Kagan L, Gershkovich P, Wasan KM, Mager DE (2011) Physiologically based pharmacokinetic model of amphotericin B disposition in rats following administration of deoxycholate formulation (Fungizone(R)): pooled analysis of published data. AAPS J 13(2):255–264. https://doi.org/10.1208/s12248-011-9267-8
Kato K, Wong LY, Jia LT, Kuklenyik Z, Calafat AM (2011) Trends in exposure to polyfluoroalkyl chemicals in the US population: 1999–2008. Environ Sci Technol 45(19):8037–8045. https://doi.org/10.1021/es1043613
Kerstner-Wood C, Butenhoff L, G G (2003) Protein binding of perfluorobutane sulfonate, perfluorohexane sulfonate, perfluorooctane sulfonate and perfluorooctanoate to plasma (human, rat and monkey), and various human-derived plasma protein reactions. Washington, US Environmental Protection Agency. EPA docket AR-226-1354. https://doi.org/10.7748/ns.14.36.26.s40
Khalil N, Chen A, Lee M et al (2016) Association of Perfluoroalkyl Substances, Bone Mineral Density, and Osteoporosis in the U.S. Population in NHANES 2009–2010. Environ Health Perspect 124(1):81–87. https://doi.org/10.1289/ehp.1307909
Kim DH, Lee MY, Oh JE (2014) Perfluorinated compounds in serum and urine samples from children aged 5–13 years in South Korea. Environ Pollut 192:171–178. https://doi.org/10.1016/j.envpol.2014.05.024
Kim SJ, Heo SH, Lee DS, Hwang IG, Lee YB, Cho HY (2016) Gender differences in pharmacokinetics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances in rats. Food Chem Toxicol 97:243–255. https://doi.org/10.1016/j.fct.2016.09.017
Kimura O, Fujii Y, Haraguchi K et al (2017) Uptake of perfluorooctanoic acid by Caco-2 cells: Involvement of organic anion transporting polypeptides. Toxicol Lett 277:18–23. https://doi.org/10.1016/j.toxlet.2017.05.012
Lee YJ, Choi SY, Yang JH (2014a) NMDA receptor-mediated ERK 1/2 pathway is involved in PFHxS-induced apoptosis of PC12 cells. Sci Total Environ 491–492:227–234. https://doi.org/10.1016/j.scitotenv.2014.01.114
Lee YJ, Choi SY, Yang JH (2014b) PFHxS induces apoptosis of neuronal cells via ERK1/2-mediated pathway. Chemosphere 94:121–127. https://doi.org/10.1016/j.chemosphere.2013.09.059
Li Y, Cheng Y, Xie Z, Zeng F (2017) Perfluorinated alkyl substances in serum of the southern Chinese general population and potential impact on thyroid hormones. Sci Rep 7:43380. https://doi.org/10.1038/srep43380
Liu B, Zhang H, Yao D et al (2015) Perfluorinated compounds (PFCs) in the atmosphere of Shenzhen, China: Spatial distribution, sources and health risk assessment. Chemosphere 138:511–518. https://doi.org/10.1016/j.chemosphere.2015.07.012
Liu Y, Su J, van Dam RM et al (2017) Dietary predictors and plasma concentrations of perfluorinated alkyl acids in a Singapore population. Chemosphere 171:617–624. https://doi.org/10.1016/j.chemosphere.2016.12.107
Loccisano AE, Campbell JL Jr, Andersen ME, Clewell HJ, 3rd (2011) Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. Regul Toxicol Pharmacol 59(1):157–175. https://doi.org/10.1016/j.yrtph.2010.12.004
Loccisano AE, Campbell JL Jr, Butenhoff JL, Andersen ME, Clewell HJ, 3rd (2012a) Comparison and evaluation of pharmacokinetics of PFOA and PFOS in the adult rat using a physiologically based pharmacokinetic model. Reprod Toxicol 33(4):452–467. https://doi.org/10.1016/j.reprotox.2011.04.006
Loccisano AE, Campbell JL Jr, Butenhoff JL, Andersen ME, Clewell HJ, 3rd (2012b) Evaluation of placental and lactational pharmacokinetics of PFOA and PFOS in the pregnant, lactating, fetal and neonatal rat using a physiologically based pharmacokinetic model. Reprod Toxicol 33(4):468–490. https://doi.org/10.1016/j.reprotox.2011.07.003
Loccisano AE, Longnecker MP, Campbell JL Jr, Andersen ME, Clewell HJ, 3rd (2013) Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages. J Toxicol Environ Health A 76(1):25–57. https://doi.org/10.1080/15287394.2012.722523
Ludwicki JK, Goralczyk K, Strucinski P et al (2015) Hazard quotient profiles used as a risk assessment tool for PFOS and PFOA serum levels in three distinctive European populations. Environ Int 74:112–118. https://doi.org/10.1016/j.envint.2014.10.001
Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL, Seacat AM (2002) Interactions of fluorochemicals with rat liver fatty acid-binding protein. Toxicology 176(3):175–185
MFDS (2009) Exposure assessment of major perfluorinated compounds among Koreans. Ministry of Food and Drug Safety, 08182MFDS499
OECD (2015) Risk reduction approaches for PFASs—a cross-country analysis, organisation for economic co-operation and development environment, health and safety publications series. Risk Management No 29. https://doi.org/10.7748/ns.14.36.26.s40
Olsen GW, Burris JM, Ehresman DJ et al (2007) Half-life of serum elimination of perfluorooctanesulfonate,perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 115(9):1298–1305. https://doi.org/10.1289/ehp.10009
Olsen GW, Mair DC, Lange CC et al (2017) Per- and polyfluoroalkyl substances (PFAS) in American Red Cross adult blood donors, 2000–2015. Environ Res 157:87–95. https://doi.org/10.1016/j.envres.2017.05.013
Rosen MB, Das KP, Rooney J, Abbott B, Lau C, Corton JC (2017) PPARalpha-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling. Toxicology 387:95–107. https://doi.org/10.1016/j.tox.2017.05.013
Ruark CD, Song G, Yoon M et al (2017) Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause. Environ Int 99:245–254. https://doi.org/10.1016/j.envint.2016.11.030
Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157(6):907–921. https://doi.org/10.1111/j.1476-5381.2009.00267.x
Sheng N, Li J, Liu H, Zhang A, Dai J (2016) Interaction of perfluoroalkyl acids with human liver fatty acid-binding protein. Arch Toxicol 90(1):217–227. https://doi.org/10.1007/s00204-014-1391-7
Shi Y, Yang L, Li J et al (2017) Occurrence of perfluoroalkyl substances in cord serum and association with growth indicators in newborns from Beijing. Chemosphere 169:396–402. https://doi.org/10.1016/j.chemosphere.2016.11.050
Sinclair E, Mayack DT, Roblee K, Yamashita N, Kannan K (2006) Occurrence of perfluoroalkyl surfactants in water, fish, and birds from New York State. Arch Environ Contam Toxicol 50(3):398–410. https://doi.org/10.1007/s00244-005-1188-z
Stein CR, Savitz DA (2011) Serum perfluorinated compound concentration and attention deficit/hyperactivity disorder in children 5–18 years of age. Environ Health Perspect 119(10):1466–1471. https://doi.org/10.1289/ehp.1003538
Sundstrom M, Chang SC, Noker PE et al (2012) Comparative pharmacokinetics of perfluorohexanesulfonate (PFHxS) in rats, mice, and monkeys. Reprod Toxicol 33(4):441–451. https://doi.org/10.1016/j.reprotox.2011.07.004
Tan YM, Clewell HJ 3rd, Andersen ME (2008) Time dependencies in perfluorooctylacids disposition in rat and monkeys: a kinetic analysis. Toxicol Lett 177(1):38–47. https://doi.org/10.1016/j.toxlet.2007.12.007
Taylor KW, Hoffman K, Thayer KA, Daniels JL (2014) Polyfluoroalkyl chemicals and menopause among women 20–65 years of age (NHANES). Environ Health Perspect 122(2):145–150. https://doi.org/10.1289/ehp.1306707
Tillett T (2010) PFCs and cholesterol: a sticky connection. Environ Health Perspect 118(2):A81. https://doi.org/10.1289/ehp.118-a81b
Verner MA, Longnecker MP (2015) Comment on “enhanced elimination of perfluorooctanesulfonic Acid by menstruating women: evidence from population-based pharmacokinetic modeling”. Environ Sci Technol 49(9):5836–5837. https://doi.org/10.1021/acs.est.5b00187
Verner MA, Ngueta G, Jensen ET et al (2016) A Simple Pharmacokinetic Model of Prenatal and Postnatal Exposure to Perfluoroalkyl Substances (PFASs). Environ Sci Technol 50(2):978–86. https://doi.org/10.1021/acs.est.5b04399
Viberg H, Lee I, Eriksson P (2013) Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose. Toxicology 304:185–191. https://doi.org/10.1016/j.tox.2012.12.013
Weaver YM, Ehresman DJ, Butenhoff JL, Hagenbuch B (2010) Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. Toxicol Sci 113(2):305–314. https://doi.org/10.1093/toxsci/kfp275
WHO (2010) Characterization and Application of Physiologically Based Pharmacokinetic Models in Risk Assessment, World Health Organization (IPCS, 2010, available online at http://www.who.int/ipcs/methods/harmonization/areas/pbpk/en. https://doi.org/10.7748/ns.14.36.26.s40
Wong F, MacLeod M, Mueller JF, Cousins IT (2014) Enhanced elimination of perfluorooctane sulfonic acid by menstruating women: evidence from population-based pharmacokinetic modeling. Environ Sci Technol 48(15):8807–8814. https://doi.org/10.1021/es500796y
Wu H, Yoon M, Verner MA et al (2015) Can the observed association between serum perfluoroalkyl substances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics? Environ Int 82:61–68. https://doi.org/10.1016/j.envint.2015.05.006
Yang CH, Glover KP, Han X (2009) 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. Toxicol Lett 190(2):163–171. https://doi.org/10.1016/j.toxlet.2009.07.011
Yang CH, Glover KP, Han X (2010) 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. Toxicol Sci 117(2):294–302. https://doi.org/10.1093/toxsci/kfq219
Zhang Y, Beesoon S, Zhu L, Martin JW (2013) Biomonitoring of perfluoroalkyl acids in human urine and estimates of biological half-life. Environ Sci Technol 47(18):10619–10627. https://doi.org/10.1021/es401905e
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This research was supported by a Grant from the Ministry of Food and Drug Safety in 2014–2017 (14162MFDS703 and 17162MFDS117).
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Kim, SJ., Shin, H., Lee, YB. et al. Sex-specific risk assessment of PFHxS using a physiologically based pharmacokinetic model. Arch Toxicol 92, 1113–1131 (2018). https://doi.org/10.1007/s00204-017-2116-5
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DOI: https://doi.org/10.1007/s00204-017-2116-5