Document 5Lj7xwRypVr9oqXvQr17Bbow0

TOXICOLOGICALRESEARCH PROGRAM IN PERFLUORINAED CHEMISTRIES John L. Butenhoff, Ph.D. Medical Department 3M Company 2206 2206.0001 lue of Legacy Fluorochemical dxicological Research * Association of Chemistry with 3M * Reduced Uncertainty in RiskAssessment * Credibility in the Health Science Field + Causal Perspective for: -- Employee medical surveillance -- Epidemiological investigation * Defensive Barriers to Litigation = Application to Current and New Products 2220066..00000022 Causal Perspective for Epidemiology The Environment and Disease:Association or Causation?! Hill (1965) Proc Royal Soc Med 58, 205-300. STENmiT|MOTE14=YAY Cesk + Consistency * Specificity R021 113Y2 * Biological Gradient * Plausibility RR OeTTT 1) Ri =TTIT = * Analogy TThhiiss aarreeaa hhaass bbeeccoommee iinnccrreeaassiinnEgllyy iimmppoorrttaanntt aass nneeww eeppiiddeemmiioolloog!~iiccaall ssttuuddiieess aarree rreelleeaasseedd., 2206.0003 Flood of New Science * Frequency of new scientific papers has increased. * Appreciation of the whole field by the newer authors is obviously limited. * Increasing attempts to associate effects with general population exposures. 2208.0008 2206.0004 3M Publication Impact + 54 3M-authored, peer-reviewed fluorochemical papers cited 1804 times in scientific literature. TM 0 _ i" I _-- ) :1 | | | | IIs Li Ea 2220066..00000055 To BroadAreas of Research * Pharmacodynamics -- Biochemical interactions -- Biochemical and physiological responses * Adaptive or pathological * Pharmacokinetics -- Absorption, distribution, metabolism, excretion 22220066..00000066 Current Research Strategies * Internal 3M research -- Pharmacodynamics and pharmacokinetics * Collaborative research -- E.g., USERNHEERL, Universities OTE Te gE) - Eg, TNO = 3M-sponsored university research = U of MN, Stockholm U, UKMC, U of Houston, Penn State 22220066..00000077 Chemical and Physical Properties * Perfluorinated alkyls (PRs) -- Exceptionally stable -- Non-reactive -- Solubility varies -- Amphiphilic, "organic" acids with low pKa -- Essentially dissociated under most conditions -- Surface active ~ Low n der Wal's forces in carbon chain 22220086..00000088 Physical/Chemical Determinants + Resemble free fatty acids (FRs); although: = Non-reactive = Not metabolized CN pron = Do not enter into the biochemical reactions that use fatty acids as substrate. Octancio acid Ag * However, PRs may present as FAs. -- Transporters EC ee) -S s "y x Ee, El OETA [Ta Teo1] 2220066..00000089 Biological Interactions of PRAs * Expected interactions -- Biological membranes -- Organic anion transport processes * Induction, competition -- Protein ionic binding sites + Competition with endogenous substrates (e.g., FRA, NE) -- Activation of biochemical processes * Nuclear receptor activation (e.g., PRR@) 2220066..00001100 Pharmacodynamics osoutt 2206.0011 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry * Body-weight change = Tumorigenesis * Reproduction/Development = Immune system * Nervous system * Endocrine system (hormones) 2220086..00001122 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health * Serum lipid chemistry * Body-weight change * Tumorigenesis * Reproduction/Development * Immune system * Nervous system - Endocrine system (hormones) 2220086..00001133 Monkey Liver at 0.75 mg/kg/d K*PFOS (human equivalent dose = 53 mg/d) Electron micrographs of liver cells from six-month monkey study with K*PFOS' P Ee E TEESl 0 SEEERExs | LAR Se] CE TONY 8 By Aa ou qa Nat oi a mTa hret Re TEE ` EN LS WEE Male control 184 d ey 4 aa b ArT SRN 2 EQ RRL Sd HE NN NERL EI 'Seacat et al. (2002) xicol Sci 68, 249-264 208.0018 2206.0014 SES GElrt ad e ated] a Be io] cS CN Ts 21 d recovery Liver Effects * Increased liver weight -- Enlarged cells (hypertrophy) + Adaptation or pathological change? -- Increased numbers of cells (hyperplasia) * Pathological change (hyperplasia -- tumor -- cancer) * Metabolic and biochemical changes - e.g. increased burning of fat * Human relevance --- PRR activation -- Other processes (e.g., CAR and PXR) -- Adaptation vs. pathological change 2220066..00001155 Diversion #1 -- Molecular Biology XXeennoobiboitoitcicss,, HHoorrmmoonneess,, Cytokines,, GGrroowwtthh FFaaccttoorrss jinn Transcription Factors FFaattttyyAAcciidd PPhheennoobbarabrb., PFOA PPFFOOAA A Gene Expression Transcription CYP4AmMRNA CYP2B mRNA PPrrootteeiinn SSyynntthheessiiss EEnnzzyymmeess OOtthheerr Commppoouunnddss 2220066..00001166 Some Common Nuclear Receptors Controlling CYP Induction Receptor E230 28d 7A DG Re 2G RXR JOT -iL UpicalActivator Fatty acids, Fibrates Rosiglitazone Phenobarbital Steroids, Dexamethasone Cholesterol [SI{ERETI Retinoic acid TFiiodothyronine Polycyclic aromatics, Dioxin "RS transcription family member not a nuclear receptor 2220086..00001177 Experimental Approaches * Engineered nuclear receptor domains * Primary cell culture * In-life exposure followed by biochemical and molecular biological methods * Fansgenic mouse studies -- Remove or repress receptor -- Insert human form of receptor 22060018 2206.0018 Species Differences in PRRa * Humans less responsive than rodents -- Lower human levels of PRR -- Human PRR & not associated with hyperplasia * Use of genetically-modified mice'234 -- Using specific activators of PRRa * mPRaR (natural) = hypertrophy and hyperplasia * hPRR& - hypertrophy but NO hyperplasia * No PRR@ -- NO hypertrophy and NO hyperplasia 1Cheung et al. (2004) Cancer Res 64, 3849-3854. 2Morimura et al. (2006)Carcinogenesis 27, 1074-1080. 5Shah et al. (2007) Mol Cell Biol 27, 4238-4247. ET RCI EEE RE 22220066.00001199 Differential Activation of PRR@ in an Engineered System AA Le Human:Perfluorinated Fatty Acid 0IT= fIowef Tom jI CE Lhe AAVe BB os polSew EN Human:NaturalFatty Acids Jr e Pe LES 4 PFOAis a weak activator of PRR compared to ciprofibrate and natural fatty acids. 22220066..00002200 Nuclear ReceptorActivation by PFOAand PFOS in an Engineered System * Mouse, rat, human receptor forms PFOAand PFOS activate PRRa -- Less potent than clofibrate and endogenous long chain 3a} * PFOS and PFOAare weak agonists for PRR -- Much less potent than rosiglitazone * No activation of RXR or LXR3 - PFOAand PFOS more specific and less potent than endogenous long--chain FAs. "Vanden Heuvel et al. (2006) Toxicol Sci 92, 476-489. 2220066..00002211 Human vs. Rat Liver Cells in Primary Culture and PaR ActivR ation by PRs = [CE[] Prima~ Rat [] Prima~ Human HepG2_.fC3A sae a ncn N CCyyppd4AAT1 mmRRNNAA 7 . . - sa 3 Ctl i . Garboxylates 3FA PFPA PFBA PFHA Carboxylates | Sulfonates.PFOS Sulfonates PN CER] JAY Tet] culture media. PRET E0 have little or no ECA [ PERE TE 22080022 2206.0022 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health + Serum lipid chemistry = Body-weight change = Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 208.0020 2206.0023 Serum Lipids * Hypolipidemia -- Reduced serum total cholesterol with + PFOS; PFHxS; PFBA; PFOA(not consistently) * Early onset clinical observation in lab animals -- Apparent reduction in HDL(female monkeys) + PFOS * Abasis for MDH HRLfor PFOS = Mode(s) of action * PRR@ activation (evidence strong) * HMG CoAreductase inhibition (evidence weak) 208.0026 2206.0024 Serum Lipids = Hyperlipidemia -- Inconsistent epidemiological association of serum PFOS and PFOAwith increased serum cholesterol in humans * C8 Science Panel Report -- "In multivariate models adjusting for other factors *** all lipid outcomes except HDLwere higher when serum PFOA and PFOS levels were higherThe positive trends were statistically significant in all cases, again with the exception of HDL." 2220066..00002255 ACase of Reverse Causation? * Do higher serum lipids increase serum binding capacities for PFOAand PFOS? * Is there a experimental basis for causation? + Continuing areas of research -- Serum lipid biochemical studies -- Binding of PFOS and PFOAto serum lipoproteins -- Pharmacokinetic distribution studies 2206.0026 Serum Lipids Experimental model: - "Humanized" lipoprotein--profile transgenic mice -- Developed by TNO in The Netherlands -- Studying PFBS, PFHxS, PFOS -- Western-style diet (high fat) - PFOS, PFHxS, PFBS at ~ 3, 6 and 30 mg/kg body weight/d in diet, respectively 22060027 2206.0027 APOE*3Leiden Mouse Study * PFOS and PFHxS -- Reduced total cholesterol and triglycerides -- Decreased cholesterol 7- a --hydroxylase -- Increased liver size -- Increased fatty acid oxidation -- Suggests a PRR agonist mode of action PFBS had no effect. 22220066.00002288 APOE*3Leiden.CETP Mouse Studies * Incorporate cholesterol ester transfer protein PFOS and PFHxS -- reduced total cholesterol and triglycerides via RE EERAVE [II IT] + increased VLDLlipolysis and clearance + increased HDLclearance * PFBS -- reduced total cholesterol and triglycerides * to a lesser extent and via * reduced VLDLproduction and * increased VLDLclearance + no effect on HDL 22220066..00002299 PFBS, PFHS, PFOS & Hypolipidemia APOE*3Leiden.CETP Mouse Grow4 000% PEHS =e-Group 1: control Group 4:0.006 % PFHS rou5 00035 PROS -~--Group 2" 0.03 % Fenofibrate -W-Group 3:0.03 % PFBS =e-Group 5:0.003 % PFOS 2 2.55I a 20 Eg 15 E 1.5- VLDL K5H 0s 0.5 00..004 0 IIDDLL LLDLL BT 7 S Seert ta 5 10 15 FFrraccttiioonn HDDLL A SN N -- 20 25 2206.03 2206.0030 Association of PFOS and PFOAwith Hyperlipidemia in Epi Studies + APOE*3Leiden mouse model argues against causation. * Serum binding studies show affinity of PFOS and PFOAfor lipoproteins. + Additional serum binding work may help [JENN CVEER UEC Loo 2206.0031 Percent Binding to Isolated Human Serum Protein Fractions at 10 pg/mL Albumin T -Globulin `@~-GGlloobbuulliinn FFiibbrrininoosg:eenn @0-z2-2--MMacarcoro-- gglloobbuulliinn [een ~ansferrin REISE RT TONAREY pr 2206.0032 Percent Binding to Isolated Human Serum Protein Fractions at 10 pg/mL (OCD Albumin T -Globulin @~-GGlloobbuulliinn FFiibbrrininoosg:eenn @0=z-22--MMaaccrroo--gglolobbuulliinn OX TX ~ansferrin REISE pre 2206.0033 Additional ExperimentalApproaches * Binding interaction studies Sled + 355-PFOS made at Stockholm University in Ake SEE CURE * Biochemical expertise of Joe DePierre's research ET + In-life experiments under consideration -- ExploitAPOE*3Leiden.CETP mice * Dietary manipulation of lipoprotein profile 206.0034 2206.0034 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry * Body--weight change * Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 2208.00 2206.0035 Body Weight 4 Decreased weight EN animals FO EA sufficient dose (TR 2 moire) i i erences | ii t HE --. : cnn, 22060036 2206.0036 Body Weight * Hypotheses = Increased burning of fat + Uncoupling of oxidative phosphorylation (mitochondria) = Only with certain sulfonamides (NOT PFOS or PFOA) * Increased mitochondrial bodies (PFOA) ~ Evidence from rat and monkey studies GL AEE -- Strong evidence from mouse studies -- Decreased appetite RTT CRE EY ITY -- Malabsorption of nutrients - Not fully investigated 2220066..00003377 Biological Interactions -- Mitochondria * 3M sponsored -- Starkov and Wllace (2002) 3xicol Sci 66, 244-252. ~ O'Brien et al. (2008) 3xicolAppl Pharmacol 227, 184-195. ~ Berthiaume and Wallace (2002) 3xicology Lett 129, 23-32. -- Butenhoff et al. (2002) 8xicol Sci 69, 244-257. ~ Mitochondrial proliferation mode of action (current) * NTP sponsored (i.e., they think its important) -- Mitochondrial interactions of PFCs in vitro (Wallace) 2220066..00003388 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry = Body-weight change * Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 208.0039 2206.0039 Tumorigenicity in SD Rats * PFOA -- At 300 ppm in diet ("15 mg/kg body weight) * Hepatocellular adenoma (males) * Pancreatic acinar--cell adenoma (males) + Esticular Leydig-cell adenoma ("Tumor triad" pattern seen with other PRR@ agonists) * No increased tumor incidence in females * PFOS -- At 20 ppm in diet ("1 mg/kg body weight) * Hepatocellular adenoma (males and females) + Thyroid follicular cell adenoma (20 ppm stop-dose males) 2206.0040 2206.0040 Tumorigenesis -- PFOA * Hepatocellular -- Consequences of PRR activation -- Oxidative stress -- Potential for contribution of CAR activation = @sticular Leydig cell adenoma -- Consequences of PRRa activation = Inductionof aromatase enzyme leading to increased estrogen * Pancreatic acinar cell adenoma -- Consequences of PRR activation = Increased cholecystokinin hormone (evidence weak) - Mitogenic activity of thyroid hormone, retinoids (not tested) 2220066..00004411 Pancreatic acinar cell proliferation From: Ohmura et al. (1997) Can Res 57, 795-798. C55 2 Fr TEs re ER Eee BAR RCP JorisA CL ACT Set PRICY EEE Rk) p Jd x | SERRTISEE Vv (Saoly ay A J =i . vd i = i of + J 2 he | I nor |i a w- - il | s WW7 Thyroid hormone (T3) Peroxisome proiferator 208.0042 2206.0042 SET] Tumorigenesis -- PFOS * Was PRR@& activation responsible? * PFOS - CXR investigation results Te * PFOS is a mixed agonist in the rat BL EO SB)(5 EY gos| * No effect of PFOS 22060043 2206.0043 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry = Body-weight change * Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 22060084 2206.0044 PRs Studied for Reproduction and Developmental Effects EER PFHxS 0 SY ZO 2206.0045 Results of Major Laboratory Studies * No effect on functional aspects of reproduction Structural anomalies associated with dosing causing maternal stress * Developmental delays noted in some cases * Birth weight and weight gain affected in some cases * Neonatal mortality with PFOS and PFOA 22060048 2206.0046 Modes ofAction -- Current Thoughts = Although /n utero exposure of both PFOS and PFOAcaused neonatal mortalitythe adverse effects may be mediated by separate mechanisms * PFOAlikely acts through the PRRa signaling pathway that regulates intermediary metabolism * PFOS likely interacts with phospholipids of lung surfactant and interferes with lung inflation and pulmonary function 208.0047 2206.0047 Lung Histology and Morphometry Control PFOS IES E=2S TATE AL A =x Zz} i NF f od y STR EI oo 3 To Le [3 4 . Xf baSnEdLNi Pi EC ps A] LE) Vg ETTY LE EI) D ESTTINTS _-- 2206.0048 Alveolar Structure Surfactant prevents lungs from collapsing during end-expiration by reducing the surface tension at the air-liquid interface Alveolartype IIIIcceellll Alvpolar tyIpceell PE a. Zod hE "INN Lamellar body" QBe]o =ssurun layer R= re L~mell ar bod3 TTubuubullaarr mmy3elin 7 bo AiArirssppaaccee VG '%, -- PFOS? AAllvveeoollaarf fluid at enti AAlvlveeoollaarr mmaaccrroopphhaagge inam Ss Modified from Hawgood & Clements, 1990. 2220066..00004499 PFOS and Pulmonary Surfactant PFOS was detected in amniotic fluid that bathed the LS NTT Oral gavage of newborn rats failed to cause mortality -- chemical has to reach within the lung PFOS interacts with phospholipids (Xie et al., 2007) - Dipalmitoylphosphatidylcholine (DPPC) is a major component of lung surfactant = In vitro study: PFOS had strong tendency to partition into and disrupt DPPC bilayers --- PFOS > PFOA>>0S - Definitive evidence is needed 2220066..00005500 Non-Occupational Human Studies - Summary l CE LN I LTS CR I GestationalAge|PFOS NS IS IN [iol NS (-1042T) | -106 NS Birth Length |PFOS NS S N/A Head Circum. |PFOS REG) IS A Abdominal PFOS N/A S N/A i SH Ponderal Index|PFOS ~0.074 (T) B A Ra EN N/A 8 [ZN EE Log transformed (change for 2.7-fold change in PFA concentration). 2220066..00005511 Birth Weight --Another Case of Reverse Causation? * Plasma volume expansion positively associated with increased birth weight. * Concentrations of plasma constituents may decrease during pregnancy * Research approach: -- Modeling of pharmacokinetics in pregnancy -- Contract with The Hamner Instutues 22080082 2206.0052 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry = Body-weight change * Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 208.0083 2206.0053 PFOS and PFOA& Immune System + Suppression of adaptive immunity in mice -- Thymic and splenic atrophy * Enhancement of innate immunity in mice * Attenuated by knocking out PRR * Appears to be a high-dose effect (DePierre) * However Peden--Adams report on PFOS effect at 91 ppb PFOS in serum. * Epi studies? 22060084 2206.0054 Immune System and PFOS -- Mice * DrDePierre's research group at Stockholm University -- Carefully repeated Peden--Adams et al. work. -- Not able to reproduce observed effects. -- Likely due to methodological issues with Peden-- Adams et al. study * Human data would be helpful 2220086..00008555 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health * Serum lipid chemistry = Body-weight change * Tumorigenesis * Reproduction/Development = Immune system * Nervous system * Endocrine system (hormones) 2220086..00005566 Nervous System * Decreased habituation consistently observed with PFOS in developing male rats and mice (transient) -- Publishing DNT study * Delayed pupillary reflex in male rats given PFOAand PFBA = Grant to DrDonald Fox, U of Houston * Brain uptake studies -- Collaborative with USER = Grant to Dr GrantAnderson, U of MN 2220066..00005577 Responses of LaboratoryAnimals & PerfluorinatedAlkyls (PRs) * Liver function and health = Serum lipid chemistry * Body-weight change * Tumorigenesis * Reproduction/Development * Immune system = Nervous system * Endocrine system (hormones) 2220086..00005588 Endocrine System * PRs can interfere with free hormone measurement * Current focus on thyroid hormones -- Publication of remaining PFOS work -- Publication of PFBAwork * Human thyroid hormone displacement studies planned * Follow-up to PFBAplanned using ultrafiltration and LC-MS/MS T4 method 22060088 2206.0059 Pharmacokinetics astieo 2206.0060 Key Questions * What are the mechanisms of PFAA transport and elimination? * What are the determinants of interspecies elimination differences? * How can interspecies dose-response extrapolations best be accomplished? 2206.0061 3M-Sponsored Research * Joe DePierre's lab at Stockholm U -- Distribution and binding * Hagenbuch's lab at KUMC -- Renal and liver tgransport * Anderson's lab at Univ of MN = Thyroid hormone transport interactions -- Brain uptake * The Hamner Institute -- Pharmacokinetic modeling 22220086..00006622 Pharmacokinetics --Tissue Distribution of Radiolabelled PFCs * Recent synthesis of 3S-PFOS at Stockholms Universitet: -- Initial distribution study in mice completed. -- Whole-body distribution in progress -- Fetal, age effects, intracellular investigations planned -- Protein binding studies to be addressed 2208.0083 2206.0063 Role of OrganicAnion Fansport * Active renal proximal tubular reabsorption * First suggested by Kudo et al. (2002) -- Based on increased mRNAfor Oatp1 in male rats - First modeled byAndersen et al. (2006) -- Cynomolgus monkey PK data for PFOAand PFOS fit resorption model * Evidence in rat by Katakura et al. (2007) -- Oat3 and Oatp1 may be reabsorption transporters 206.0064 2206.0064 input -- iv,oral) (iv, oral) Tissue Tissue Compartment Co~npartment [= { Atis~ue) kak12 [3 CCeenrttrtraall (CCVooammpCpaiarrttmmeenntt a [ |1. Qfil Fitrate Cu Filtrate Compartment Compartment Ve Cal Qu (Vfil, Cfil) Cfil Qfil 2220066..00006655 Uptake transporters in renal proximal tubule cells Luummeen BBllooood . c oatptat Q om (~ Oat2 42 oOaattpptl aa33 rota MAMepmeibmcrablarannee J oOcaattppa4cctl oOaatt1t b oOaatt3s oS 5 Sanaa Membrane Basolateral Membrane Based on subcellular localization, Oat1 and Oat3 may be responsible for active renal secretion of PFHA, PFOAand PFNAwhile Oatplal may be responsible for reabsorption of PFDA, PFNAand PFOA. (From poster by Weaver and Hagenbuch, 2008). pro 2206.0066 Pharmacokinetics -- PBPK Models + The Hamner Institutes (3M funding) + Andersen et al. (2006) Sxicology 227, 156-164. + 3n et al. (2008) Fxicol Lett 177, 38-47. = + Wambaugh et al. (2008) J Pharmacokinet Pharmacodyn 35, 683-713. + Harris and Barton (2008) 3xicol Lett 181, 148-156. + Lou et al. (2009) dxicol Sci 107, 331-341. 2220066..00006677 Protein Ionic Binding * Albumin -- Major carrier protein in serum'23 EEC -- Competition with endogenous substrates * Steroid hormones! * Thyroid hormones* -- Carbon number (size) and solubility "Jones et al. (2003) Environ 3xicol Chem 22, 2639-2649. 5?H3aMnaentdalS. ou(2t0h0e3r)n CRheesemaRrecsh I@nxsitciotlut1e6,, u7n7p5u-b7l8i1shed report, USERDocketAR-226, "Chang et al (2008) 3icology 243, 330-330. 22060068 2206.0068 Binding of PFOS to HSA Binding of -- PFOS to HSA y = -4022.7x + 22376 bR2 i= 0.a745l4 = 35000 30000 25000 5 20000 Pe ~ 15000 o_o10000 wo ~~ 5000 0 1 2 s . 5 . v (molPFOSImolHSA) p----------e----e-- Competition between PFOS and OAfor binding FHEe!4000 3500 3000 2500 2000 El Fim I 1500 1000 Iz te. 500 to HSA ~ ~, , i 500 1000 1500 2000 2500 [PFOS] (pM) premm-------- Competition between PFOS and OA for oe=, bbiinnddiinngg ttoo HHSSAA j=:2500 . 2000 Eoory 1500 1000 i 500 + . > ` E5JOO I1O0O000 11550000 22000000 2500) CTYET RYMp iras etn) 10 uM OAfixed concentration _ 2206.0069 Binding of PFOS so 1 I 166 gHEieoe!t i ix snorparrass Binding of PFOS to TTR : mm I,sm 2 0 100 200 300 [total PFOS] (plVl) : wm 400 500 Saturable To CCoommpepteittitiioonn bbeettwweeeennPPFFOOSSaannddtthhyyrroxoixneifnfooerr binding to TTR i Sp fa T i. EL CFT ee 10 15 20 25 [thyroxine] (pM) to TTR rere Determination of the Ka for binding of PFOS to TTR 860000050. ee 50000 |yy==-3-311557755xx++ 5577111144. R2 = 0.7217 pest40000 30000 E+ owme - - 20000 oo a -- 10000 Sorina 0 os 10 1s 20 0.0 1.5 v mol PFOS / mol TTR) LUCE 5 uM PFOS fixed concentration _. 2206.0070 Summary -- Key ResearchAreas - Differential effects: human vs. lab animals * Mechanism of effects on serum lipids * Immune effects -- human relevance = Transporters -- species differences = Pharmacokinetic models; e.g, pregnancy * Distribution studies * Binding studies 2220086..00007711