Document YG14bGbDkMjMaQEXYmxXm4M38

CMA 119748 Estimating Human Risk from Exposure to VC Quantification with PB-PK Modeling Richard H. Reitz Michael L. Gargas McLaren/Hart, ChemRisk Division for CMA Vinyl Chloride Panel May 19,1994 smm 1 CotlaboiratoireJ McLaren/Hart: R. H. Reitz M. L. Gargas ICl Toxicology Lab (Zeneca) T. L. Green W. M. Provan U. S. E. P. A. (Res Tri Park) M. E. Andersen 5fwn 2 VC Histoiyl Low Acute Toxicity Occup. Expos. Limits - 500 ppm Viola (1970,1971) Rats, Increased Tumor Incidence Maltoni (1974) Confirmed Viola's Results Identified Rare Liver Angiosarcoma Dose Response Plat > 1,000 ppm Creech & Johnson (1974) Found Same Cancer Type (Liver Anglosacroma) in Homans Human Tumor Registry (to Present) 14,000 Subjects, 19 VC Plants 3 Objectives / Opportunity | Develop A Process for Quantitatively Estimating Risk in Humans + Low, Noa-Occnpatlonal Exposures - Sttperfund Sites - Fugitive Emission - Drinking Water Test the Utility of our Cancer Risk Assessment Procedures + Rich Animal Data Set In Rats and Mice + Unique Opportunity to Compare Risk Assessment with Actual Results In Humans 4 Expectations for Pharmacokinetic Modeling Modeling Cannot Eliminate ALL Uncertainty from Risk Assessments Modeling Can Quantitatively Describe: Metabolic Saturation Changes tat Dose Route Physiological Differences in Species PREMISE: Risk Assessments based on Estimates of "Delivered Dose" wfll be More Reliable than Risk Assessments based Only on Administered Dose 5/20^4 5 Classical Pharmacokinetics: "Stripping the Curve" Curna Stripping fEmnnentlUl C(t) - A, . o' a i * saom 6 CMA 119751 Classical Pharmacokinetics: Compartments! Models C2 = A2/V2 i--r K21 K12 J________L Input ka C1 = A1/V1 _ Him , ke Differential iatioDi <U0/dt - -ka*Doae dAl/dt - Iu*Dom - HI2*0 4- X21*C2 - ke*Cl dA2/dt - +K21*C1 - K21*C2 dCllm/ t - -ke*Cl *10/94 7 Advantages of PB-PK Models: Compound Specific Information Vapor Prtmtrt SotaUBOn (Partitlonl**) la Tissues Species Specific Information Phjretotagy MetaboHsm Route Specific Information Oral Route, 1st Pass Through Liver Allow Extrapolations Between Pwt Routes Between High Dose / Low Doee Between Species CMA 119752 A PB-PK Model! for VC I MetabditM Bim4 ob Ransuey St Aadwen, Itti Capabilities of PB-PK Models Will use examples from studies of Reitz et al., at Dow Chemical Co., with 1,1,1-triehloroethane (Methykhlorofomi, MC) * Data used to Illustrate potential applications for VC PB-PK Model. ram 10 MC Rat Inhalation _______ (Blood Levels) Methylchloroform, (MC) used as an example of the technique. MC Mouse Inhalation (Blood Levels) atom Methylchtorofonn, (MC) used as an example of the technique. n mm* MC Mouse Inhalation (Other Endpoints) 2 1.5 MC Human Inhalation (Exhaled Air) Humans - Inhalation Burden Fat Bi 150 ppm Liver Metab 1500 ppm 13 yam 14 CMA 119754 MC Rat Water (Exhaled Air) sram is Approach; VC PBPK ModeT| (1) Parameterize Model Physiological Constants - Andersen etai., 1987 Partittoa Coefficients - Vial Equilibration - Fat, Liver, Muscle, Blood Metabolic Rate Constants - In Vivo (Rats, Mice) (2) Validate Model Independent Rat, Mouse and Humaa In Vivo Studies (3) Extrapolate Risks - Rats to Mice Rats to Homans worn 16 VC Partition Coefficients Vial Equilibration Measure: Hood/Alr Llver/Alr Fat/AIr MustJe/Alr Calculate: TIssue/BJood VC Metabolic Rate Constants Gas Uptake Apparatus 5/20/91 is CMA 119756 Gas Uptake Data (Male Rats) Gas Uptake Data I (Female Rats) | Sf2(V94 19 2Q Estimating Mouse Metabolic Rate Constants Small, Halogensted Hydrocarbons Metabolized by CyP450 2E1 In Vivo VMax's from Experiments Methylene Chloride (MeClj) (Rats, Mice, Hiunaas) Chloroform (CHC1}) (Rats, Mice) Calculate VMax / gram Liver Normalize to Rat In Vivo MeCl2 CHC13 Average Mouse 2.57 2.71 2.64 Human 0.21 0.21 saw* 22 CMA 119758 Testing Estimated Mouse Metabolic Constants Optimized Mouse Data | *2om 23 5/10/94 24 Validation of Human Model (Barettaetal., 1969) 5/20/9* 25 Deriving Rat Potency! Baaed on Maltont's Experiments 12 Months Exposure 0,1, 5, IS, 25,54, 100,15% 200, 250,SSS, 2500, MOO, (0000,30000 ppm tested Poor Survival 10000 aud 30000; Use Remaining 13 Dose Groups Use PB-PK Model to Calculate Dose Average Amount VC Metabolites per day per Liter of Liver Tissue Howe & Crump's GLOBAL83 Multistage Model Dose Response (Maximum Likelihood Estimate) Comparison: Linear Model Pitted to Top Two Doses (MTD, MTD/2) sijom u PPM Vinyl Chloride Extrapolating Rat -> Mouse (Maltom, Swiss Albino Mice) Cone 0 50 250 500 2,500 Males 0/80 1/30 9/30 6/30 6/29 Females 0/70 0/30 9/30 8/30 10/30 LADD 0.0 38.4 173.1 265.2 331.0 Equivalent Amounts of Metabolite produce Equivalent Tumor Yields No Surface Area Correction Factor Used. The 1(H RSD = 0.80 x 1CH 5/20/9* 27 5/20/9* 28 Comparing RSD's) Maltoni et al., (Rat) Maltoni et a!., (Mouse) Lee et al., (Mouse) 0.177 0.080 0.120 Drew et al., (B6 Mouse)^^r04)032 Drew eMtfT reported angiosacromas in :>ls. Lee and Maltoni saw none. B6C3F1 Ultrasensitive? Reported to have partial oncogene activation in absence of any chemical treatment. 5/20m 29 Extrapolating Rat -> Humans (Maltoni, Rat Potency) Equivalent Amounts of Metabolite produce Equivalent Tumor Yields No Surface Area Correction Factor Used. Calculated "Unit Risk", Lifetime Exposure to 1/ig/m3,24 hr/day. PBPK MLE = 4 x la7 PBPKUCL = 6xia7 IRIS Number = 840 x la7 j/wm 30 VC Tumor Registry (Simonato et al., 1991) 12,706 Individuals from Population of 14,351 Completeness of Followup = 97.7% Cohort has > 2$ Years since 1st Exposure to VC Exposure Groupings: + 0 - 2,000 pfan year* + 2,000 0,000 ppm years + 4,000 - 10,000 ppm years v > 10,000 ppn years Absolute Risks Estimated to Range from 6.2/100,000 to 280/100,000 5fflWt 31 PBPK Risk Assessment I Versus Simonato et al (1991) | IPM Too Yoan Cxpoowt SO 500 100 1,000 200 2000 -- 4000 500 SjOOO -- sxoa HUB -- 2000 10X100 >1(1000 20,000 IMrln Imnr 50 tooo 100 2000 200 4000 -- 4000 500 ioooo -- 1000 2000 15O00 20000 40000 ij run LADD PB-FK PlcdktMB rmimjm OWwl fun gwwua 3.33 6.63 1206 -- 2460 -- 3125 -- 3603 IBS 374 736 -- 1,497 -- 1253 -- 2632 -- (62J* -- 422 -- 1S2.3 -- 050.(5* -- 666 1326 2611 -- 5335 -- 6257 7207 376 747 1465 -- 2.971 -- 3476 3,993 (62)* -- 422 1523 080154 WWW yi Summary] Straight-Forward Modification of Existing PBPK Model Based on Rat In Vivo Studies, Validated with Mouse and Human Data Described Tumor Data 1-6,000 ppm in Rats and Predicted Tumor Data in Mouse Studies Unit Risk Based on PBPK Principles 150 Fold Lower than Current IRIS Value. Tumor Predictions Most Accurate WITHOUT Surface Area Correction Factor When Mechanism Is Known, PBPK Procedures Should Be Capable of Giving Much More Accurate Estimates of Risk. 3/2IV94 33