Document 6bzyxOo8k5aXXXBLEKqaybj6g

CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Panel Health Committee Tentative Agenda DATE: TIME: PLACE: October 6, 1994 10:00 a.m. - 4:30 p.m. General A CMA Offices 2501 M Street, NW Washington, D.C. 1.0 Develop Strategy for Meeting with EPA to Discuss Vinyl Chloride Risk Assessment 2.0 Meet with EPA to Discuss Vinyl Chloride Risk Assessment DATE: TIME: PLACE: October 7, 1994 8:30 a.m. - 3:00 Board A CMA Offices p.m. 1.0 Approval of September 9, 1994 Record of Conference Call 2.0 Discussion of Vinyl Chloride Epidemiology Study Update Proposals from Contractors 2.1 Evaluation of Each Proposal 2.2 Selection of Contractor(s) for Further Consideration 2.3 Identification of Issues Needing Additional Information 2.4 Determination of Need for Site Visit 3.0 Discussion of Short-term Vinyl Chloride Exposure Effects Studies with James Swenberg of the University of North Carolina at Chapel Hill 4.0 Discussion of Meeting with EPA on Vinyl Chloride Risk Assessment 5.0 Discussion of Dow Chemical's Literature Review of Vinyl Chloride Teratology and Reproductive Effects Studies 6.0 Discussion of Course of Action with EPA on VC and EDC Testing Programs Under TSCA Section 4 7.0 Distribution of Financial Statement 8.0 Approval of Line Item Budgets for Health Committee Activities 9.0 Set Date for Next Conference Call or Meeting R&S 144672 Subject to Approval Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Health Committee and EPA Record of Meeting Date: Time: Place: October 6,1994 2:00 p.m. - 4:00 p.m. U.S. EPA 401 M Street, SW Washington, D.C. List of Attendees: James Barter David Bayliss Ed Beeler Chou Chen Arthur Chin Harvey Clewell (Via CC) Jim Cogliano Mike Gargas Mark Gruenwald Charli Hiremath Karen Hogan Jim Holder James Knaak John Balbus Komfeld Patrick Logue Elizabeth Margosches Hugh McKinnon David Penney Bill Pepelko Jonathan Ramlow David Reese Richard Reitz Sheila Rosenthal James Swenberg Linda Tuxen Larry Valeovie Alan Youkeles PPG Industries EPA GEON EPA EPA ICF/Kaiser EPA ChemRisk/McLaren/Hart Borden EPA EPA EPA Occidental Chemical EPA Georgia Gulf EPA EPA Vista Chemical EPA Dow Chemical EPA ChemRisk EPA University of North Carolina EPA EPA EPA Has Shah CMA 1.0 Richard Reitz described the physiologically-based pharmacokinetic model for risk assessment of vinyl chloride. EPA representatives indicated interest in receiving the manuscript when the PB-PK model is published in a peer-reviewed journal. Has Shah will send a draft manuscript to James Cogliano when it is received from Dr. Reitz. R&S 144673 CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Health Committee Record of Meeting Date: Time: Place: October 6,1994 10:30 a.m. -1:30 p.m. General A CMA Offices Washington, D.C. List of Attendees: James Barter Ed Beeler Mike Gargas Mark Gruenwald James Knaak Patrick Logue David Penney Jonathan Ramlow Dick Reitz Janies Swenberg PPG Industries GEON ChemRisk/McLaren Hart Borden Occidental Chemical Georgia Gulf Vista Chemical Dow Chemical ChemRisk University of North Carolina Has Shah CMA 1.0 The Committee discussed the risk assessment of vim physiologically-based pharmacokinetic model (PB-PK). The model was developed by Richard Reitz. Dr. Reitz will present this model to EPA scientists at the meeting this afternoon. The model predicts the true risk more accurately because it is based on actual pharmacokinetic data. For vinyl chloride, the unit risk based on the PB-PK principles is 150-fold lower than that predicted by non PB-PK models (Heast Table, May 1993, EPA). The PB-PK model is described in the attachment. 2.0 James Swenberg described his research proposal to determine TH of the ethenoguanine DNA adduct in rats using [13CJ vinyl chloride, and quantifying the amount of the methyl purine DNA glycosylase and P450 2 El in tissues of humans of different ages. The Committee will consider Dr. Swenberg's proposal in relation to other research projects and decide if funds are available for his proposal. 3.0 The meeting adjourned at approximately 11:45 a.m. Subject to Approval ^kjjjr-- - Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel R&S 144675 Expectations for Pharmacokinetic Modeling Modeling Cannot Eliminate ALL Uncertainty from Risk Assessments Modeling Can Quantitatively Describe: * Metabolic Saturation Changes in Dose Route * Physiological Differences in Species PREMISE: Risk Assessments based on Estimates of "Delivered Dose" will be More Reliable than Risk Assessments based Only on Administered Dose Advantages of PB-PK Models: Compound Specific Information Vapor Pressure Solubilities (Partitioning) in Tissues Species Specific Information Physiology Metabolism Route Specific Information Oral Route, 1st Pass Through Liver Allow Extrapolations Between Dose Routes Between High Dose / Low Dose Between Species 10/1/94 3 l<VM4 6 Metabolites Based on Ramsey & Andersen, 1984. 00 9f> (/) 44O-4**l -4 8 In Vivo Metabolism (Watanabe) High Specific Activity 14C-Vinyl Chloride Six Hour Inhalation Exposure Several Different Concentrations Above and Below Metabolic Saturation Radioactivity Quantitates Metabolite Production DIRECT measurement of metabolism (Gas Uptake Indirect Measure) One or Two Metabolic Pathways 10/sm 13 Estimating Mouse Metabolic Rate Constants Small, Halogenated Hydrocarbons Metabolized by CyP450 2E1 In Vivo VMax's from Experiments Methylene Chloride (MeCl2) (Rats, Mice, Humans) Chloroform (CHCI3) (Rats, Mice) Calculate VMax / gram Liver Normalize to Rat In Vivo MeCl2 CHCI3 Average Mouse 2.57 2.71 2.64 Human 0.21 - 0.21 10/5/94 Parallelogram Approach! In Vivo In Vivo 10/5/94 -t* 4* -J (O Predicted Tumor Incidence in Rats Administered and PB-PK Dose Scales Risk Specific Dose (1(H) = 1.77 x 101 (mg metabolite/liter/day) Extrapolating Rat -> Mouse (Maltoni, 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 1CHRSD = 0.80 xlO1 10/5/94 21 10/5/94 22 Comparing RSD*s| Maltoni et al., (Rat) Maltoni et al., (Mouse) Lee et al., (Mouse) 0.177 0.080 0.120 Drew et al,, (B6 Mouse)^^W).0032 reported angiosacromas in Lee and Maltoni saw none. B6C3F1 Ultrasensitive? Reported to have partial oncogene activation in absence of any chemical treatment. 10/5/94 23 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 l(tg/m3,24 hr/day. PBPKMLE = 4x10-7 PBPKUCL =6x10-7 IRIS Number = 840 x 10-7 3J W o4t>** 09 KV5/94 24