Document 60KqxMn6vM7xXmVZN4RnLxmg

CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Health Committee Meeting With the University of Louisville Tentative Agenda DATE: April 18,1997 TIME: 8:30 a.m. - 2:30 p.m. PLACE: Health Sciences Center University of Louisville Louisville, KY 8:30-9:00 1.0 Review Agenda Items and Objectives 9:00-9:30 2.0 Status of Work in Progress at the University of Louisville 9:30-9:45 3.0 Update on Cohort Mortality Study at the Applied Epidemiology, Inc. 9:45-10:15 4.0 Discussion of Greenberg/Tamburro Methodology for Analysis of BF Goodrich Cohort Data, Including Statistical Power 10:45-11:00 Break 11:00-12:00 5.0 Discussion of Classical Case Control Analysis of BF Goodrich Cohort Data 12:00-12:30 6.0 Consensus on Methods of Analysis and Publication of Final Study Results 12:30-1:30 Lunch 1:30-2:30 7.0 Development of Final Protocol 7.1 Review GEP's to Assure that the Final Protocol Meets All Applicable Guidelines 7.2 Develop a Strategy for Addressing Peer Reviewers Comments in the Protocol 7.3 Establish a Time Line for Preparation, Reviews, and Approval of Final Protocol 7.4 Discuss Peer Reviewers' Sign-off of the Final Protocol SL 109814 IT THE APPLICATION OF PHARMACOKINETIC AND DOSE-RESPONSE MODELING IN THE DEVELOPMENT OF MRLs Harvey J. Clewell KS Crump Group ICF Kaiser International Ruston, Lopisiana SL 109815 Benchmark Dose Analysis Benchmark Dose (BMD) = dose (or exposure) predicted to result in a specified increase in risk: the benchmark risk (BR) Calculated using a statistical dose-response model applied to either experimental toxicological or epidemiological data Statistical lower bound on the Benchmark Dose (BMDL) has been proposed as a replacement for the NOAEL SL 109816 Benchmark Dose Analysis Advantages over NOAEL/LOAEL Does not require arbitrary categorization of the data Makes better use of dose-response information Statistical lower bound appropriately reflects the sample size of the study and the variability of the data SL 109817 Minimum Data Requirements for Benchmark Dose Modeling I. Quantal Data (incidence/prevalence of a response): A. Ungrouped Data (individual animal/subject data): 1. Dose or exposure concentration for each subject. 2. Response status (normal or abnormal) for each subject. B. Grouped Data: (results summarized by dose group or exposure category) 1. Number of animals/subjects in each dose group. 2. Number of animals/subjects in each dose group with abnormal response. 3. Dose or exposure concentration for each dose group. SL 109818 Minimum Data Requirements for Benchmark Dose Modeling II. Continuous Data (quantitative measures of response): A. Ungrouped Data: 1. Dose or exposure concentration for each animal/subject. 2. Quantitative response for each animal/subject. B. Grouped Data: 1. Number of animals/subjects in each dose group. 2. Mean response in each dose group. 3. Standard deviation (or standard error) of response in each dose group. 4. Dose or exposure concentration for each dose group. SL 109819 Impact of Benchmark Dose Modeling on Intermediate Inhalation MRL for TCE LOAEL: 50 ppm LOAEL/IO: 5 ppm BMDLq i using all dose groups: 56 ppm BMDLq , omitting highest dose: -- with PBPK dose metrics: 31 ppm 21 ppm SL 109820 Impact of Benchmark Dose Modeling on Intermediate Oral MRL for TCE LOAEL: 0.18 mg/kg/d LOAEL/10: 0.018 mg/kg/d BMDLq , using all dose groups: 65 mg/kg/d BMDL0j omitting highest dose: 0.24 mg/kg/d SL 109821 MRLs for Methylene Chloride Using PBPK Approach in Comparison with Current MRLs MRL Current Approach PBPK Approach Ratio PBPK/ Current Inhalation Acute _ Interme diate 0.4 ppm 0.03 ppm a 0.8-4 ppm 0.25 ppm b 2-10 8 Oral Chronic 0.06 mg/kg/d 0.13 mg/kg/d b a 2 SL 109822 MRLs for Trichloroethylene Using PBPK Approach in Comparison with Current MRLs MRL Current Approach PBPK Approach Ratio PBPK/ Current Inhalation Acute 2 ppm 2-8 ppm 1-4 Interme 0.1 (0.04)c diate ppm b 0.1-0.2 ppm b 1 - 2 (2.5 5)' Oral Acute 0.5 mg/kg/d * 0.02-0.04 mg/kg/db 0.04 - 0.08 P > >-- Interme 0.002 diate mg/kg/d a 0.0002-0.0004 mg/kg/d b Io I 1 1 SL 109823 Review of Chemicals for Suitability of PBPK or BMD Modeling in MRLs Chemical Aldrin Dieldrin Arsenic Cadmium Carbon Tetrachloride Chlordane Chloroform DDT Mercury Tetrachloroethylene PBPK -- A/H A/H A/H A/H -- A/H -- A/H A/H BMD 1/2 1/3 0/1 1/2 0/4 3/4 2/6 0/2 3/5 0/3 Total 7/9 11/32 SL 109824 Conclusions Use of PBPK Modeling in MRL Process Most important impact: Cross-species scaling (and route-to-route) Challenge: Selection of dose metric ("mode of action") Pharmacokinetic principles can be applied without full PBPK model Need multiple "mode-of-action" defaults for cross-species extrapolation (cf. EPA RfC Dosimetry Guidelines) SL 109825 Cross-Species Dosimetry for Inhalation Traditional: mg/kg/day metric: CxVxTxF/BW New RfC Dosimetry Guidelines: Category 1: reactive materials (e.g., formaldehyde) metric: CxVxTxF/SA Category 2: water-soluble materials (e.g., propanol) metric: C x V x T x F / BW Category 3: water-insoluble materials (e.g., styrene) metric: C x T SL 109826 Human Equivalent Concentrations Based on Pharmacokinetic Dose Metrics for Three Volatile Chemicals1 Inhalation Exposure Toxicity Due to Parent Chemical Exposure (MC, TCE, VC): - PBPK HEC within a factor of 2 of default Toxicity Due to Reactive Metabolite (MC, VC): -- PBPK HEC 2.5- to 25-fold higher than default Toxicity Due to Stable Metabolite (TCE): -- PBPK HEC 10- to 100-fold lower than default 1 Based on PBPK model calculations for methylene chloride (MC), trichloroethylene (TCE), and vinyl chloride (VC) SL 109827 Human Equivalent Concentrations Based on Pharmacokinetic Dose Metrics for Three Volatile Chemicals1 Qrai Exposure; Toxicity Due to Parent Chemical Exposure (MC, TCE, VC): -- PBPK human dose 3- to 30-fold lower than RfD default Toxicity Due to Reactive Metabolite (MC, VC): -- PBPK human dose 2- to 10-fold higher than RfD default Toxicity Due to Stable Metabolite (TCE): -- PBPK human dose 5- to 20-fold lower than RfD default 1 Based on PBPK model calculations for methylene chloride (MC), trichloroethylene (TCE), and vinyl chloride (VC) SL 109828 Conclusions Use of BMD Modeling in MRL Process Most important impact: Replacement of LOAEL/IO Challenge: "Goodness of fit" evaluation Need better reporting of data in toxicology literature SL 109829 Conclusions Use of PBPK and BMD Modeling in the MRL Process Both techniques synergistically improve accuracy of quantitative dose-response calculations Impact of greater accuracy in quantitative analysis is typically small compared to impact of qualitative factors: -- Selection of critical study -- Choice of Uncertainty/Modifying Factors SL 109830 Interaction of PBPK/BMD with Uncertainty Factors Interindividual variability / Sensitive subpopulations (10) Typically unaffected by PBPK or BMD modeling Subchronic to chronic / Acute to subchronic (10) Typically unaffected by PBPK or BMD modeling LOAEL vs NOAEL (10) EPA: BMDLfc, = NOAEL Animal to human (10) EPA: 10 = 3 (PK) x 3 (PD) UF reduced to 3 for either default (parent) dosimetry or use of PBPK model SL 109831 Priorities for the Application of PBPK and BMD Modeling for MRLs 1 MRLs based on a LOAEL where the benchmark dose (BMD) method could be used to estimate a NOAEL 2 Oral MRLs where the toxicity is due to a stable metabolite and the current MRL may underestimate the human hazard 3 MRLs where the toxicity is due to a reactive intermediate and the current MRL may overestimate the human hazard SL 109832 Recommended MRL Cases 1. Manganese: BMD analysis of 1 MRL. The chronic inhalation MRL is based on a LOAEL in an epidemiological study, and the critical study includes adequate data to perform BMD analysis to determine a NOAEL. Recommended MRL Cases 2. Dieldrin: BMD analysis of 1 MRL and PBPK analysis of 3 MRLs. The acute oral MRL is based on a LOAEL, and the critical study includes adequate data to perform a BMD analysis to determine a NOAEL. Moreover, all 3 MRLs for dieldrin represent oral toxicity by a stable compound and the default animal-to-human extrapolation may underestimate the relative human hazard. SL 109834 Recommended MRL Cases 3. Mercury: BMD analysis of 2 MRLs and PBPK analysis of 1 MRL. Both the metallic and organic mercury acute inhalation MRLs are based on LOAELs, and the critical studies include adequate data to perform BMD analysis to determine NOAELs. SL 109835 Recommended MRL Cases 4. Cadmium: BMD analysis of 2 MRLs. Both the oral and inhalation chronic MRLs for cadmium are based on human epidemiological studies which are suitable for BMD analysis to evaluate the NOAELs. SL 109836 Recommended MRL Cases 5. Tetrachloroethylene (PERC): PBPK analysis of 1 MRL. A PBPK model for PERC could be applied to evaluate the animal-to-human dosimetry for the acute oral MRL, which represents oral toxicity by a stable compound and for which the default animal-to-human extrapolation may underestimate the relative human hazard. SL 109837 Recommended MRL Cases 6. Chloroform: PBPK analysis of 1 MRL. A PBPK model for chloroform could be used to correct the animal-to-human dosimetry for the acute inhalation MRL. (It is currently calculated incorrectly.) Recommended MRL Cases 7. Carbon tetrachloride: PBPK analysis of 4 MRLs. A PBPK model for carbon tetrachloride could be applied to evaluate the animal-tohuman dosimetry for the acute and intermediate inhalation MRLs, which represent inhalation toxicity by a reactive metabolite and for which the default animal-to-human extrapolation may overestimate the relative human hazard. The model could also be used to evaluate the oral MRLs, although they are not likely to be effected significantly. Page 1 of 5 Vinyl Chloride Health Committee Activities MEMORANDUM OF UNDERSTANDING (MOU) WITH THE AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY (ATSDR) The MOU has been signed. A revised study plan was sent to ATSDR because of the delay in the initiation of the study. IMPORTANCE ACTION ITEMS 04/22/97 DEADLINES Initial progress reports are due at ATSDR in April 1997 with subsequent reports due every 6 months thereafter until studies are completed and final reports are submitted. The MOU was developed to meet the research needs of ATSDR and the Environmental Protection Agency in lieu of a TSCA Section 4 testing requirement. REPRODUCTIVE & DEVELOPMENTAL TOXICITY STUDIES AT HUNTINGDON LIFE SCIENCES (HLS) The contract with Huntingdon has been signed. Analytical work on the test material is complete and the exposure portion of the study has begun. Preliminary results of the analytical work were delivered to CMA for inspection. Jim Knaak reviewed the material and approved it. Jim Knaak, David Penney, and Wendy Sherman visited Huntingdon on April 10,1997 to monitor the progress of the studies. ACTION ITEMS Continue monitoring progress of study. DEADLINES Progress reports are due to ATSDR at intervals specified in the revised study plan of April 22,1997. IMPORTANCE This research is in lieu of a potential TSCA Section 4 testing requirement. MOLECULAR CARCINOGENESIS SATELLITE STUDIES AT HLS/ UNIVERSITY OF NORTH CAROLINA-JAMES SWENBERG Ray Schroeder (HLS) and James Swenberg (UNC) revised the protocols for the satellite studies. Fewer animals will be needed to conduct the studies and studies will not be subject to GLP standards. This significantly reduces the cost of the satellite studies. ACTION ITEMS Execute agreement with HLS for in-life portion of satellite study. Prepare a gift letter for $50K to University of North Carolina for the post-exposure treatment of animals and the adducts analyses. DEADLINES IMPORTANCE This series of studies on the formation and repair of DNA adducts induced by vinyl chloride should provide a better understanding of the mechanisms of vinyl chloride carcinogenesis. SL 109840 Page 2 of 5 Vinyl Chloride Health Committee Activities 04/22/97 SYNTHESIS OF 13C2 VINYL CHLORIDE / CAMBRIDGE ISOTOPE LABORATORIES The product was delivered to Huntingdon. According to Gary Hoffman (HLS) the analytical specifications of the material are acceptable. ACTION ITEMS DEADLINES IMPORTANCE By utilizing 13C2-vinyl chloride, the formation and repair of vinyl chloride-induced DNA adducts can be studied relative to those adducts formed endogenously. This aspect of the satellite studies could provide important information for risk assessment dealing with low exposures, such as might be associated with accidental releases that reach the fenceline. INTERNATIONAL LIFE SCIENCES INSTITUTE (ILSI) The VCHC contributed $101)00 to ILSI for .a project on the use erf non-tumor data in cancer risk assessment. Case studies are being performed for three chemicals: bezene. vinyl chloride and butadiene. Gino Scarano of ILSI provided a progress report on the project. ACTION ITEMS Continue to monitor ILSI activities on this project through Gino Scarano. DEADLINES A meeting of committee members and sponsors is expected sometime this fall. Gino Scarano will notify CMA of the date of die meeting. IMPORTANCE The current scientific and regulatory climate is such that the use of endpoints other than tumors to quantitatively estimate cancer risk is on the horizon. This project was initiated to address the question of whether and how genotoxicity and other data could be used as part of a cancer risk assessment. EPA INTEGRATED RISK INFORMATION SYSTEM PILOT PROJECT ACTION ITEMS EPA has selected vinyl chloride as one of eleven plus chemicals for its IRIS pilot project. The goal of die pilot is to improve the efficiency in gathering and reviewing data and the quality of the information available through IRIS. A peer review of vinyl chloride is scheduled for the week of May 12*. The pilot study is scheduled to conclude this summer, with a decision on the success of the program expected by the fall of 1997. Monitor EPA activities on this project through Amy Mills (202/260-0569), the project manager and William Pepelko (202/260-5904), the chemical manager for the vinyl chloride risk assessment. DEADUNES SL 109841 Page 3 of 5 Vinyl Chloride Health Committee Activities 04/22/97 According to Mike Gargas, Harvey Ciewell is the EPA contractor examining vinyl chloride. IMPORTANCE IRIS is an EPA database which contains consensus scientific positions on potential human health effects from environmental contaminants. The database has expanded and its use has increased over the last decade. It is the primary source of risk assessment and management information for many other agencies at the federal, state and local levels. BRAIN CANCER STUDY / UNIV OF LOUISVILLE ACTION ITEMS The study is proceeding on schedule. IMPORTANCE The 20-year prospective assessment of B.F. Goodrich's Louisville cohort provides a unique opportunity to determine whether there is any association between brain cancer and vinyl chloride exposure. The Committee and University of Louisville representatives met on April 18"' to explore alternative methods for analyzing data so the final study is seen as credible by both clinical and traditional epidemiological communities. Dr. Carlo Tamburo will revise the protocol to incorporate the comments received at the meeting and will send a revised draft protocol to Has Shah at CMA by May 18,1997. DEADLINES VINYL CHLORIDE COHORT STUDY UPDATE / APPUED EPIDEMIOLOGY INC Study progress reports are due at CMA on dates indicated in the agreement. ACTION ITEMS Ken Mundt received the remaining death certificate information from ENSR. He asked for assistance from Committee members to track employment and vital status on some of the cohort members. DEADLINES Study progress reports are due at CMA on dates indicated in the study agreement. IMPORTANCE ATSDR TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE ACTION ITEMS Committee provided comments on the health and environmental portions of foe profile to ATSDR. Data on production volume, facilities and use in die profile, is inaccurate. Caffey Norman has drafted a letter to ATSDR correcting die data and suggesting an alternative to the presentation of the storage data in Chapter 4 of the Toxicological Profile. Follow up with ATSDR on Committee comments. DEADLINES SL 109842 Page 4 of 5 Vinyl Chloride Health Committee Activities IMPORTANCE 04/22/97 ATSDR MEDICAL MANAGEMENT GUIDELINES FOR VINYL CHLORIDE Committee provided comments on the guidelines. As of April 1997, there was no established timeline for finalizing the Guidelines. IMPORTANCE ACTION ITEMS Follow-up with Jennifer Hiese (617/674-7358) on when the guidelines will be finalized. DEADLINES EPA / PETITION TO RAISE THE "REPORTABLE QUANTITY" (RQ) OF VINYL CHLORIDE The Vinyl Institute will take the lead on determining whether a petition to raise the RQ is feasible. The VCHC will provide technical expertise if the VI decides that it is feasible. Caffey Norman will provide background on tile criteria for determining the RQ. ACTION ITEMS DEADLINES IMPORTANCE EPA / AIR TOXICS PROGRAM ACTION ITEMS EPA identified vinyl chloride and 36 other chemicals as "high priorities" for regulation under its Air Toxics Program. The Agency plans to develop a comprehensive integrated strategy for establishing an "air toxics management model." Caffey Norman provided background on EPA's activities with the Air Toxics Program, and CMA has asked to be a stakeholder. DEADLINES IMPORTANCE ASSOCIATION OF PLASTICS MANUFACTURERS IN EUROPE (APME) / REGISTRY OF CASES OF ANGIOSARCOMA APME has developed a protocol for the maintenance of a register of cases of angiosarcoma related to PVC production. ACTION ITEMS CMA will monitor the development of the registry. DEADLINES IMPORTANCE SL 109843 AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS (ACG1H) / INITIATIVE TO LOWER THE THRESHOLD LIMIT VALUE (TLV) FOR VINYL CHLORIDE ACTION ITEMS The Committee will examine the Simonato paper and make contact with William Waddell to propose presenting information to ACGIH. Page 5 of 5 Vinyl Chloride Health Committee Activities The concern from ACGIH is based on an article by Simonato, et al. in the Scand J. Work &E.H. ACGtH met on October 5,6,7,19% in Philadelphia. Peter de la Cruz of Keller & Heckman (Vinyl Institute) responded to Dr. William Waddell of the Univ. of Louisville (ACGIH) for Frank Borelli. DEADLINES 04/22/97 IMPORTANCE CALEPA / DEVELOPMENTAL AND REPRODUCTIVE TOXICANT (DART) IDENTIFICATION COMMITTEE PRIORITY LIST Vinyl chloride is a potential candidate for listing under Proposition 65. Hie VCHC submitted comments to CalEPA. ACTION ITEMS The Committee will monitor this issue. IMPORTANCE DEADLINES SL 109844