Document zzVO54rR8j2V0X14p0j3XXKK3

Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 3 The Honorable Lisa P. Jackson 4 Administrator 5 U.S. Environmental Protection Agency 6 1200 Pennsylvania Avenue, N.W. 7 Washington, D.C. 20460 8 9 Subject: SAB Review of EPA's Reanalysis of Key Issues Related to Dioxin 10 Toxicity and Response to NAS Comments 11 12 Dear Administrator Jackson: 13 14 EPA's Office of Research and Development (ORD) requested that the Science 15 Advisory Board (SAB) review the Agency's draft report entitled EPA's Reanalysis o f 16 Key Issues Related to Dioxin Toxicity and Response to NAS Comments ("Report"). The 17 Report contains EPA's technical response to key comments in the 2006 National 18 Academy of Sciences (NAS) report, Health Risks from Dioxin and Related Compounds: 19 Evaluation o f the EPA Reassessment. The NAS reviewed EPA's 2003 exposure and 20 human health reassessment of dioxin and recommended that the Agency should: more 21 thoroughly justify and communicate its approaches to dose-response modeling for the 22 health effects of dioxin, taking into consideration both nonlinear and linear methods for 23 characterizing cancer risk; improve the transparency and clarity of the selection of key 24 data sets for the dioxin dose-response analysis; reevaluate its cancer weight-of-evidence 25 determination for dioxin based on the Agency's 2005 Cancer Guidelines; consider using 26 physiologically-based pharmacokinetic (PBPK) modeling in the dioxin risk assessment; 27 and improve transparency, thoroughness and clarity in quantitative uncertainty analysis. 28 The NAS also encouraged EPA to calculate a reference dose (RfD), which had not been 29 derived in the 2003 reassessment. 30 31 In response to EPA's request, the SAB convened an expert panel to review the 32 Agency's Report. The SAB Panel was asked to comment on the scientific soundness of 33 EPA's responses to the NAS recommendations. The enclosed SAB report provides the 34 consensus advice and recommendations of the Panel, with the exception of one member 35 who offered a dissenting opinion mainly on 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) 36 carcinogenicity. 37 38 The SAB finds that EPA's Report is clear, logical, and responsive to many but not 39 all of the recommendations of the NAS. We have provided recommendations to further 40 enhance the transparency, clarity, and scientific integrity of the Report. The SAB has 41 identified deficiencies in EPA's Report with respect to the completeness of its 42 consideration of two critical elements of the TCDD assessment: 1) nonlinear dose43 response for TCDD carcinogenicity, and 2) uncertainty analysis of TCDD toxicity. Our 44 major comments and recommendations are provided below: Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 The SAB commends EPA for the comprehensive and rigorous process that was 3 used to identify, review, and evaluate the TCDD literature. The criteria for study 4 selection have been clearly articulated, well justified, and applied in a 5 scientifically sound manner. To further improve clarity and transparency of the 6 Report, we recommend that EPA include a better means of tracking and 7 describing which studies did not satisfy inclusion criteria. Similarly, we 8 recommend that EPA strengthen its justification for excluding studies of dioxin 9 like compounds. The Report can be enhanced by incorporating information from 10 studies with dioxin-like compounds into a qualitative discussion of the weight-of11 evidence for cancer and noncancer endpoints. 12 13 EPA used the Emond physiologically-based pharmacokinetic model to evaluate 14 the internal dose of TCDD in human and rodent tissue, and to estimate the 15 continuous daily TCDD intake over the relevant period of exposure. The SAB 16 agrees with EPA that this model provides the best available basis for the dose 17 metric calculations. We also support EPA's use of blood TCDD concentrations 18 as the relevant dose metric. However, we recommend that EPA expand the 19 discussion of other published models, evaluate the impact of model selection on 20 dose metric prediction, provide a more quantitative uncertainty analysis, and 21 conduct an external peer review of the mouse model because it has not been 22 published in the peer-reviewed literature. 23 24 The SAB agrees with EPA's classification of TCDD as carcinogenic to humans in 25 accordance with EPA's 2005 Guidelinesfor Carcinogen Risk Assessment. The 26 SAB recommends that in the weight-of-evidence characterization EPA build upon 27 all available data to support its decision and clearly indicate how different types 28 of data support each other. One Panel member, however, indicated that at best, 29 there is equivocal evidence for TCDD classification as a human carcinogen. 30 31 The SAB agrees with EPA's selection of the Cheng et al. (2006) study, which 32 analyzed the National Institute for Occupational Safety and Health (NIOSH) 33 occupational cohort, as the critical study for the quantitative cancer assessment. 34 The SAB also agrees that it is appropriate to use all-cancer mortality as the basis 35 of the oral slope factor because of the extensive dose-response information. 36 37 The SAB finds that the Report did not respond adequately to the NAS 38 recommendation to adopt both linear and nonlinear methods of extrapolation in 39 order to account for the uncertainty of the dose-response curve for TCDD. The 40 Report states that only a linear approach could be justified. We recommend that 41 EPA revise the Report to provide a discussion of evidence of possible modes of 42 action that include both linear and nonlinear alternatives for the cancer endpoint. 43 In the absence of a definitive nonlinear mode of action, estimates based on the 44 linear option can serve as the baseline for comparison with other estimates. ii Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 The SAB supports EPA's selection and use of two co-critical epidemiologic 3 studies for the derivation of the RfD for TCDD. These studies evaluated the 4 effects of human exposure to TCDD following accidental release at a chemical 5 plant near Seveso, Italy. The SAB finds that the study endpoints used by EPA to 6 determine the RfD (decrease in sperm count and motility and increased thyroid 7 stimulating hormone in blood) are relevant to public health. The selection of 8 these endpoints also resolves the critical issue of differing windows of 9 susceptibility to environmental toxic agents over the course of the life cycle, with 10 pre- and periconceptional exposures comprising the window of greatest 11 susceptibility. We recommend, however, that EPA provide a discussion of the 12 strengths and weaknesses of the studies and an indication of whether these 13 weaknesses affect the RfD determination. 14 15 The SAB also agrees with the benchmark dose modeling approaches used by EPA 16 in the Report and the decision to use human data as preferred to animal data for 17 the RfD determination. 18 19 EPA's Report discusses a broad range of philosophical and methodological issues 20 to be considered in conducting an uncertainty analysis for TCDD toxicity. 21 Although the SAB acknowledges the challenges of a unified quantitative 22 uncertainty analysis, we do not agree with the position taken in the Report that 23 such an analysis is unfeasible and we have suggested a number of methods that 24 could be used for this purpose. 25 26 Finally, EPA's Report could be improved by editing and restructuring to better 27 integrate the material presented in various sections, eliminate redundancies, and 28 move some material into appendices to provide more succinct responses to NAS 29 concerns. In addition, we recommend including a glossary in the Report to help 30 minimize confusion and misinterpretation among diverse users. 31 32 The SAB appreciates the opportunity to provide EPA with advice on this important 33 subject. We support EPA in its effort to move in a proficient and expeditious manner to 34 finalize the IRIS document for dioxin and look forward to receiving the Agency's 35 response. 36 37 Sincerely, 38 39 40 41 42 Dr. Deborah L. Swackhamer, Chair Dr. Timothy J. Buckley, Chair 43 EPA Science Advisory Board SAB Dioxin Review Panel iii Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 3 4 5 NOTICE 6 7 8 This report has been written as part of the activities of the EPA Science Advisory 9 Board, a public advisory committee providing extramural scientific information and 10 advice to the Administrator and other officials of the Environmental Protection Agency. 11 The Board is structured to provide balanced, expert assessment of scientific matters 12 related to problems facing the Agency. This report has not been reviewed for approval 13 by the Agency and, hence, the contents of this report do not necessarily represent the 14 views and policies of the Environmental Protection Agency, nor of other agencies in the 15 Executive Branch of the Federal government, nor does mention of trade names or 16 commercial products constitute a recommendation for use. Reports of the EPA Science 17 Advisory Board are posted on the EPA Web site at: http://www.epa.gov/sab 18 19 iv Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 U.S. Environmental Protection Agency 2 Science Advisory Board 3 Dioxin Review Panel 4 5 6 CHAIR 7 Dr. Timothy Buckley, Associate Professor and Chair, Division of Environmental Health 8 Sciences, College of Public Health, The Ohio State University, Columbus, OH 9 10 11 MEMBERS 12 Dr. Harvey Clewell, Director of the Center for Human Health Assessment, The Hamner 13 Institutes for Health Sciences, Research Triangle Park, NC 14 15 Dr. Louis Anthony (Tony) Cox, Jr., President, Cox Associates, Denver, CO 16 17 Dr. Elaine Faustman, Professor and Director, Institute for Risk Analysis and Risk 18 Communication, School of Public Health, University of Washington, Seattle, WA 19 20 Dr. Scott Ferson, Senior Scientist, Applied Biomathematics, Setauket, NY 21 22 Dr. Jeffrey Fisher, Research Toxicologist, National Center for Toxicological Research, 23 U.S. Food and Drug Administration, Jefferson, AR 24 25 Dr. Helen Hakansson, Professor of Toxicology, Unit of Environmental Health Risk 26 Assessment, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 27 Sweden 28 29 Dr. Russ Hauser, Frederick Lee Hisaw Professor, Department of Environmental Health, 30 Harvard School of Public Health, Boston, MA 31 32 Dr. B. Paige Lawrence, Associate Professor, Departments of Environmental Medicine 33 and Microbiology and Immunology, School of Medicine and Dentistry, University of 34 Rochester School of Medicine and Dentistry, Rochester, NY 35 36 Dr. Michael I. Luster, Professor, Department of Community Medicine, West Virginia 37 University Health Sciences Center, Morgantown, WV 38 39 Dr. Paolo Mocarelli, Professor of Clinical Biochemistry, Department of Clinical 40 Laboratory, Hospital of Desio-Nuovo Monoblous, University of Milano Bicocca, Desio41 Milano, Italy 42 43 Dr. Victoria Persky, Professor, Epidemiology and Biostatistics Program, School of 44 Public Health, University of Illinois at Chicago, Chicago, IL v Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Dr. Sandra L. Petersen, Professor, Associate Graduate Dean, Department of Veterinary 3 and Animal Sciences, College of Natural Sciences, University of Massachusetts4 Amherst, Amherst, MA 5 6 Dr. Karl Rozman*, Professor, Pharmacology, Toxicology and Therapeutics, The 7 University of Kansas Medical Center, Kansas City, KS 8 9 Dr. Arnold Schecter, Professor, Environmental and Occupational Health Sciences, 10 School of Public Health-Dallas Campus, University of Texas, Dallas, TX 11 12 Dr. Allen E. Silverstone, Professor, Department of Microbiology and Immunology, 13 Health Science Center, SUNY Upstate Medical University, Syracuse, NY and Adjunct 14 Professor of Environmental Medicine, University of Rochester School of Medicine and 15 Dentistry, Rochester, NY. 16 17 Dr. Mitchell J. Small, The H. John Heinz III Professor of Environmental Engineering, 18 Department of Civil and Environmental Engineering and Engineering and Public Policy, 19 Carnegie Mellon University, Pittsburgh, PA 20 21 Dr. Anne Sweeney, Professor of Epidemiology, Department of Epidemiology and 22 Biostatistics, School of Rural Public Health, Texas A&M Health Science Center, College 23 Station, TX 24 25 Dr. Mary K. Walker, Professor, Division of Pharmaceutical Sciences, College of 26 Pharmacy, University of New Mexico, Albuquerque, NM 27 28 29 SCIENCE ADVISORY BOARD STAFF 30 Dr. Thomas Armitage, Designated Federal Officer, U.S. Environmental Protection 31 Agency, Washington, DC 32 33 Dr. Diana Wong, Designated Federal Officer, U.S. Environmental Protection Agency, 34 Washington, DC 35 36 37 * Dissenting opinion in Appendix A 38 vi Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 U.S. Environmental Protection Agency 2 Science Advisory Board 3 BOARD 4 5 6 CHAIR 7 Dr. Deborah L. Swackhamer, Professor and Charles M. Denny, Jr. Chair in Science, 8 Technology and Public Policy - Hubert H. Humphrey School of Public Affairs and Co 9 Director of the Water Resources Center, University of Minnesota, St. Paul, MN 10 11 12 SAB MEMBERS 13 Dr. David T. Allen, Professor, Department of Chemical Engineering, University of 14 Texas, Austin, TX 15 16 Dr. Claudia Benitez-Nelson, Full Professor and Director of the Marine Science 17 Program, Department of Earth and Ocean Sciences, University of South Carolina, 18 Columbia, SC 19 20 Dr. Timothy J. Buckley, Associate Professor and Chair, Division of Environmental 21 Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 22 23 Dr. Patricia Buffler, Professor of Epidemiology and Dean Emerita, Department of 24 Epidemiology, School of Public Health, University of California, Berkeley, CA 25 26 Dr. Ingrid Burke, Director, Haub School and Ruckelshaus Institute of Environment and 27 Natural Resources, University of Wyoming, Laramie, WY 28 29 Dr. Thomas Burke, Professor, Department of Health Policy and Management, Johns 30 Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 31 32 Dr. Terry Daniel, Professor of Psychology and Natural Resources, Department of 33 Psychology, School of Natural Resources, University of Arizona, Tucson, AZ 34 35 Dr. George Daston, Victor Mills Society Research Fellow, Product Safety and 36 Regulatory Affairs, Procter & Gamble, Cincinnati, OH 37 38 Dr. Costel Denson, Managing Member, Costech Technologies, LLC, Newark, DE 39 40 Dr. Otto C. Doering III, Professor, Department of Agricultural Economics, Purdue 41 University, W. Lafayette, IN 42 43 44 vii Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Dr. David A. Dzombak, Walter J. Blenko, Sr. Professor of Environmental Engineering, 2 Department of Civil and Environmental Engineering, College of Engineering, Carnegie 3 Mellon University, Pittsburgh, PA 4 5 Dr. T. Taylor Eighmy, Vice President for Research, Office of the Vice President for 6 Research, Texas Tech University, Lubbock, TX 7 8 Dr. Elaine Faustman, Professor and Director, Institute for Risk Analysis and Risk 9 Communication, School of Public Health, University of Washington, Seattle, WA 10 11 Dr. John P. Giesy, Professor and Canada Research Chair, Veterinary Biomedical 12 Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, 13 Canada 14 15 Dr. Jeffrey K. Griffiths, Associate Professor, Department of Public Health and 16 Community Medicine, School of Medicine, Tufts University, Boston, MA 17 18 Dr. James K. Hammitt, Professor, Center for Risk Analysis, Harvard University, 19 Boston, MA 20 21 Dr. Bernd Kahn, Professor Emeritus and Associate Director, Environmental Radiation 22 Center, Georgia Institute of Technology, Atlanta, GA 23 24 Dr. Agnes Kane, Professor and Chair, Department of Pathology and Laboratory 25 Medicine, Brown University, Providence, RI 26 27 Dr. Madhu Khanna, Professor, Department of Agricultural and Consumer Economics, 28 University of Illinois at Urbana-Champaign, Urbana, IL 29 30 Dr. Nancy K. Kim, Senior Executive, Health Research, Inc., Troy, NY 31 32 Dr. Catherine Kling, Professor, Department of Economics, Iowa State University, 33 Ames, IA 34 35 Dr. Kai Lee, Program Officer, Conservation and Science Program, David & Lucile 36 Packard Foundation, Los Altos, CA (affiliation listed for identification purposes only) 37 38 Dr. Cecil Lue-Hing, President, Cecil Lue-Hing & Assoc. Inc., Burr Ridge, IL 39 40 Dr. Floyd Malveaux, Executive Director, Merck Childhood Asthma Network, Inc., 41 Washington, DC 42 43 Dr. Lee D. McMullen, Water Resources Practice Leader, Snyder & Associates, Inc., 44 Ankeny, IA 45 viii Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Dr. Judith L. Meyer, Professor Emeritus, Odum School of Ecology, University of 2 Georgia, Lopez Island, WA 3 4 Dr. James R. Mihelcic, Professor, Civil and Environmental Engineering, University of 5 South Florida, Tampa, FL 6 7 Dr. Jana Milford, Professor, Department of Mechanical Engineering, University of 8 Colorado, Boulder, CO 9 10 Dr. Christine Moe, Eugene J. Gangarosa Professor, Hubert Department of Global 11 Health, Rollins School of Public Health, Emory University, Atlanta, GA 12 13 Dr. Horace Moo-Young, Dean and Professor, College of Engineering, Computer 14 Science, and Technology, California State University, Los Angeles, CA 15 16 Dr. Eileen Murphy, Grants Facilitator, Ernest Mario School of Pharmacy, Rutgers 17 University, Piscataway, NJ 18 19 Dr. Duncan Patten, Research Professor, Hydroecology Research Program, Department 20 of Land Resources and Environmental Sciences, Montana State University, Bozeman, 21 MT 22 23 Dr. Stephen Polasky, Fesler-Lampert Professor of Ecological/Environmental 24 Economics, Department of Applied Economics, University of Minnesota, St. Paul, MN 25 26 Dr. Arden Pope, Professor, Department of Economics, Brigham Young University, 27 Provo, UT 28 29 Dr. Stephen M. Roberts, Professor, Department of Physiological Sciences, Director, 30 Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 31 32 Dr. Amanda Rodewald, Professor of Wildlife Ecology, School of Environment and 33 Natural Resources, The Ohio State University, Columbus, OH 34 35 Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of 36 Preventive Medicine, University of Southern California, Los Angeles, CA 37 38 Dr. James Sanders, Director and Professor, Skidaway Institute of Oceanography, 39 Savannah, GA 40 41 Dr. Jerald Schnoor, Allen S. Henry Chair Professor, Department of Civil and 42 Environmental Engineering, Co-Director, Center for Global and Regional Environmental 43 Research, University of Iowa, Iowa City, IA 44 45 ix Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Dr. Kathleen Segerson, Philip E. Austin Professor of Economics, Department of 2 Economics, University of Connecticut, Storrs, CT 3 4 Dr. Herman Taylor, Director, Principal Investigator, Jackson Heart Study, University of 5 Mississippi Medical Center, Jackson, MS 6 7 Dr. Barton H. (Buzz) Thompson, Jr., Robert E. Paradise Professor of Natural 8 Resources Law at the Stanford Law School and Perry L. McCarty Director, Woods 9 Institute for the Environment, Stanford University, Stanford, CA 10 11 Dr. Paige Tolbert, Professor and Chair, Department of Environmental Health, Rollins 12 School of Public Health, Emory University, Atlanta, GA 13 14 Dr. John Vena, Professor and Department Head, Department of Epidemiology and 15 Biostatistics, College of Public Health, University of Georgia, Athens, GA 16 17 Dr. Thomas S. Wallsten, Professor and Chair, Department of Psychology, University of 18 Maryland, College Park, MD 19 20 Dr. Robert Watts, Professor of Mechanical Engineering Emeritus, Tulane University, 21 Annapolis, MD 22 23 Dr. R. Thomas Zoeller, Professor, Department of Biology, University of Massachusetts, 24 Amherst, MA 25 26 27 SCIENCE ADVISORY BOARD STAFF 28 Dr. Angela Nugent, Designated Federal Officer, U.S. Environmental Protection Agency, 29 Washington, DC 30 31 Ms. Stephanie Sanzone, Designated Federal Officer, U.S. Environmental Protection 32 Agency, Washington, DC 33 x Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 TABLE OF CONTENTS 3 4 5 ABBREVIATIONS AND ACRONYMS....................................................................... xii 6 EXECUTIVE SUMMARY.............................................................................................. 1 7 INTRODUCTION............................................................................................................. 9 8 RESPONSES TO EPA'S CHARGE QUESTIONS......................................................11 9 Charge Question 1. General Charge Questions............................................................................. 11 10 Charge Question2. Transparency and Clarity inthe SelectionofKey Data Sets for Dose-Response 11 Analysis......................................................................................................................... 13 12 Charge Question 3. The Use of Toxicokinetics inthe Dose-Response Modeling for Cancer 13 and Noncancer Endpoints.................................................................................................. 19 14 Charge Question4. Reference dose............................................................................................25 15 Charge Question 5. Cancer assessment.......................................................................................33 16 Charge Question6. Feasibility ofQuantitative Uncertainty Analysis................................................ 40 17 REFERENCES................................................................................................................ 50 18 APPENDIX A: DISSENTING OPINION FROM KARL ROZMAN, PH.D.........A-1 19 APPENDIX B: VALUE OF INFORMATION.......................................................... B-1 20 APPENDIX C: EDITORIAL COMMENTS AND CORRECTIONS..................... C-1 21 APPENDIX D: EPA'S CHARGE QUESTIONS...................................................... D-1 22 23 24 25 26 27 28 xi Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 3 4 AhR 5 BMD 6 BMDL 7 BMR 8 CYP 9 DLC 10 ED 11 EPA 12 HED 13 IRIS 14 LASC 15 LOAEL 16 MOA 17 NAS 18 NHEERL 19 NIOSH 20 NOAEL 21 NRC 22 OSF 23 PBPK 24 PCDDs 25 PCDFs 26 POD 27 RfD 28 RR 29 SAB 30 T3 31 T4 32 TCDD 33 TEF 34 TEQ 35 TSH 36 UF 37 WHO ABBREVIATIONS AND ACRONYMS aryl hydrocarbon receptor benchmark dose benchmark dose lower bound benchmark response level cytochrome P450 dioxin-like compound effective dose U.S. Environmental Protection Agency human equivalent dose integrated risk information system lipid-adjusted serum concentrations lowest-observed-adverse-effect level mode of action National Academy of Sciences National Health and Environmental Effects Research Laboratory National Institute for Occupational Safety and Health no-observed-adverse-effect level National Research Council oral slope factor physiologically-based pharmacokinetic polychlorinated dibenzo-p-dioxin polychlorinated dibenzofuran point of departure reference dose relative risk Science Advisory Board triiodothyronine thyroxine 2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity equivalence factor toxicity equivalence thyroid stimulating hormone uncertainty factor World Health Organization xii Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 EXECUTIVE SUMMARY 2 3 In 2003, EPA, along with other federal agencies, asked the National Academy of 4 Sciences (NAS) to review aspects of the science in EPA's draft dioxin reassessment 5 entitled, Exposure and Human Health Reassessment o f 2,3,7,8-Tetrachlorodibenzo-p6 Dioxin (TCDD) and Related Compounds and, in 2004, EPA sent the 2003 draft dioxin 7 reassessment to the NAS for review. In 2006, the NAS released the report of its review 8 entitled, Health Risksfrom Dioxin and Related Compounds: Evaluation o f the EPA 9 Reassessment. The NAS recommended that EPA should: more thoroughly justify and 10 communicate its approaches to dose-response modeling for the health effects of dioxin, 11 taking into consideration both nonlinear and linear methods for characterizing cancer 12 risk; improve the transparency and clarity of the selection of key data sets for the dioxin 13 dose-response analysis; reevaluate its cancer weight-of-evidence determination for dioxin 14 based on the Agency's 2005 Cancer Guidelines; consider using physiologically-based 15 pharmacokinetic (PBPK) modeling in the dioxin risk assessment; and improve 16 transparency, thoroughness and clarity in quantitative uncertainty analysis. The NAS 17 also encouraged EPA to calculate a reference dose (RfD), which had not been derived in 18 the 2003 reassessment. 19 20 EPA's Office of Research and Development (ORD) prepared the draft report, 21 entitled EPA's Reanalysis o fKey Issues Related to Dioxin Toxicity and Response to NAS 22 Comments (EPA, 2010) (hereafter referred to as the Report), and requested that the EPA 23 Science Advisory Board (SAB) conduct an independent external peer review of the 24 Report. This Executive Summary highlights the findings and recommendations of the 25 SAB Dioxin Review Panel (the "Panel") in response to charge questions concerning each 26 of the six sections of the Report. 27 28 General Charge 29 30 The SAB Panel was asked to comment on: whether the Report was clear and 31 logical, whether the Agency had objectively and clearly presented the key National 32 Academy of Sciences (NAS) recommendations, and whether there were other critical 33 studies that would make a significant impact on the conclusions of the hazard 34 characterization or dose-response assessment of the chronic noncancer and cancer health 35 effects of TCDD. 36 37 As further discussed in the responses to Charge Question 1, the Panel found that 38 EPA was effective in developing a report that was clear, logical, and responsive to many 39 but not all of the recommendations of the NAS. The Panel has provided 40 recommendations to further improve the clarity, organization, and responsiveness of 41 various parts of the Report. The Panel was impressed with the process that EPA used to 42 identify, review, and evaluate the relevant literature. The Panel found that EPA's process 43 was comprehensive and rigorous and included public participation. However, the Panel 44 recommends that the Report be improved by: incorporating text to better integrate the 45 material presented in the individual chapters, providing greater clarity and transparency 1 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 in indicating which studies did not satisfy criteria for inclusion in EPA's assessment of 2 TCDD, and editing the Report to provide greater clarity in writing and make it more 3 concise by moving some material into appendices. 4 5 During the course of its discussion, the Panel did not identify any additional 6 studies that would make a significant impact on the conclusions of the hazard 7 characterization and dose-response assessment. The Panel recommends that EPA 8 provide an assessment of both the null studies and positive studies with more discussion 9 and clarity concerning the exclusion of null epidemiologic studies. In addition, as further 10 discussed in the responses to the relevant charge questions, the Panel has identified 11 deficiencies in the Report with respect to the completeness of its consideration of two 12 critical elements: 1) nonlinear dose-response for TCDD carcinogenicity, and 2) 13 uncertainty analysis. As discussed below, the Panel has provided recommendations to 14 improve the Report in these areas. 15 16 Transparency and Clarity in the Selection of Key Data Sets for Dose-Response 17 Analyses 18 19 The NAS proposed that EPA develop a clear and readily understandable 20 methodology for evaluating and including epidemiologic and animal bioassay data sets in 21 dose-response evaluations. The SAB Panel was asked to comment on: whether EPA had 22 been responsive to NAS concerns about transparency and clarity in data set selection, 23 whether the epidemiology and animal bioassay study criteria and considerations had been 24 scientifically justified and clearly described, and whether EPA had applied the 25 epidemiology and animal bioassay study criteria considerations in a scientifically sound 26 manner. 27 28 Section 2 of the Report contains a clear presentation of the process EPA used to 29 select key data sets for dose-response analysis and is thus responsive to NAS 30 recommendations in this area. The Report also clearly identifies the studies that were 31 used for dose-response analysis. However, the Panel has provided recommendations to 32 further enhance the overall clarity and transparency of Section 2 of the Report. The Panel 33 recommends careful and extensive editing to revise and consolidate Section 2. 34 Specifically, editing should include aspects of grammar and syntax, minimizing 35 redundancies, and use of more succinct language in responses to NAS concerns. The 36 Panel also recommends restructuring Section 2 to improve its integration into the overall 37 document and make it easier to follow the studies used by EPA from one section of the 38 Report to another. In this regard, the Panel suggests that Section 2 could be used as the 39 foundation for the entire document. 40 41 The Panel also found that EPA's epidemiology and animal bioassay study criteria 42 and considerations were scientifically justified, clearly described, and applied in a 43 scientifically sound manner. The Panel has provided recommendations to improve and 44 strengthen the scientific justification and clarity of description of EPA's study criteria and 45 considerations. The Panel recommends that EPA better justify the rationale for using 2 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 only studies where the exposure was primarily to TCDD for derivation of the reference 2 dose. This justification should include both scientific and practical reasons. The Panel 3 also recommends that EPA incorporate information from studies with dioxin-like 4 compounds (DLCs) into a qualitative discussion of the weight-of-evidence for cancer and 5 noncancer endpoints. In addition, the Panel has provided a number of specific 6 recommendations to further clarify the justifications for some of the study inclusion and 7 exclusion criteria. 8 9 Use of Toxicokinetics in Dose-Response Modeling for Cancer and Noncancer 10 Endpoints 11 12 In the Section 3 of the Report, EPA discussed the use of a physiologically-based 13 pharmacokinetic (PBPK) model (Emond et al., 2004, 2005, 2006) with blood 14 concentration as the dose metric rather than first-order body burden. The Panel was 15 asked to comment on the scientific justification for EPA's application of this model, the 16 model modifications that EPA implemented, and EPA's characterization of uncertainty in 17 the model. EPA also developed a PBPK model to estimate TCDD concentration in 18 mouse tissues. The Panel was asked to comment on the scientific rationale for 19 development of the mouse model, the performance of the mouse model, and whether 20 model uncertainty had been adequately characterized. In addition, the Panel was asked to 21 comment on the use of the Emond PBPK model to estimate human intake based on 22 internal exposure measures, EPA's sensitivity analysis of the kinetic modeling, and 23 EPA's estimate of lifetime average daily dose. 24 25 The Panel agrees with EPA's use of blood TCDD concentration as a surrogate for 26 tissue TCDD exposure. Blood TCDD concentration is a better choice than using body 27 burden (as in the 2003 Reassessment) because it is more closely related to the 28 biologically relevant dose metric: the free concentration of dioxin in the target tissues. 29 The Panel further agrees that the PBPK model developed by Emond et al. (2004, 2005, 30 2006) provides the best available basis for the dose metric calculations in the assessment. 31 However, the Panel recommends that EPA clarify how the model was used in studies that 32 reported the concentrations of dioxin in plasma, serum, blood, or blood fat:blood 33 measurements. The Panel also recommends additional discussion of: other published 34 models, the intended use of the Emond model in the assessment, and the basis for 35 selection of the Emond model. The Panel found that the EPA modifications to the 36 published Emond model were minor and appropriate. However, the Panel notes that the 37 use of 0.6 as the Hill coefficient in the Emond model for CYP1a2 induction is well 38 outside the confidence interval of 0.78 and 1.14 reported by Walker et al. (1999). The 39 use of a Hill coefficient value well below unity would lead to a nonlinear model behavior 40 that is biologically implausible. As a result, when the human model was used for 41 extrapolation to lower doses (in the calculation of risk-specific doses), the model would 42 estimate a lower exposure level for a given blood concentration. The Panel suggests 43 repeating the human Emond model calculations with multiple values for the Hill 44 coefficient to characterize the resulting uncertainty in the exposure estimates. 45 3 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 The Panel also recommends that a more quantitative uncertainty analysis be 2 conducted for the PBPK model. Methods that could be useful and informative for such 3 analysis are suggested in the response to Charge Question 6.2. The sensitivity analysis in 4 the Report left out the Hill coefficient, which is one of the most important parameters in 5 the model for low-dose extrapolation. Model sensitivities are species, dose, and dose6 scenario dependent, so they need to be determined under the same exposure conditions 7 that dose metrics are calculated. 8 9 The Panel found that the mouse model developed by EPA based on the published 10 rat model (Emond et al., 2004, 2005, 2006) was appropriate, but it is recommended that 11 an external peer review of the mouse model be performed. The Panel agrees with the 12 average daily dose calculation approaches described in the Report. However, the Panel 13 recommends that EPA carefully explain how the early life stage internal doses were 14 calculated because serum thyroid stimulating hormone (TSH) levels in newborns are used 15 as a critical effect. 16 17 Reference Dose 18 19 In Section 4 of the Report EPA discussed the use of two co-critical studies 20 (Mocarelli et al., 2008 and Baccarelli et al., 2008) for development of the reference dose 21 for TCDD. The Panel was asked to comment on the scientific justification for selection 22 and use of these studies to develop the reference dose. 23 24 a. Selection o f Critical Studies and Effects 25 26 The Panel supports EPA's selection of the Mocarelli et al. (2008) and Baccarelli 27 et al. (2008) studies for identifying "co-critical" effects for the derivation of the reference 28 dose (RfD). The Panel found that these two human epidemiological studies were well 29 designed. The studies provided sufficient exposure information, including biological 30 concentrations that could be used to establish acceptable lifetime daily exposure levels. 31 The rationale for selecting these two studies over numerous other available studies for 32 determining the RfD was clearly described but study weaknesses were not clearly 33 delineated. The Panel recommends that EPA provide a discussion of the strengths and 34 weaknesses of these studies with an indication of whether the weaknesses affect 35 determination of the RfD. In addition, the Panel recommends that the comprehensive 36 data base of both animal and human epidemiological studies be used to demonstrate a 37 consistent and integrative signal of toxicity across species and endpoints for TCDD. The 38 collective impact of the studies should be made stronger in the Report by including 39 discussion of both human and experimental animal studies that have examined the effects 40 of dioxin and DLCs on other reproductive and endocrine endpoints. In this regard, dose41 response relationships as well as comparisons of no-observed-adverse-effect levels 42 (NOAELs) and lowest-observed-adverse-effect levels (LOAELs) should be discussed. 43 44 The Panel agrees with EPA's assertion that traditional (e.g., immune, endocrine, 45 reproductive) endpoints are more appropriate than biochemical endpoints for establishing 4 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 points of departure (PODs). The associations of traditional endpoints with health 2 outcomes have been well studied and they are more tightly associated with adverse 3 outcomes than biochemical endpoints. However, EPA should discuss biochemical 4 endpoints, particularly P450s, relevant to establishing and strengthening the proposed 5 reference dose. 6 7 b. Estimation o f Continuous Exposure _for Mocarelli et al. (2008) 8 9 Mocarelli et al. (2008) reported male reproductive effects (decrease in sperm 10 count and motility) observed later in life for boys with high acute exposure to TCDD 11 between the ages of 1 and 9 (average age 5 years), followed by low level background 12 dietary exposure. EPA identified a 10 year critical exposure window and estimated the 13 continuous TCDD intake as the average of the high acute exposure and the 5 year 14 average exposure during the critical exposure window. The Panel found that the pattern 15 of exposure from Seveso posed some extrapolation issues for the EPA, particularly 16 whether the same endpoints and or dose-response from high acute exposures would be 17 expected when extrapolating to low-dose chronic exposures. It would be useful for EPA 18 to provide a discussion of published examples in which dioxin studies were conducted 19 using both high-dose acute and low-dose chronic exposures in animals for the same 20 endpoint and how the outcomes compare both qualitatively and quantitatively. The life 21 stage-specific approach to hazard and dose-response characterization for children's health 22 risk assessment in EPA's Frameworkfor Assessing Health Risks o fEnvironmental 23 Exposures to Children (EPA, 2006) is also relevant to addressing this issue and should be 24 discussed. 25 26 c. Designation o f a 20% Decrease in Sperm Count as a LOAEL for Mocarelli et al. 27 (2008) 28 29 The Panel supports the use of the change from normal sperm counts and sperm 30 motility for determining an RfD. While the shifts observed in sperm counts may or may 31 not pose a significant health effect in a single individual, such shifts on a population basis 32 could presumably lead to an increased incidence of adverse health outcomes. The Panel 33 recommends that World Health Organization (WHO) reference values for male 34 reproductive parameters and life stage differences in sperm counts in humans be 35 discussed in the Report. 36 37 d. Determination o fEffective Exposure Estimate _for the Baccarelli et al. (2008) 38 Study 39 40 EPA determined the maternal intake at the LOAEL from the maternal serum41 TCDD vs. neonatal TSH regression model by finding the maternal TCDD lipid-adjusted 42 serum concentrations (LASC) at which neonatal TSH exceeded 5 pU/ml. EPA then used 43 the Emond PBPK model under the human gestational scenario to estimate the continuous 44 daily oral TCDD intake that would result in a TCDD LASC corresponding to a neonatal 45 TSH of 5 pU/ml at the end of gestation. EPA estimated the effective maternal intake as 5 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 0.024 ng/kg-day. The Panel supports EPA's decision to use the Baccarelli et al. (2008) 2 estimates of the relevant effective doses. The Panel also suggests that since the bulk of 3 the calculations were based on zonal averages of exposed individuals in Baccarelli et al. 4 (2008), EPA should clarify how these measurements relate to ranges and variations in 5 exposure in utero. 6 7 e. Designation o f 5u-units TSH_per ml blood as a LOAEL _for Baccarelli et al. 8 (2008) 9 10 EPA selected a LOAEL of 5p-units TSH per ml blood in neonates. The Panel 11 supports EPA's designation of the TSH endpoint within the context of the broader dioxin 12 literature. While the shift observed in TSH levels may or may not pose a significant 13 health effect in a single individual, such a shift on a population basis could presumably 14 lead to an increased incidence of adverse health outcomes. There is a need to better 15 describe the potential adverse health outcomes related to altered neonatal TSH levels. 16 For example, in addition to effects on growth, both cognitive and motor deficits have 17 been found in young adults with congenital hypothyroidism. The Report could better 18 describe the consequences of transient hypothyroidism on reproductive outcomes. 19 20 f. Selection o f Uncertainty Factors 21 22 A composite uncertainty factor of 30 (an uncertainty factor of 10 for the lack of a 23 NOAEL, and an uncertainty factor of 3 for human interindividual variability) was applied 24 to the LOAEL of 0.020 ng/kg-day from Mocarelli et al. (2008) to obtain the RfD. The 25 Panel agrees that EPA has used the appropriate uncertainty factors for the derivation of 26 the RfD. However, a short discussion of the decision not to include an uncertainty factor 27 for data quality is needed. 28 29 g. Benchmark Dose (BMD) Modeling o f animal bioassay data and EPA's Choice o f 30 POD from These Studies 31 32 The Panel agrees with the BMD modeling approaches used in the Report. In 33 addition, the Panel agrees that the animal data have sufficient limitations that preclude 34 their use to establish a RfD. 35 36 Cancer Assessment 37 38 In Section 5 of the Report EPA has provided: a weight-of-evidence 39 characterization of TCDD as a known human carcinogen, conclusions regarding the 40 mode of carcinogenic action for TCDD, EPA's selection of data sets for cancer dose41 response modeling, and consideration of approaches for assessment of TCDD 42 carcinogenicity. The Panel was asked to comment on the scientific soundness of these 43 aspects of EPA's cancer assessment. 44 45 6 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 a. Weight-of-Evidence Cancer Descriptor 2 3 The Panel agrees with EPA's conclusion that TCDD is "Carcinogenic to 4 Humans." The Panel recommends that the Agency provide more discussion of the 5 power of the studies used and the difficulties involved when assessing rare tumors. The 6 Panel also recommends that EPA consider including studies with substantial DLC 7 exposure where toxicity equivalence factors (TEFs) can be calculated in the weight-of8 evidence discussion. EPA should also attempt to characterize the uncertainty regarding 9 the carcinogenicity of TCDD at low human exposures, since the minimum dose at which 10 carcinogenic effects would be expected to occur cannot be clearly delineated from the 11 current epidemiological human data. 12 13 b. Mode o fAction 14 15 The Panel believes the mode of action for TCDD toxicity should be "reasonably 16 well known" rather than "largely unknown," although the Panel agrees that the exact 17 mechanism of action has not been fully delineated for any distinct TCDD toxicity 18 endpoint. The Panel recommends that EPA provide a discussion of the evidence for 19 possible modes of action that include both linear and nonlinear alternatives; and that the 20 description of the nature of a receptor mediated dose-response be expanded by including 21 more evidence regarding the nonlinearity of the receptor mediated dose-response for 22 dioxin. 23 24 c. Selection o f Critical Study for Cancer Endpoint 25 26 The Panel agrees with the inclusion of the Cheng et al. (2006) study in the cancer 27 assessment. This study incorporated information on gradation of exposure. However, 28 expanded discussion of several other studies would support the weight-of-evidence for 29 carcinogenicity in less common cancers such as lymphomas and soft tissue sarcoma. The 30 Panel agrees that Cheng et al. (2006) was the appropriate study for quantitative cancer 31 assessment, and that it was appropriate to use all-cancer mortality in this case, because of 32 the extensive dose-response information. The Panel also agrees that the use of the 33 Emond model to estimate risk-specific doses from Cheng et al. (2006) dose-response 34 modeling results was scientifically justified and clearly described but, as previously 35 discussed, the value of the Hill coefficient used in the model is problematic. The Panel 36 found that Cheng et al. (2006) study did not provide completely clear information 37 regarding risks below current background exposure levels. The Panel therefore suggests 38 that EPA expand the discussion to consider the possibility that mode of action 39 considerations could help indicate whether linear extrapolation of the Cheng et al. (2006) 40 data is appropriate to obtain risk estimates in this range of exposures. 41 42 d. Nonlinear Approach for Assessment o f TCDD Carcinogenicity 43 44 The Panel found that the Report did not respond adequately to the NAS 45 recommendation to adopt "both linear and nonlinear methods of risk characterization to 7 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 account for the uncertainty of dose-response relationship shape below the ED01." The 2 Panel recommends that EPA present both linear and nonlinear risk assessment 3 approaches. The nonlinear examples in the document should be formalized and 4 extended. In the absence of a definitive nonlinear mode of action, the linear option 5 results can serve as the baseline for comparison with these other estimates. 6 7 Quantitative Uncertainty Analysis 8 9 Section 6 of the Report discusses a broad range of philosophical and 10 methodological issues to be considered in conducting an uncertainty analysis for TCDD 11 toxicity. The Panel was asked to comment on: whether the discussion in this section of 12 the Report was clearly presented and scientifically justified, the conclusion that a 13 comprehensive quantitative uncertainty analysis (QUA) is not feasible, the discussion 14 regarding volitional uncertainty and how it limits the ability to conduct a QUA, and 15 approaches that EPA used to conduct sensitivity analyses. 16 17 The Panel found that Section 6 of EPA's Report was clearly presented and 18 provided many useful insights for EPA's dioxin reassessment, but it was not scientifically 19 justified. As further discussed in the responses to Charge Question 6, the Panel does not 20 agree with EPA's argument that conducting a unified QUA for TCDD toxicity is 21 unfeasible. EPA's decision to not conduct an integrated QUA may be based primarily on 22 grounds of practicality or timeliness. In particular, EPA argues that a complete 23 quantitative uncertainty analysis would require data and resources not available. We 24 disagree with this logic. More limited evaluations can, and should, be implemented to 25 inform critical issues in the dioxin reassessment. In the response to Charge Question 6.2 26 we suggest a number of methods that could be used. The Panel recommends that EPA 27 revise its argument that QUA for dioxin toxicity is unfeasible. 28 29 EPA's document contrasted volitional uncertainty with cognitive uncertainty. 30 The Panel recommends that the term "volitional uncertainty," which might also have 31 been called "decisional uncertainty," be dropped from the Agency's document. The 32 Panel recommends that EPA focus on uncertainties about the state of the world and 33 display different modeling choices and the consequences of making them. The Panel 34 recommends that EPA apply standard tools and techniques for analysis of model 35 uncertainty. 36 37 In addition, the Panel found that the sensitivity studies EPA has already 38 completed are useful. The Panel is mindful of the need to minimize further delay of the 39 finalization of EPA's already protracted dioxin assessment and we recommend that 40 sensitivity studies that EPA has already completed be integrated into whatever overall 41 uncertainty analysis the Agency elects to undertake. 42 8 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 INTRODUCTION 2 EPA has been preparing an assessment of the potential health impacts of 2,3,7,83 Tetrachlorodibenzo-p-Dioxin (TCDD) for many years. In 2003, EPA released an 4 external review draft report entitled, Exposure and Human Health Reassessment of 5 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds (U.S. EPA, 2003) 6 (hereafter referred to as the 2003 Reassessment) that was reviewed by the EPA Science 7 Advisory Board (SAB), and then by the National Academy of Sciences (NAS). In 2006, 8 the National Research Council (NRC) of the National Academies published their 9 evaluation of EPA's reassessment, Health Risksfrom Dioxin and Related Compounds: 10 Evaluation o f the EPA Reassessment (NRC, 2006). 11 12 The NAS identified key recommendations that they believed would result in 13 substantial improvement to the 2003 Reassessment and thus support a scientifically 14 robust characterization of human responses to exposures to TCDD. The NAS 15 recommended that EPA should: more thoroughly justify and communicate its approaches 16 to dose-response modeling for the health effects of dioxin, taking into consideration both 17 nonlinear and linear methods for characterizing cancer risk; improve the transparency and 18 clarity of the selection of key data sets for the dioxin dose-response analysis; reevaluate 19 its cancer weight-of-evidence determination for dioxin based on the Agency's 2005 20 Cancer Guidelines; consider using physiologically-based pharmacokinetic (PBPK) 21 modeling in the dioxin risk assessment; and improve transparency, thoroughness and 22 clarity in quantitative uncertainty analysis. The NAS also encouraged EPA to calculate a 23 reference dose (RfD), which had not been derived in the 2003 Reassessment. 24 25 In 2010, EPA's Office of Research and Development (ORD) prepared the draft 26 report, EPA's Reanalysis o fKey Issues Related to Dioxin Toxicity and Responses to NAS 27 Comments (EPA, 2010) (hereafter referred to as the Report). The Report includes new 28 analyses completed in response to the NAS recommendations and recently published 29 literature, as well as a discussion of topics where EPA's views differed from those of the 30 NAS. The Report is not an assessment per se; it was designed to supplement the 31 information provided in EPA's 2003 Reassessment. However, the Report provides a 32 noncancer reference dose and updated cancer values. Detailed discussions of many of the 33 issues addressed in the Report are available in the 2003 Reassessment and were not 34 reproduced in the Report. 35 36 ORD requested that the EPA Science Advisory Board (SAB) conduct an 37 independent external peer review of the Report. In its review, the SAB was asked to 38 consider the accuracy, objectivity, and transparency of EPA's reanalysis and responses. 39 40 In response to ORD's request, the SAB convened an expert panel to conduct the 41 review. The Panel held an initial public teleconference on June 24, 2010 to receive an 42 orientation to EPA's Report. The Panel then held two public face-to-face meetings (July 43 13 - 15, 2010 and October 27 - 29, 2010) to deliberate on the charge questions (see 44 Appendix D) and two public teleconferences (March 1 and 2, 2011) to discuss its report. 9 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Public comments were provided in oral and written form to the Panel at the 2 teleconferences and face-to-face meetings. There were charge questions on the 6 sections 3 of EPA's Report. The questions focused on: transparency and clarity in the selection of 4 key data sets for dose-response analysis, the use of physiologically-based 5 pharmacokinetic (PBPK) modeling in dose-response modeling for cancer and noncancer 6 endpoints, derivation of a proposed oral reference dose (RfD) for noncancer endpoints, 7 cancer weight-of-evidence classification, mode of action of dioxin carcinogenicity, 8 derivation of oral slope factor (OSF) for dioxin, and quantitative uncertainty analysis. 9 This report provides the consensus advice and recommendations of the Panel, with the 10 exception of one member who offered a dissenting opinion mainly on the TCDD 11 carcinogenicity (see Appendix A). 12 10 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 RESPONSES TO EPA'S CHARGE QUESTIONS 2 3 Charge Question 1. General Charge Questions 4 5 The Panel was asked to comment on: whether the EPA's Report was clear and 6 logical, whether the Agency had objectively and clearly presented the key National 7 Academy of Sciences (NAS) recommendations, and whether there were other critical 8 studies that would make a significant impact on the conclusions of the hazard 9 characterization or dose-response assessment of the chronic noncancer and cancer health 10 effects of TCDD. 11 12 1.1. Is the draft Response to Comments clear and logical? Has EPA objectively and 13 clearly presented the three key NRC recommendations? 14 15 Response: 16 17 The Panel found that EPA has developed a report that is clear, logical and 18 responsive to many but not all of the recommendations of the NAS. While we provide a 19 general assessment of opportunities for improvement in the context of this overview 20 charge question, most of the issues related to clarity, organization, and responsiveness are 21 addressed more completely and specifically in the context of the subsequent, more 22 specific charge questions. 23 24 With respect to the first question, the Panel found that the EPA was effective in 25 developing a clear, transparent, and logical response. The Panel was particularly 26 impressed with the process that EPA used for identifying, reviewing, and evaluating the 27 relevant literature. EPA's process was comprehensive, rigorous, and included public 28 participation. The Agency's report, EPA's Reanalysis o fKey Issues Related to Dioxin 29 Toxicity and Response to NAS Comments, consists of two volumes. The first volume 30 contains the main text of the Report and is 690 pages long (including 37 pages of 31 references). The second volume contains appendices and is 1,159 pages long. Because 32 of the size and complexity of EPA's Report, the Panel found the Executive Summary to 33 be particularly important and valuable in providing a concise and accurate summary. As 34 described in detail in the response to Charge Question 2, the Panel identified the need for 35 better integration across chapters and greater clarity and transparency in indicating which 36 studies did not satisfy inclusion criteria, and therefore were not carried forward for 37 further consideration in subsequent chapters of the Report to meet particular needs. In 38 contrast, the Panel was satisfied that the inclusion criteria and the associated retained 39 studies were well described and transparent. The Panel acknowledges that, given the 40 enormity of the dioxin published literature, it is not a trivial matter to characterize what 41 has been "left on the cutting room floor." We therefore suggest that EPA do this in a way 42 that provides only a general consideration of this issue. 43 11 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 The Report is long and dense with a considerable amount ofjargon and in some 2 places it is quite repetitive. These features, while a necessity of this type of document, at 3 times detract from clarity or make the EPA's logic difficult to discern. The Panel found 4 some instances where the Report would benefit from greater clarity in writing. For 5 example, topic sentences are sometimes not easily connected to paragraph content. A 6 specific example of this is in the second paragraph on page xxvii of volume 1 where the 7 text does not clearly identify separate EPA activities to address NAS comments. 8 Another example of a Report section that could be edited to improve clarity is the 9 qualitative discussion of the uncertainty in the RfD (Section 4.4 of volume 1). The 10 clarity of this section could be improved by including bullet points to highlight and 11 separate key points and/or provide links to information in other sections of the document 12 (e.g., Section 6 - Feasibility of Quantitative Uncertainty Analysis). The Panel suggests a 13 careful review by a qualified technical editor. Similarly, the Panel suggests that the 14 clarity and accessibility of the Report could be enhanced by the inclusion of a glossary to 15 help minimize confusion and misinterpretation among the diverse users of the document. 16 At 690 pages, volume 1 is a formidable report. The Panel appreciates the dilemma of 17 preparing a report that is both complete and rigorous and at the same time succinct and 18 efficient, but it is suggested that EPA find additional efficiencies (e.g., greater use of 19 appendices and elimination of redundancies) that would yield a more approachable 20 document. 21 22 With respect to the second part of Charge Question 1.1 (i.e., objectivity and 23 clarity of presentation of the three key NAS recommendations), the Panel found that EPA 24 has been successful. The Panel found EPA's Report to be clear in presentation of the key 25 NAS recommendations. However, as described more fully in responses to the relevant 26 specific charge questions below, the Panel identified deficiencies in the Report with 27 respect to the completeness of its consideration of two critical elements: 1) nonlinear 28 dose-response for TCDD carcinogenicity and 2) uncertainty analysis. 29 30 Recommendations 31 32 As further discussed in the response to Charge Question 2, the Panel recommends 33 that the Report be revised to provide greater clarity and transparency in the 34 discussion of studies that did not satisfy inclusion criteria for use in the dioxin 35 assessment. Given the enormity of the dioxin published literature, the Panel 36 recognizes that it is not a trivial matter to characterize the studies that were not 37 considered, and therefore the Panel suggests that the Report be revised to 38 generally indicate how this issue was considered. 39 40 The Report is long and dense and contains a considerable amount ofjargon. It 41 would benefit from greater clarity in writing. The Panel therefore recommends 42 that the Report be carefully reviewed by a qualified technical editor and revised to 43 incorporate such improvements as better integration across chapters, better 12 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 connection between topic sentences and paragraph content, and elimination of 2 repetition. 3 4 The Panel recommends that the clarity and accessibility of EPA's Report be 5 enhanced by the inclusion of a glossary to help minimize confusion and 6 misinterpretation among the diverse users of the document. 7 8 The Panel recommends that EPA find additional efficiencies (e.g., greater use of 9 appendices and elimination of redundancies) to yield more succinct and 10 approachable document. 11 12 As discussed in the responses to other charge questions in this report, the Panel 13 identified deficiencies in EPA's Report with respect to the completeness of its 14 consideration of two critical elements: 1) nonlinear dose-response for TCDD 15 carcinogenicity, and 2) uncertainty analysis. In the relevant charge question 16 responses below, the Panel has provided recommendations to improve the Report 17 in these areas. 18 19 1.2. Are there other critical studies that would make a significant impact on the 20 conclusions o f the hazard characterization and the dose-response assessment o f 21 the chronic noncancer and cancer health effects o f TCDD? 22 23 Response: 24 25 During the course of its discussion, the Panel did not identify any additional 26 studies that would impact the hazard characterization or the dose-response assessment. 27 However, the Panel found that EPA's Report should provide more clarity on the 28 exclusion of null epidemiologic studies. 29 30 Recommendations 31 32 The Panel recommends that EPA's Report provide more discussion and clarity on 33 the exclusion of null epidemiologic studies. 34 35 36 Charge Question 2. Transparency and Clarity in the Selection of Key Data Sets for 37 Dose-Response Analysis 38 39 General Comments: 40 41 The NAS committee proposed that EPA develop a clear and readily 42 understandable methodology for evaluating and including epidemiologic and animal 43 bioassay data sets in dose-response evaluations. Section 2 of EPA's Report describes the 44 Agency's approach to ensuring transparency and clarity in the selection of the studies for 13 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 dose-response analyses. The Panel was asked to comment on: whether EPA had been 2 responsive to NAS concerns about transparency and clarity in data set selection, whether 3 the epidemiology and animal bioassay study criteria and considerations had been 4 scientifically justified and clearly described, and whether EPA had applied the 5 epidemiology and animal bioassay study criteria considerations in a scientifically sound 6 manner. 7 8 EPA developed and applied two sets of criteria for the animal bioassays and 9 epidemiologic data. The Agency collected and evaluated these studies, including studies 10 from the 2003 Reassessment and newer studies found through literature searches and 11 through public submissions. The Panel viewed with favor all of the efforts made by EPA 12 to develop this section of the document. The Panel compliments the Agency for its 13 efforts to present the nuanced differences and complicating issues surrounding this 14 subject in a comprehensive and logical manner. The intention of the comments and 15 recommendations provided below is to assist the EPA in further improvement of Section 16 2. 17 18 2.1. Is this section responsive to the NAS concerns about transparency and clarity in 19 data set selectionfor dose-response analysis? 20 21 Response: 22 23 Members of the Panel found that Section 2 of the Report was responsive to NAS 24 concerns about transparency and clarity. Moreover, it was perceived and appreciated 25 that, in addressing these concerns, EPA had improved the approach in the original 2003 26 Reassessment. The EPA's collaboration with Argonne National Laboratory, and 27 invitation to the public to engage in updating the literature search to identify all 28 appropriate studies for evaluation, as well as the conduct of the Dioxin Workshop in 29 February of 2009, were instrumental in enhancing the transparency and clarity regarding 30 the process of selection of studies for the dose-response analysis. The development of 31 clear criteria for study evaluation and inclusion was crucial in addressing the concerns 32 raised by the NAS. 33 34 EPA's Report presents a clear identification of the study selection process and the 35 studies that were used for dose-response analysis. For example, the process and criteria 36 used to select key data sets for dose-response analyses is described in Section 2.3 of the 37 Report and in the Executive Summary. Flow diagrams (e.g., ES-1 and ES-2) clearly 38 demonstrate how studies were chosen for inclusion. Likewise, Appendix B, which 39 includes a point-by-point evaluation of which epidemiological studies were included and 40 excluded, was useful and provides a detailed rationale explaining why the EPA used the 41 particular studies selected in the Report. In addition, the results of the literature search 42 performed by EPA are available online. Clarity could be improved by providing search 43 words used for the MedLine searches. A clear case for including high-quality human 44 studies over animal studies is also made. 45 14 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 While Section 2 of the Report is deemed responsive to NAS concerns, the Panel 2 found that overall clarity and transparency regarding dataset selection would be further 3 and markedly enhanced if EPA were to make Section 2 (and the document as a whole) 4 more concise. In its present form, Section 2 was viewed by the Panel as overly verbose, 5 to the detriment of overall clarity and we provide the following recommendations to 6 improve the Report. 7 8 Recommendations 9 10 The Panel strongly recommends careful and extensive editing to revise and 11 consolidate Section 2 and the Report as a whole. Specifically, editing should 12 include aspects of English grammar and syntax, minimizing redundancies, and 13 efforts to provide more succinct responses to NAS concerns. 14 The Panel recommends restructuring Section 2 to make it easier to follow a study 15 used by EPA from one section of the Report to another. In other words, EPA 16 should improve overall document integration using Section 2 as the foundation 17 for this integration. 18 19 Charge Questions 2.2 and 2.3 20 21 2.2. Are the epidemiology and animal bioassay study criteria/considerations 22 scientificallyjustified and clearly described? 23 24 2.3. Has EPA applied the epidemiology and animal bioassay study 25 criteria/considerations in a scientifically sound manner? I f not, please identify 26 andprovide a rationalfor alternative approaches. 27 28 Response: 29 30 The Panel's discussion of Charge Questions 2.2 and 2.3 was highly integrated. 31 Therefore, comments and specific recommendations that stem from these two questions 32 are presented together. 33 34 The Panel found that EPA's study criteria and considerations were scientifically 35 justified and clearly described, and that these were presented in a scientifically sound 36 manner. Thus, Section 2 was deemed responsive to NAS concerns regarding the 37 scientific justification and clarity of description for epidemiology and animal bioassay 38 study criteria/considerations. However, several concerns were discussed by the Panel, 39 and are summarized here. 40 41 The Panel's major concern pertains to improving clarity with regard to the 42 decision to include or exclude particular studies and groups of studies from the data sets 43 to be used. The rationale for distinct criteria for epidemiological and animal studies 44 should be made stronger, and data set selection for noncancer and cancer endpoints has 15 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 room for further clarification and justification. There was discussion, with differences of 2 opinion among members of the Panel, regarding EPA's scientific justification and clarity 3 of description concerning the Agency's decision to exclude dioxin-like compounds. 4 There was consensus among Panel members that the following recommended 5 improvements would strengthen this section, and thus the document as a whole. 6 7 Recommendations 8 9 Rationale for excluding dioxin-like compounds 10 11 EPA should better justify the rationale for using studies where the exposure is 12 primarily to TCDD (or for animal studies only to TCDD) to calculate the 13 reference dose. This justification should include scientific and practical reasons. 14 EPA should incorporate information from studies with dioxin-like chemicals into 15 a qualitative discussion of the weight-of-evidence for cancer and noncancer 16 endpoints. 17 18 Study inclusion and exclusion criteria and considerations 19 20 EPA should further clarify the justifications for study inclusion and exclusion 21 criteria/considerations. To be clear, this recommendation does not indicate that 22 the Panel suggests that a different approach to data set selection is needed. 23 However, the approach used should be explained more effectively and clearly. In 24 this regard, the following specific recommendations are provided to address 25 points of concern raised by Panel members about the study inclusion and 26 exclusion criteria: 27 o EPA should remove the criterion that studies must contain an explicit 28 statement of TCDD purity. For research purposes, TCDD is available from a 29 limited set of vendors, and all sell it as a highly purified compound. Thus, for 30 the animal studies, it is highly unlikely that any study would be conducted 31 using impure TCDD. Therefore, excluding a study simply due to absence of 32 statements regarding TCDD purity runs the risk of excluding high quality 33 studies because the author or journal editorial staff did not elect to include this 34 piece of information. 35 o EPA should revise the explanation of the in vivo mammalian bioassay 36 evaluation indicating that the "study design is consistent with standard 37 toxicological practices." This is too vague as it likely has different meaning to 38 readers from different backgrounds. In addition to defining this more clearly, 39 it is recommended that, if possible, a reference should be provided to an EPA 40 document in which these practices are described in detail. 16 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 o EPA should consider eliminating use of the phrase "outside the range of 2 normal variability," especially when discussing animal studies. 3 o EPA should define the phrase "common practices," and if possible cite 4 appropriate Agency documents to which the reader can refer for further detail. 5 To provide further context, this recommendation refers specifically to 6 statements such as the following one on page 2-5: "The study criteria shown 7 below and in Figure 2-3 for animal bioassay data reflect EPA's preferences 8 for TCDD-specific study inclusion, some of which are based on common 9 practices and guidance for POD selection and RfD and OSF derivation." 10 o EPA should provide a more thorough (albeit concise) discussion of data set 11 limitations to educate the reader regarding Agency decisions about study 12 inclusion/exclusion criteria. For instance, consider adding an expanded 13 discussion on suitability of studies of immunological effects and/or thyroid 14 and diabetes (e.g., Baccarelli et al., 2002, 2004; Calvert, 1999; Steenland, 15 2001). 16 17 Considerations concerning selection o f epidemiology studies 18 19 The Panel recommends that EPA better justify and explain considerations relating 20 to the selection of epidemiology studies. The following specific 21 recommendations are provided. Many of these specifically address the use of 22 more standard epidemiology vocabulary and descriptors. 23 o EPA evaluated the available epidemiologic cohorts and studies based on five 24 considerations presented on pages 2-6 and 2-7 of the Report. The Panel found 25 that Consideration #2 (page 2-6) was worded awkwardly and that 26 epidemiologic terms are misspecified. The Panel therefore recommends that 27 EPA revise Consideration #2 as follows: 28 Define "susceptible to important biases." This is a non-specific term and 29 the biases should be explained. 30 Clarify what is meant by "control for potential confounding exposures." 31 Does this refer to only exposure to dioxin-like compound exposures or 32 was it meant to more broadly refer to other exposures as well (NIOSH 33 cohort studies)? Does the text "bias arising from study design" refer to 34 selection bias or is this phrase used more broadly to describe how 35 exposure and outcome are measured and covariate data collected? 36 Define what is meant by the phrase "bias arising from statistical analyses." 37 It is unclear if bias is the correct term, rather this may refer to model 38 misspecification. 17 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 o With regard to scientific justification and application of Consideration #3 2 (listed on page 2-7), the Panel recommends that EPA provide more discussion 3 and clarity on the exclusion of null epidemiologic studies. 4 o In Exclusion Criterion #3 (listed on page 2-7) EPA should define "reported 5 dose." 6 o The Panel recommends that the discussion in Section 2 of the consideration of 7 "confounding and other potential sources of bias" be clarified. The 8 differences between males and females with regard to TCDD half-life are 9 discussed, but the description of the number of males and females in each 10 study population were often missing or very difficult to determine. Also, in 11 the occupational cohort studies, the possibility of men and women performing 12 different job tasks also increased the possibility that the men and women were 13 exposed at different levels. However, when the job categories with assigned 14 TCDD exposure levels were presented, there was often no discussion of the 15 numbers by gender in the categories. For example, the Manz et al. study 16 (1991) of the Hamburg cohort (1,583 men and 399 women) does not describe 17 the TCDD categories by gender. In addition, the validity of the TCDD 18 exposure levels assigned to the categories was examined "in a group of 48 19 workers who provided adipose tissue samples" (Page 2-41, lines 18-19). 20 How were these workers selected? How many were approached but refused 21 to provide a sample? Assessment of selection bias in this and other similar 22 circumstances was lacking in some of the studies. This is particularly notable 23 in the lack of overall response rates reported for several of these studies. 24 Inclusion of these factors in the study review would be very helpful. 25 o The Panel recommends that discussion of the consideration that "statistical 26 precision, power, and study follow-up are sufficient" be clarified. These 27 metrics can be difficult to determine with the smaller sample size populations, 28 but there are studies that can be very useful even given the small samples. For 29 example, the relative risks calculated for increasing TCDD exposure and risk 30 of breast cancer in the Seveso study were greatly increased in the 3rd and 4th 31 highest exposure categories, but the relative risks were not statistically 32 significant (page 2-56, lines 1-8). 33 34 35 Charge Question 3. The Use of Toxicokinetics in the Dose-Response Modeling for 36 Cancer and Noncancer Endpoints 37 38 In its Report, EPA used a physiologically-based pharmacokinetic (PBPK) model 39 (Emond et al., 2004, 2005, 2006) with blood concentration as the dose metric rather than 40 first-order body burden. The Panel was asked to comment on the scientific justification 41 for EPA's application of this model, the model modifications that EPA implemented, and 18 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 EPA's characterization of uncertainty in the model. EPA also developed a PBPK model 2 to estimate TCDD concentration in mouse tissues. The Panel was asked to comment on 3 the scientific rationale for development of the mouse model, the performance of the 4 mouse model, and whether model uncertainty had been adequately characterized. In 5 addition, the Panel was asked to comment on the use of the Emond PBPK model to 6 estimate human intake based on internal exposure measures, EPA's sensitivity analysis of 7 the kinetic modeling, and EPA's estimate of lifetime average daily dose. 8 9 3.1. The 2003 Reassessment utilizedfirst-order body burden as the dose metric. In the 10 draft Response to Comments document, EPA used a physiologically-based 11 pharmacokinetic (PBPK) model (Emond et al., 2004, 2005, 2006) with whole 12 blood concentration as the dose metric rather thanfirst-order body burden. This 13 PBPK model was chosen, in part, because it includes a biological description o f 14 the dose-dependent elimination rate o f TCDD. EPA made specific modifications 15 to the published model based on more recent data. Although lipid-adjusted 16 serum concentrations (LASC)for TCDD are commonly used as a dose metric in 17 the literature, EPA chose whole blood TCDD concentrations as the relevant dose 18 metric because serum and serum lipid are not true compartments in the Emond 19 PBPK models (LASC is a side calculation proportional to blood concentration). 20 21 Please comment on thefollowing: 22 23 3.1. a. Please comment on thejustification o f applying a PBPK model with whole blood 24 TCDD concentration as a surrogatefor tissue TCDD exposure in lieu o f using 25 first-order body burdenfor the dose-response assessment o f TCDD. 26 27 Response: 28 29 The use of body burden in the 2003 Reassessment represents an improvement 30 over the usual default metric of administered dose (mg/kg/d) because the default metric 31 would not properly reflect the accumulation of dioxin in the tissues over time. However, 32 because the accumulation of dioxin in liver is dose-dependent, body burden would not 33 serve as a direct surrogate for tissue exposure. The use of blood concentration is a better 34 choice than body burden because it is more closely related to the biologically relevant 35 dose metric: the free concentration of dioxin in the target tissues (liver, fetus, etc.). 36 Blood concentrations are routinely used to estimate biologically effective exposures for 37 pharmaceuticals. 38 39 The rationale for the use of blood concentration rather than lipid adjusted serum 40 concentration (LASC) should not be based on the Emond model structure. It would be 41 trivial to change the model so that LASC could be predicted. Indeed, the model is 42 apparently used to estimate LASCs in the RfD calculations (e.g., page xli, line 21 in the 43 Executive Summary of the Report). The question that should be addressed is only 44 whether blood concentrations or LASCs provide better surrogates for cross-species and 19 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 cross-study comparisons of free dioxin concentration in the target tissues. LASC is the 2 preferred measure for reporting dioxin biomonitoring data, and is the measurement 3 reported in most of the human epidemiological studies. A metric that considers blood 4 lipid content is also more likely to reflect free dioxin concentration in the plasma, and 5 hence free concentration in the target tissue. The EPA pointed out (page xxxiv in the 6 Executive Summary of the Report) that the LASC was related to the blood concentration 7 by a scalar; however, EPA incorrectly concluded that the metrics are equivalent and later 8 (page 3-511, line 6 of the Report) discussed the fact that the relationship between them 9 was subject to inter-individual and inter-species variation. If the LASC were used to 10 drive the distribution of TCDD to tissues, the pharmacokinetic outcome would be 11 different from using blood as the driver because the tissue:blood ratio would differ. If the 12 blood fat:blood and tissue:blood values were accounted for in the model, the use of blood 13 and LASC would be similar. It's not clear at this point how this issue was addressed in 14 the dose metric calculations. Consideration of this issue is unlikely to drastically affect 15 the outcome of the risk calculations, but it would be important for a quantitative 16 uncertainty analysis. 17 18 Recommendations 19 20 The use of the blood metric is acceptable for the PBPK model. EPA should 21 clarify how the model deals with studies that report the concentration of dioxin in 22 plasma, serum, blood or blood fat:blood measurements. 23 24 3.1.b. Please comment on the scientificjustificationfor using the Emond et al. model as 25 opposed to other available TCDD kinetic models. 26 27 Response: 28 29 The Emond model provided the best available basis for the dose metric 30 calculations in the assessment. It is the product of a high-caliber, multi-year research 31 effort at EPA's National Health and Environmental Effects Research Laboratory, and 32 represents a significant effort in terms of data collection. This model builds on prior 33 PBPK modeling efforts conducted by Andersen et al. (1997). However, additional 34 discussion of other published models and quantitative evaluation of the impact of model 35 selection on dose metric predictions should also be provided. 36 37 Recommendations 38 39 The Report should discuss how the model was intended to be used in the 40 assessment, which would then dictate why a particular model was selected. That 41 is, for the intended purposes, was the Emond model more robust and/or simpler 42 than other models, and did it contain sufficient details for biological determinants 43 deemed important by the Agency? 44 20 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 3.1.c. Please comment on the modifications implemented by EPA to the published 2 Emond et al. model. 3 4 Response: 5 6 The EPA modifications to the published Emond model (modifications described 7 on page 3-44 of the Report account for volume of plasma and describe urinary clearance 8 using blood concentration and not a lumped compartment) are minor and appropriate. 9 The model changes are scientifically appropriate and well supported. 10 11 3.1. d. Please comment on whether EPA adequately characterized the uncertainty in the 12 kinetic models. 13 14 Response: 15 16 The Report presents a reasonably thorough qualitative characterization of the 17 uncertainty in the kinetic models that is sufficient to support their use in the assessment. 18 A more quantitative uncertainty analysis is needed. Methods that could be useful and 19 informative for such an analysis are suggested in the response to Charge Question 6.2. It 20 is critical to demonstrate the dependence of human equivalent dose (HED) and risk 21 predictions on uncertainty and variability in the model parameters, particularly those with 22 high sensitivity (Evans and Andersen, 2000). Moreover, dose metric uncertainty needs to 23 be determined under the same exposure conditions that dose metrics are calculated: both 24 for the various studies that serve as the basis for the dose-response assessments and for 25 human exposures at the corresponding HEDs and risk specific doses. 26 27 The Hill coefficients for CYP1a1 and CYP1a2 induction used in the Emond 28 model were 1.0 and 0.6, respectively, based on fitting of kinetic data from single doses of 29 dioxin (Wang et al., 1997; Santostefano et al., 1998). However, Walker et al. (1999) 30 subsequently estimated a Hill coefficient of 0.94 for both CYP1a1 and CYP1a2 induction 31 using chronic exposures which were more relevant to the use of the Emond model in the 32 dioxin risk assessment. The value of 0.6 used in the Emond model was well outside the 33 confidence interval of 0.78 to 1.14 reported by Walker et al. (1999). The use of a Hill 34 coefficient value well below unity would lead to a nonlinear model behavior that is 35 biologically implausible (hypersensitivity to induction at doses near zero). As a result, 36 when the human model was used for extrapolation to lower doses (as in the calculation of 37 risk-specific doses) the model would tend to estimate a lower exposure level for a given 38 blood concentration. This effect could be seen in Table ES-1 of the Report, where a 5 39 order-of-magnitude change in risk was associated with a 6 order-of-magnitude change in 40 risk specific dose. That is, the model-estimated risk specific doses in the vicinity of 10-6 41 risk were about a factor of 10 lower (more conservative) than linear extrapolation. The 42 evidence for this parameter needs to be carefully reviewed and the reasonable range of 43 values determined. At the least, the human Emond model calculations will need to be 44 repeated with multiple values to characterize the resulting uncertainty in the estimates. 21 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 When this is done, the Agency should also consider increasing the fat:blood partition in 2 the human model from 100 to 200 to be more consistent with the human data (Patterson 3 et al., 1988; Schecter and Ryan, 1989; Schecter et al., 1989; Iida et al., 1999; Maruyama 4 et al., 2002). The Hill coefficient is not likely to have as significant an effect on 5 calculations with the animal models, since low-dose extrapolation was not performed in 6 the animals, but this should also be verified by sensitivity/uncertainty analysis of the 7 animal models. Public comments were submitted to the Panel recommending 8 consideration of a Hill coefficient value of 1.0 and pointing out why lower values are 9 inappropriate (comments from Drs. Thomas Starr, July 7, 2010 and October 26, 2010 and 10 Melvin E. Andersen, November 4, 2010). 11 12 Recommendations 13 14 The Panel recommends additional efforts to fully characterize the uncertainty in 15 the models with special consideration of the Hill coefficient value. 16 17 3.2. Several o f the critical studiesfor both noncancer and cancer dose-response 18 assessment were conducted in mice. A mouse PBPK model was developedfrom 19 an existing rat model in order to estimate TCDD concentrations in mouse tissues, 20 including whole blood. 21 22 Please comment on thefollowing: 23 24 3.2.a. Please comment on the scientific rationalefor the development o fEPA 's mouse 25 model based on the published rat model (Emond et al., 2004, 2005, 2006). 26 27 Response: 28 29 The Panel agrees that an appropriate approach was used to develop the mouse 30 model on the basis of the published rat model and the available mouse kinetic data. It 31 should be noted that the NAS recommendation to use human data for dose metric could 32 be accomplished because dose-dependent elimination of TCDD has been described in 33 humans, albeit in just a few cases. Dose-dependent elimination has been reported 34 repeatedly in animals and the PBPK model reflected this dose-dependence. Using 35 CYP1A2 data from humans (caffeine metabolism) and mice would offer an opportunity 36 to validate and/or adjust the mouse model. 37 38 Recommendations 39 40 An external peer review of the mouse model should be conducted because this 41 model has not been published in the peer-reviewed literature. This is typically a 42 requirement for models to be used by the Agency. 43 22 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 3.2. b. Please comment on the performance o f the mouse model in reference to the 2 available data. 3 4 Response: 5 6 The Panel found that the mouse model performed reasonably well, apart from 7 under-prediction of urinary excretion data. The urinary excretion data can be improved 8 by taking into account the fact that urine contains metabolites only, which partition 9 differently from the parent compound. The model appeared to be adequate for use in 10 estimating dose metrics for the assessment, but with greater uncertainty than the rat and 11 human models. This was considered a reasonable approach to solve a deficiency in 12 published PPBK models to meet the needs of this assessment. 13 14 The EPA's suggestion in the RfD chapter that the clustering of mouse points of 15 departure (PODs) at the lowest doses was due to mouse model failure was inappropriate 16 and should be rewritten. 17 18 Recommendations 19 20 EPA should use the mouse model. The scientific credibility of the model will be 21 enhanced by its publication in an appropriate peer reviewed journal. 22 23 3.2. c. Please comment on whether EPA adequately characterized the uncertainty in the 24 mouse and rat kinetic models. Please comment specifically on the scientific 25 justification o f the kinetic extrapolationfactorfrom rodents to humans. 26 27 Response: 28 29 EPA provided an adequate characterization of the qualitative uncertainty in the 30 mouse and rat kinetic models sufficient to justify their use, together with the human 31 model, to estimate rodent-to-human extrapolation factors. On the other hand, formal 32 recalibration of the PBPK model parameters using a Hierarchical Bayesian approach such 33 as Markov chain Monte Carlo analysis was not considered necessary or particularly 34 useful. However, a more quantitative uncertainty analysis is needed. 35 36 Recommendations 37 38 A more quantitative uncertainty analysis is recommended. Methods that could be 39 useful and informative for such an analysis are suggested in the response to 40 charge question 6.2 in this report. 41 42 3.3. Please comment on the use o fEmond et al. PBPK model to estimate human 43 intakes based on internal exposure measures. 44 23 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Response: 2 3 The modified Emond model is the best available approach for estimating 4 exposures on the basis of internal exposure measurements. Nevertheless, there is 5 considerable uncertainty associated with attempting to reconstruct prior exposures in a 6 human population (e.g., Seveso). 7 8 Recommendations 9 10 The modeling of the Cheng et al. (2006), Moccarelli et al. (2008), and Bacarelli et 11 al. (2008) studies needs to be described in more detail and the impact of model 12 parameter uncertainty and exposure uncertainty in these studies should be 13 evaluated quantitatively. 14 15 3.4. Please comment on the sensitivity analysis o f the kinetic modeling (see Section 16 3.3.5). 17 18 Response: 19 20 The Report only presented the sensitivity analysis published by Emond et al. 21 (2006), which was not entirely adequate for the purposes of this assessment. The analysis 22 left out the Hill coefficient, which was one of the most important parameters in the model 23 for low dose extrapolation (Evans and Andersen, 2000). Moreover, model sensitivities 24 were species, dose, and dose-scenario dependent, so they need to be determined under the 25 same exposure conditions as those for which dose metrics were calculated: both for the 26 various studies that serve as the basis for the dose-response assessments and for human 27 exposures at the corresponding HEDs and risk specific doses. This represents the most 28 pragmatic path forward for an evaluation of model sensitivity as it relates to potential 29 environmental regulation. 30 31 Recommendations 32 33 EPA should provide a sensitivity analysis of the model to authenticate the model 34 for its intended purpose. 35 36 3.5. Both EPA's noncancer and cancer dose-response assessments are based on a 37 lifetime average daily dose. Did EPA appropriately estimate lifetime average 38 daily dose? I f not, please suggest alternative approaches that could be readily 39 developed based on existing data. 40 41 Response: 42 43 The Panel agrees with the average daily dose calculation approaches described in 44 the Report. It was not clear to some Panel members how the computational estimates of 24 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 internal dose for newborns were carried out since a lactation model was not used. This is 2 important because of the use of TSH in newborns as a critical effect. EPA, and 3 Baccarelli et al. (2008), developed an empirical description of the relationship between 4 maternal TCDD levels (lipid adjusted) in serum at birth of neonate and the measured 5 serum TSH in the newborns up to 3 days of age. The Emond et al. model was run in an 6 iterative fashion by adjusting chronic daily intake (ng/kg/day) in the human gestation 7 model to predict maternal serum level of TCDD at term that was associated with infant 8 serum thyroid stimulating hormone (TSH) concentration of 5 uU/ml (by using the 9 regression equation). The result was 0.024 ng/kg bw/day. 10 11 Recommendations 12 13 EPA should carefully explain how the early life stage internal doses are 14 calculated. 15 16 17 Charge Question 4. Reference dose 18 19 EPA selected two co-critical studies (Mocarelli et al., 2008 and Baccarelli et al., 20 2008) for development of the reference dose for TCDD. The Panel was asked to 21 comment on the scientific justification for selection and use of these studies to develop 22 the reference dose. 23 24 4.1. The Mocarelli et al. (2008) and Baccarelli et al. (2008) studies were selected as 25 co-critical studies for the derivation of the RfD. Is the rationale for the choice of 26 Mocarelli and Baccarelli scientificallyjustified and clearly described? Please 27 identify andprovide the rationalefor any other studies that should be selected, 28 including the rationalefor why the study would be considered a superior 29 candidatefor the derivation o f the RfD. Also comment on whether the selection o f 30 male reproductive effects and changes in neonatal thyroid hormone levels was 31 scientificallyjustified and clearly described. 32 33 Response: 34 35 The Panel found that use of the Mocarelli et al. (2008) and Baccarelli et al. (2008) 36 studies was appropriate for identifying "co-critical" effects for the RfD calculation. 37 These are human epidemiological studies that were well designed and executed. The 38 studies provided sufficient exposure information, including biological concentrations that 39 could be used to help establish acceptable life-time daily exposure levels. Some of the 40 strengths of the human studies included the use of a well-characterized human cohort, 41 conducted by dioxin epidemiology experts, and the fact that similar PODs were found 42 across a broad spectrum of other reported dioxin toxicities in multiple species. The 43 rationale for selecting these two studies over numerous other available studies was clearly 44 described and the Panel believed that, overall, EPA provided a well-considered and 45 rational discussion of why these two human studies were selected for determining the 25 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 RfD. However, one issue discussed by the Panel was that, while the strengths of the two 2 human studies were well-described, the study weaknesses were not always clearly 3 delineated. For example, in the Baccarelli (2008) study there was limited discussion of 4 how the presence of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated 5 dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (PCBs) that were also 6 found in the blood might confound the interpretation of TCDD association with elevated 7 TSH levels. In addition there was no discussion of the potential impact of residential 8 histories (e.g., individuals who may have moved in and out of Zone A after the accident). 9 The Panel believes that more discussion of the strengths and weaknesses of these two 10 studies is needed. 11 12 As indicated above, the Panel agreed that the major strengths of the human studies 13 were the use of a well-characterized dioxin-exposed human cohort, conducted by dioxin 14 epidemiology experts, and the fact that similar PODs were found across a broad spectrum 15 of other reported dioxin toxicities in multiple species. However, in isolation from each 16 other, and lacking a description of supportive animal and epidemiological studies, the 17 studies were less useful for setting the RfD. The Panel emphasizes the need to consider 18 these other supportive studies within the context of the weight of the dioxin and dioxin 19 like compound (DLC) database. The strength of the RfD should not be based solely on 20 these two human epidemiology studies, but rather should be supported by integration 21 with other similar supporting dioxin and DLC studies. A strong voice from the 22 committee was given for looking at the comprehensive data base of both animal and 23 human epidemiological studies together to demonstrate a consistent and integrative signal 24 of toxicity across species and endpoints for TCDD. It was suggested that similar studies 25 with DLCs should also be included as these would be supportive, at least for a semi 26 quantitative comparative analysis. This "collective" impact of the studies was stated in 27 the Report but needs to be made stronger as it represents the contextual framing for 28 understanding dioxin health impacts. This response would include discussions of both 29 human and experimental animal studies that have examined the effects of dioxin or DLCs 30 on other reproductive and endocrine endpoints and should, for example, include 31 discussion of dose-response relationships as well as comparisons of no-observed-adverse 32 effect levels (NOAELs) and lowest-observed-adverse effect levels (LOAELs). 33 34 The Panel notes that Figures 4.3 and 4.4 in the Report show quantitative 35 comparisons across the RfDs and benchmark dose lower bounds (BMDLs) calculated 36 from the animal and epidemiological studies. These figures are useful in understanding 37 the quantitative similarities (to the PODs in the chosen studies) in these calculations. The 38 Panel also notes that since the figures did not have an indication of endpoints being 39 measured, just the reference to the publications, the consistency in signal (i.e., the 40 similarities in PODs determined) was not as readily apparent as it could be. 41 42 Although it has been addressed in the Report, the Panel recommends expanding 43 the discussion of the known human age-specific variability in endpoints such as sperm 44 counts, though the data from Moccarelli et al. (2008) do show ranges and variance (in 45 Figure 3/Table 2), and neonatal TSH levels. 26 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Recommendations 3 4 EPA should provide a discussion of the strengths and weaknesses of the Mocarelli et 5 al. (2008) and Baccarelli et al. (2008) studies with an indication of whether the 6 weaknesses affect determination of the RfD. 7 8 EPA should label the endpoints for studies included in Figures 4.3 and 4.4. 9 10 The comprehensive data base of both animal and human epidemiological studies, 11 including studies with DLCs (e.g., studies cited in Goodman et al., 2010), should be 12 discussed together to demonstrate a consistent and integrative signal of toxicity across 13 species and endpoints for TCDD. 14 15 4.2. In the Seveso cohort, the pattern o f exposure to TCDD is differentfrom the 16 average daily exposure experienced by the general population. The explosion in 17 Seveso created a high dose pulse o f TCDDfollowed by low level background 18 dietary exposure in the exposedpopulation. In the population, this high dose 19 pulse o f TCDD was slowly eliminatedfrom body tissues over time. There is 20 uncertainty regarding the influence o f the high-dose pulse exposure on the effects 21 observed later in life. 22 23 4.2. a. Mocarelli et al. (2008) reported male reproductive effects observed later in life 24 for boys exposed to the high dose pulse o f TCDD between the ages o f 1 and 10. 25 EPA identified a 10 year critical exposure window. In the development o f the 26 candidate RfD, EPA used an exposure averaging approach that differsfrom the 27 typical approach utilizedfor animal bioassays. EPA determined that the relevant 28 exposure should be calculated as the mean o f the pulse exposure and the 10-year 29 critical exposure window average. Please comment on thefollowing: 30 31 4.2. a.i. Please comment on EPA's approachfor identifying the exposure window and 32 calculating average exposurefor this study 33 34 Response: 35 36 The Panel discussed extensively, both as part of the deliberations on Section 4 of 37 the Report and also as part of the discussion on Section 3, extrapolation issues posed by 38 the pattern of exposure from Seveso. Issues raised included the question of whether the 39 same endpoints and or dose-response would be expected from such exposure scenarios 40 with high acute exposures when extrapolating to low-dose chronic exposures. It would 41 be useful for EPA to provide a discussion of published examples in which dioxin studies 42 were conducted using both high-dose acute and low-dose chronic exposures in animals 43 for the same endpoint and how the outcomes compare both qualitatively and 44 quantitatively. It would be important to determine whether similar results were observed 27 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 for similar endpoints. Several Panel members thought there were sufficient data in the 2 immunological or reproductive areas that may allow such a comparison. Several chronic 3 dioxin animal studies may be useful in this regard (Yoshizawa et al., 2009; Sand et al., 4 2010; Yoshizawa et al., 2010). The life stage-specific approach to hazard and dose5 response characterization for children's health risk assessment found in EPA's 6 Framework for Assessing Health Risks o fEnvironmental Exposures to Children (EPA, 7 2006), is also relevant to addressing this issue and should be discussed. The Panel also 8 recommends that the publication of Bell et al., (2010), which summarized and presented 9 data on some differences about chronic vs. acute exposure in maternal transfer, be 10 considered in this discussion. 11 12 4.2a.ii. Please comment on EPA's designation o f a 20% decrease in sperm count (and 13 an 11% decrease in sperm motility) as a LOAELfor Mocarelli et al. (2008). 14 15 Response: 16 17 The Panel found that changes from normal sperm counts and sperm motility are 18 of public health relevance and therefore of interest for determining an RfD. 19 Collectively, there was support for these endpoints within the context of the broader 20 dioxin literature. The Panel discussed whether the magnitude of these changes would 21 represent an adverse health effect. While the shifts observed in sperm counts may or 22 may not pose a significant health effect in a single individual, such shifts on a population 23 basis could presumably lead to an increased incidence of adverse health outcomes. 24 Although there was concern expressed about the sample size used for sperm number and 25 known variability in the biological endpoint, the Panel found that sample collection was 26 conducted consistently across subjects and the differences in groups were apparent. 27 28 The Panel supports EPA's approach of using the World Health Organization 29 (WHO) reference value for determining relevant TSH levels, and the Panel strongly 30 suggests that further discussion of WHO reference values for male reproductive 31 parameters be included in the Report. Several references were available which provided 32 background information and current values recommended by WHO regarding sperm 33 counts (e.g., Skakkebaek, 2010). The Panel suggests that the standard deviations or range 34 of changes from Mocarelli et al. (2008) be discussed in the Report because this provides a 35 better understanding of the potential magnitude of effect. 36 37 Life stage differences in sperm counts were discussed by the Panel. Members of 38 the public also provided comments on this issue. It would be appropriate to indicate in 39 the Report that life stage differences clearly exist in sperm counts in humans and to cite 40 and discuss the EPA life stage document (EPA, 2006). 41 42 43 44 45 28 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Recommendations 2 3 Discussion on WHO reference values for male reproductive parameters should be 4 included in the Report (e.g., Skakkebaek, 2010). 5 6 The standard deviations or range of changes from the Mocarelli (2008) study should 7 be discussed in the Report to provide a better understanding of the potential 8 magnitude of effect. 9 10 4.2. b. For Baccarelli et al. (2008), the critical exposure window occurs long after the 11 high-dose pulse exposure. Therefore, the variability in the exposure over the 12 critical exposure window is likely to be less than the variability in the Mocarelli et 13 al. subjects. EPA concluded that the reported maternal exposuresfrom the 14 regression model developed by Baccarelli et al. provide an appropriate estimate 15 o f the relevant effective dose as opposed to extrapolatingfrom the measured 16 infant TCDD concentrations to maternal exposure. Additionally, EPA selected a 17 LOAEL o f 5 p-units TSHper ml blood in neonates; as this was established by 18 World Health Organization (WHO) as a level above which there was concern 19 about abnormal thyroid development later in life. Please comment on the 20 following: 21 22 4.2. b.i. Please comment on EPA's decision to use the reported maternal levels and the 23 appropriateness o f this exposure estimatefor the Baccarelli et al. study. 24 25 Response: 26 27 The Panel discussed and supports EPA's decision to use the Baccarelli et al. 28 (2008) estimates of the relevant effective doses. Since the bulk of the calculations were 29 based on zonal averages, it should be made clearer how these measurements relate to 30 ranges and variations in exposure in utero. 31 32 4.2. b.ii. Please comment on EPA's designation o f 5 u-units TSHper ml blood as a 33 LOAELfor Baccarelli et al.,( 2008.) 34 35 Response: 36 37 The change in TSH levels reported by Baccarelli et al. (2008) was of public health 38 relevance and therefore of interest for determining an RfD. Collectively, there was 39 support for this endpoint within the context of the broader dioxin literature. There was 40 discussion on whether the magnitude of these changes would represent an adverse health 41 effect. The Panel notes that the shift observed in TSH levels may or may not pose a 42 significant health effect in a single individual, but such a shift on a population basis could 43 presumably lead to an increased incidence of adverse health outcomes. The Panel also 44 discussed the variability in neonatal TSH levels but concerns about this issue were 29 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 minimized by the fact that samples were all collected on the same postnatal day. The 2 Panel suggests that if any follow-up data on thyroid hormone levels, such as T3, T4 or 3 TSH levels, are available from the population studied, then these results should be 4 discussed in the Report. The Panel discussed several studies describing health effects 5 associated with elevated neonatal TSH levels not always recognized as associated with 6 congenital hyperthyroidism (CH). There is a need to better describe the potential adverse 7 health outcomes related to altered neonatal TSH levels. For example, in addition to 8 effects on growth, both cognitive and motor deficits have been found in young adults 9 with congenital hypothyroidism (Oerbeck et al., 2003; Oerbeck et al., 2007). The Report 10 could better describe the consequences of transient hypothyroidism on reproductive 11 outcomes e.g., see Anbalagan et al. (2010). Other references that relate to this question 12 include: Chevrier et al. (2007), Dimitropoulos et al. (2009), and Yr (2008). 13 14 Recommendations 15 16 EPA should better describe the potential adverse health outcomes related to altered 17 neonatal TSH levels (e.g., effects on both cognitive and motor deficits). 18 19 4.3. Please comment on the rationale for the selection o f the uncertaintyfactors (UFs) 20 for the RfD. I f changes to the selected UFs are proposed, please identify and 21 provide a rationale. 22 23 Response: 24 25 A composite uncertainty factor of 30 (an uncertainty factor of 10 for the lack of a 26 NOAEL, and an uncertainty factor of 3 for human interindividual variability) was applied 27 to the LOAEL of 0.020 ng/kg-day from Mocarelli et al. (2008) to obtain the RfD. The 28 Panel agrees that the appropriate uncertainty factors (UFs) were included. The exclusion 29 or inclusion of the UFs in the Report is obvious, clearly discussed, and adequately 30 rationalized. The Report would be more transparent if EPA included a short discussion 31 of the basis for the decision not to include a UF for data quality. 32 33 4.4. EPA did not consider biochemical endpoints (such as CYP induction, oxidative 34 stress, etc.) as potential critical effectsfor derivation o f the RfDfor TCDD due to 35 the uncertainties in the qualitative determination o f adversity associated with 36 such endpoints and quantitative determination o f adversity associated with such 37 endpoints and quantitative determination o f appropriate response levelsfor these 38 types o f endpoints in relation to TCDD exposure. Please comment on whether the 39 decision not to consider biochemical endpoints is scientificallyjustified and 40 clearly described. 41 42 Response: 43 44 Biochemical endpoints such as P450 activation, increased oxidative stress, etc. 45 may be acceptable endpoints to establish PODs, particularly when the quantitative 30 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 relationship between the biochemical endpoint and an adverse health outcome is clearly 2 evident. However, with respect to TCDD, the Panel agrees that more traditional 3 endpoints (e.g., immune, endocrine, reproductive) are more appropriate because 4 associations of these endpoints with health outcomes are well studied and provide a 5 stronger association to an adverse outcome than biochemical endpoints. However, 6 because of the wealth of data on P450s and their importance in disease development, 7 normal development, and chemical response to exogenous agents, EPA should discuss 8 biochemical endpoints, particularly P450s, relevant to establishing and strengthening the 9 proposed reference dose. 10 11 4.5. In using the animal bioassays, EPA averaged internal blood TCDD 12 concentrations over the entire dosingperiod, including 24 hoursfollowing the 13 last exposure. Please comment on EPA's approachfor averaging exposures 14 including intermittent and one-day gestation exposure protocols. 15 16 Response: 17 18 For animal studies it has been shown that for some effects acute exposure could 19 give different results than chronic exposure. For TCDD, however, its persistence might 20 suggest that such differences would be partly negated. In Baccarelli et al., (2008), there 21 was extensive discussion regarding the use of the exposure average time for the TCDD 22 concentrations. This is of biological significance as several papers have indicated the 23 unique aspects of high peak exposure of TCDD as occurred in Seveso and in several of 24 the animal studies. The endpoints affected as a result of these peaks do not always 25 translate to impacts from lower chronic exposures. As stated earlier in this section, it 26 would be helpful to discuss any available animal studies comparing high-dose acute vs. 27 low-dose chronic effects on similar endpoints for dioxin or DLCs. By returning to the 28 broader animal literature and using time and dose-response studies from the dioxin and 29 DLC studies, biological support for the two critical endpoints might be found. 30 31 4.6. Please comment on the benchmark dose (BMD) modeling conducted by EPA to 32 analyze the animal bioassay data and EPA's choice o fpoints o f departure 33 (PODs)from these studies. 34 35 Response: 36 37 The Panel agrees with the BMD modeling approaches used in Section 4 of the 38 Report. EPA conclusions that the animal data had sufficient limitations that precluded 39 their use to establish a RfD are adequately justified. The reasons provided, however, are 40 quite diverse, (e.g., no NOAEL, not considered an adverse effect, the effect at the 41 LOAEL is too divergent from the control group, insufficient dose groups at the low-end 42 of the dose-response curve, monotonic responses) and there is no way for the reader to 43 determine which study has particular deficiencies without going back to the original 44 paper. To help address this gap, the Panel suggests that several of the best animal studies 45 be discussed in some detail so these limitations are more apparent to the reader. As 31 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 indicated previously, the EPA authors need to better cite the endpoint guidance that is 2 present within EPA documents for defending these approaches and application of BMD 3 models for the critical effects. This is especially necessary given public comments that 4 EPA was not following its own guidelines 5 6 4.7. For the animal bioassay modeling, EPA applied the kinetic extrapolation at the 7 level o f the POD prior to applying the uncertaintyfactors because EPA has less 8 confidence in the kinetic model output at lower doses reflective o f the RfD. 9 Please comment on whether the kinetic extrapolation at the level o f the POD 10 prior to applying the uncertaintyfactors was scientificallyjustified and clearly 11 described. 12 13 Response: 14 15 The EPA approach of applying the kinetics on the actual data present at the POD 16 is preferred in this assessment (see additional discussion in the response to Charge 17 Question 3 - The use of toxicokinetics in the dose-response modeling for cancer and 18 noncancer endpoints). 19 20 4.8. Please comment as to whether EPA's qualitative discussion o f uncertainty in the 21 RfD isjustified and clearly described. 22 23 Response: 24 25 The Panel agrees that EPA provided a clear and justified discussion of the 26 uncertainties in deriving the RfD using the Seveso cohort. Section 4 of the Report 27 discussed study limitations regarding the need to adjust from acute exposure to average 28 daily dose, the issue of critical windows, co-exposure to DLCs, and the 29 strength/weaknesses of the animal data. The Panel agrees with EPA that the major 30 limitation of the Seveso cohort is the uncertainty arising from how well the effects 31 resulting from high-dose acute exposure translate to low-dose daily exposures. Again, it 32 might be useful to re-review the animal studies to identify whether there are any studies 33 where dioxin or DLCs were administered by acute as well as chronic (or even 34 subchronic) exposure and comparable endpoints were examined. If so, the information 35 can be used to help confirm or refute the accuracy of the "average daily dose" 36 adjustment. This is of particular concern in the Mocarelli study as "time periods of 37 susceptibility" appear in male reproductive development and these periods (windows) 38 may be very short. Again, animal studies, particularly those involving male reproduction, 39 may be helpful. 40 41 It would also be useful to include a discussion of potential uncertainty in the 42 exposure estimates from the Baccarelli study. Serum dioxin levels were only established 43 in a subset of the cohort (approximately 51) at the time of the study while dioxin levels 44 from the main cohort were estimated from data collected from zone of residence (A or B) 45 at a much earlier time. 32 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 The discussion in the Report of whether the background DLC exposure may have 3 a significant impact, particularly at the lower TCDD exposure levels, is important. While 4 the Panel agrees that the true DLC impact can't be determined, it might be helpful to 5 provide some general estimates of the variability that may occur at the proposed RfD. 6 7 8 Charge Question 5. Cancer assessment 9 10 In the Report EPA has provided: a weight-of-evidence characterization of TCDD 11 as a known human carcinogen, conclusions regarding the mode of carcinogenic action for 12 TCDD, EPA's selection of data sets for cancer dose-response modeling, and 13 consideration of approaches for assessment of TCDD carcinogenicity. The Panel was 14 asked to comment on the scientific soundness of these aspects of EPA's cancer 15 assessment. 16 17 General Comment: 18 19 The Panel was impressed by the extensive work performed by EPA in its response 20 to the NAS comments on cancer assessment. The comments below are intended to 21 support the Agency in further developing Section 5 of the Report. 22 23 5.1. Weight-of-Evidence Cancer Descriptor: The 2003 Reassessment concluded that 24 TCDD is a "known human carcinogen. " In the current draft Response to 25 Comments document, EPA concluded that under the 2005 Guidelinesfor 26 Carcinogen Risk Assessment (U.S. EPA, 2005) TCDD is "carcinogenic to 27 humans." Is the weight-of-evidence characterization scientificallyjustified and 28 clearly described? 29 30 Response: 31 32 The Panel agrees on the classification that "TCDD is carcinogenic to humans" 33 under EPA's 2005 Guidelinesfor Carcinogen Risk Assessment. Available occupational 34 epidemiologic studies provide convincing evidence of an association between TCDD and 35 human cancer that cannot be reasonably attributed to chance or confounding and other 36 types of bias, and with a demonstration of temporality, strength of association, 37 consistency, biological plausibility, and a biological gradient. Additional evidence from 38 animal studies and from mechanistic studies provides additional support for the 39 classification of TCDD as carcinogenic to humans. A dissenting opinion (see Appendix 40 A of this report) was expressed by one Panel member who indicated that at best, there is 41 equivocal evidence for the carcinogenicity of TCDD in the occupational setting where 42 body burdens were much higher than current or previous background levels. The Panel 43 provides the following recommendations to strengthen the Report. 44 33 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Recommendations 2 3 EPA should provide more discussion of the power of studies used and the 4 difficulties involved when assessing rare tumors. Thoroughly addressing these 5 aspects will make the weight-of-evidence characterization in Section 5 of the 6 Report more clear and transparent. 7 8 In the weight-of-evidence characterization, the Agency should build on all the 9 available data to support the decision. It needs to be made clear how different 10 types of data (in vitro, in vivo, human) support each other; or not. 11 12 EPA should consider including studies with substantial DLC exposure where 13 TEFs can be calculated. Specific experimental studies include Li and Rozman 14 (1995), Rozman et al. (1993, 2005), and Viluksela et al. (1994, 1997a,b, 1998a,b). 15 16 EPA should attempt to characterize the uncertainty regarding the carcinogenicity 17 of TCDD at low human exposures, since the minimum dose at which 18 carcinogenic effects would be expected to occur cannot be clearly delineated from 19 the current epidemiological human data. The agency has concluded that AhR 20 activation is a necessary but not sufficient precursor event in the carcinogenic 21 activity of TCDD. Therefore, it would be beneficial if the Agency could evaluate 22 available data on AhR activation and related effects in human cells and animal 23 models to help inform the doses at which these precursor events are observed for 24 comparison with the epidemiological data. 25 26 5.2. Mode o fAction: The mode o f action o f a carcinogen can inform identification of 27 hazards and approaches usedfor a dose-response assessment. The mode o f 28 carcinogenic actionfor TCDD has not been elucidatedfor any tumor type. EPA 29 concluded that, while interaction with the Ah receptor is likely to be a necessary 30 early event in TCDD carcinogenicity in experimental animals, the downstream 31 events involved are unknown. 32 33 5.2. a. Are the available data related to mode(s) o f actionfor the carcinogenicity o f 34 TCDD appropriately characterized and clearly presented? 35 36 Response: 37 38 The Panel appreciates the attempts by the Agency to further develop cancer mode 39 of action concepts based on available dioxin liver, lung, and thyroid toxicity data. Such 40 innovative and explorative work is clearly fundamental to the continued need to further 41 develop risk assessment sciences and make more detailed and integrated use of already 42 existing and published data. 43 34 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 The Panel complements the Agency for providing an up-to-date dioxin cancer 2 mode of action section in its response to NAS comments. It could, however, be improved 3 by incorporating additional data on linear and nonlinear modes of action in different 4 target tissues and life stages. A large amount of data related to the mode of action for the 5 carcinogenicity of TCDD is described in the Report, but the focus appears to be on 6 presenting evidence that supports the use of a default linear approach rather than 7 providing a balanced evaluation of alternative mode of action hypotheses. 8 9 The discussion of the likely dose-response for receptor mediated processes 10 focuses only on the first step, binding of the agonist to the receptor, which is ultimately 11 linear at low concentrations. However, no discussion is given to the nature of the dose12 response for the down-stream sequelae of receptor activation, for which there is evidence 13 of nonlinearity. It is, in fact, the fundamentally nonlinear nature of the dose-response for 14 receptor mediated processes that underlies the conviction of a large segment of the 15 scientific community that a nonlinear approach should be preferred for the risk 16 assessment for dioxin. 17 18 Recommendations 19 20 EPA should further expand the discussion of mode of action data available to 21 delineate linear versus nonlinear modes of action and effects in different target 22 tissues at different life stages. 23 24 5.2.b. Do the available data support EPA 's conclusion that the overall mode(s) o f action 25 for TCDD-induced carcinogenesis is largely unknown? Please comment on 26 whether this evaluation is clearly described. 27 28 Response: 29 30 The Panel notes that much is known about TCDD toxicity and mode of action. 31 Some Panel members indicated that the characterization of the mode of action should be 32 "reasonably well known" rather than "largely unknown." Nevertheless, the Panel agrees 33 that the exact mechanism-of-action has not been fully delineated for any distinct TCDD34 toxicity end-point. For example, it was pointed out that most TCDD toxicities are 35 mediated by activation of the AhR. Many studies have demonstrated that TCDD can 36 activate or interfere with the activity of estrogen receptors, as well as other steroid 37 receptors. Such interference can disrupt the regulation of cell proliferation, cell death and 38 tissue differentiation. By disrupting these cell functions, TCDD can have profound and 39 lasting effects as demonstrated by studies showing that TCDD exposure during 40 development produces adult neural dysfunctions. 41 42 43 44 45 35 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Recommendations 2 3 EPA should provide a discussion of the evidence for possible modes of action that 4 include both linear and nonlinear alternatives. 5 6 EPA should describe the receptor mediated nonlinear mode of action for dioxin 7 (e.g., Van den Heuvel et al., 1994; Li and Rozman 1995; Andersen et al., 1997; 8 Bhattacharya et al 2010; Gim et al., 2010) and DLCs (e.g., Rozman et al., 1993; 9 2005, Stahl et al., 1994; Viluksela et al., 1994, 1997a,b, 1998a,b), as well as 10 evidence regarding the fundamentally nonlinear nature of receptor mediated 11 cellular responses (e.g., Andersen et al., 1999; Louis and Becskei, 2002; Zhang et 12 al., 2010). 13 14 5.3. Is EPA's approachfor selecting data setsfrom the key epidemiologic studies and 15 animal bioassays identifiedfor cancer dose response modeling scientifically 16 justified and clearly described? 17 18 Response: 19 20 The Panel agrees with the inclusion of the Cheng study in the cancer assessment. 21 The study incorporated information on gradation of exposure. Expanded discussion of 22 several other studies would support the weight-of-evidence for carcinogenicity in less 23 common cancers such as lymphomas and soft tissue sarcoma. The Panel discussed the 24 possible value of including studies with DLCs in the evaluation of the weight-of25 evidence, in light of the small number of studies involving primarily exposure to TCDD. 26 There are a numerous studies in the literature involving the health effects of DLCs. 27 These include rice oil poisoning incidents in Japan and Taiwan. These incidents have 28 been described, and additional references have been provided, in Schecter and Gasiewicz 29 (2003). 30 31 Recommendations 32 33 EPA should present in a clear and visible format, for example in a table, which 34 studies were carried forward or not, and the reasons for the decisions made. The 35 weight-of-evidence discussion should be expanded to include evidence from 36 studies of individual cancers for which precise gradation of exposure data is 37 lacking. 38 39 5.4 . For the animal bioassay data, potential cancer oral slopefactors (OSFs) were 40 calculated by linear extrapolation (using a linear, non threshold cancer 41 approach) from the point o f departure (POD). EPA also estimated the composite 42 risk o f the occurrence o f several tumor typesfrom the animal cancer bioassay 43 data. 44 36 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 5.4. a. Please comment on whether the approachfor estimating cancer risk, including 2 the use of tumor modeling of the TCDD animal cancer bioassay data, is 3 scientificallyjustified and clearly described. 4 5 Response: 6 7 The Panel agrees that the approach for estimating cancer risk from animal studies 8 was scientifically justified and clearly described. 9 10 5.4. b. Please comment on the choice of using a BMDL01 as the PODfor the 11 development of candidate oral slopefactors derivedfrom the TCDD animal 12 cancer bioassays. 13 14 Response: 15 16 The Panel notes the consistency of the selection of the BMDL01 as the POD with 17 Agency guidelines and has no further comments. 18 19 5.5. EPA selected Cheng et al. (2006) - an analysis of the NIOSH occupational 20 cohort - as the critical studyfor oral slopefactor (OSF) development. This study 21 was chosen because it considers dose-dependent elimination of TCDD rather than 22 first-order kinetics. 23 24 5.5. a. Please comment on whether the rationalefor this selection is scientifically 25 justified and clearly described. Please identify andprovide the rationalefor any 26 other studies that should be considered andprovide a critical evaluation of the 27 study and of its suitabilityfor meeting the goals ofa quantitative cancer 28 assessment. 29 30 Response: 31 32 The Panel agrees that Cheng et al (2006) is the appropriate study for OSF 33 development. The selection of this study is well described. 34 35 5.5. b. Cheng et al. (2006) analyzed all-cancer mortality. Please comment on the use of 36 all-cancer mortality as the basis of the OSF. 37 38 Response: 39 40 The Panel agrees that it is appropriate to use all-cancer mortality in this case 41 because of the extensive dose-response information. 42 43 5.5. c. Please comment on whether the use of the Emond PBPK model in the estimation 44 ofrisk-specific dosesfrom the Cheng et al. dose-response modeling results is 45 scientificallyjustified and clearly described. 37 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Response: 3 4 The Panel agrees that the use of the Emond model to estimate risk-specific doses 5 from the Cheng et al. (2006) dose-response modeling results is scientifically justified and 6 clearly described. This is because the "concentration-and-age-dependent elimination 7 model" (CADM) used in Cheng et al. (2006) did not facilitate this process. Also, the 8 dose conversions were consistent with those used in the derivation of the RfD. However, 9 as discussed in the response to charge question 3.1.d, the Panel is concerned about the 10 value of the Hill coefficient used. 11 12 5.5. d. EPA elected to use the log linear relationship o ffa t concentration and rate ratio 13 to estimate risk-specific doses at all risk levels. EPA could have estimated a POD 14 for cancer risk itselfat a single risk level (BMR)for extrapolation to the origin. 15 Please comment on EPA's choice o f extrapolation approach. 16 17 Response: 18 19 Since the fat concentrations generated by CADM were not linear with the oral 20 exposure at higher doses, a single oral slope factor to be used for all risk levels could not 21 be obtained. EPA used the upper 95% bound on the slope (from Cheng et al., 2006) of 22 the linear relationship between the natural logarithm of the rate ratio and the cumulative 23 fat TCDD concentration (fat-AUC) to estimate risk-specific doses for TCDD at all risk 24 levels. The Panel agrees that the Agency has chosen the appropriate extrapolation 25 approach. 26 27 5.5. e. The slopefactor derivedfrom Cheng et al. (2006) was extrapolated below the 28 background TCDD exposure levels experienced by the NIOSH cohort. Please 29 comment on this extrapolation. 30 31 Response: 32 33 The ability of the Cheng study to be informative regarding risks below current 34 background exposure levels is not completely clear. 35 36 Recommendations 37 38 EPA should expand the discussion in the Report to consider the possibility that 39 mode of action considerations could help to inform whether linear extrapolation 40 of the Cheng data to obtain risk estimates in this range of exposures is 41 appropriate. 42 43 5.6. Please comment on whether EPA has clearly described the major qualitative 44 uncertainties in the derivation o f the OSF. 45 38 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Response: 2 3 The Panel found the description of qualitative uncertainties in the derivation of 4 the OSF to be clear and adequate. 5 6 5.7. EPA did not consider dioxin-like compounds (DLCs) in the cancer dose-response 7 modeling because the occupational exposures in the available cohorts were 8 primarily to TCDD. Background DLC exposures were not incorporated in the 9 dose-response modeling because EPA judged that it was not possible to 10 disaggregate the responsesfrom background exposure to DLCs and occupational 11 exposure to TCDD. Please comment on whether this approach is scientifically 12 justified and clearly described. 13 14 Response: 15 16 While the Panel found that it was important to include DLC studies in the weight17 of-evidence analysis, we are conflicted on their use as a source of dose-response 18 estimates for TCDD. The Panel notes the scientific importance and regulatory relevance 19 of including a coordinated TEQ/DLC discussion in the Report. Including TEQ/DLC 20 aspects in the evaluation would allow for the use of additional studies with dose-response 21 information that more closely mirror environmental exposures. On the other hand, the 22 Panel recognizes the complications associated with developing a TCDD risk estimate that 23 is dependent on current TEF values. 24 25 Recommendations 26 27 DLC studies should be considered in the weight-of-evidence discussion. 28 29 5.8. The NRC suggested that EPA consider nonlinear approachesfor the assessment 30 o f TCDD carcinogenicity. In the Response to Comments, EPA presents two 31 illustrative nonlinear approachesfor cancer, but considers both inappropriate to 32 use because lack o f MOA information. 33 34 5.8. a. Please comment on these two illustrative nonlinear approaches including EPA's 35 conclusions regarding the limitations o f these approaches. 36 37 Response: 38 39 EPA's Report did not respond adequately to the NAS recommendation to adopt 40 "both linear and nonlinear methods of risk characterization to account for the uncertainty 41 of dose-response relationship shape below the ED01." Instead of adopting both linear 42 and nonlinear methods, the EPA argued that only a linear approach could be justified, and 43 derived two examples of RfD development using a nonlinear approach that they 44 characterized as an illustrative exercise only. The choice not to include both linear and 39 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 nonlinear risk assessment approaches for TCDD was inconsistent with the EPA (2005) 2 cancer guidelines (page 3-23/24): 3 4 "Nonlinear extrapolation having a significant biological support may be presented 5 in addition to a linear approach when the available data and a weight-of-evidence 6 evaluation support a nonlinear approach, but the data are not strong enough to 7 ascertain the mode of action applying the Agency's mode of action framework." 8 9 "In the absence of data supporting a biologically based model for extrapolation 10 outside of the observed range, the choice of approach is based on the view of 11 mode of action of the agent arrived at in the hazard assessment. If more than one 12 approach (e.g., both a nonlinear and linear approach) are supported by the data, 13 they should be used and presented to the decision maker." 14 15 Recommendations 16 17 EPA should present both linear and nonlinear risk assessment approaches. In the 18 absence of a definitive nonlinear mode of action, the linear option results can 19 serve as the baseline for comparison with other estimates. The examples in the 20 current document should be formalized and extended to allow for such a 21 comparison. 22 23 5.8.b. Are there other nonlinear approaches that could be readily developed based on 24 existing data for the assessment of TCDD carcinogenicity? If so, please suggest 25 alternative approaches and describe their utility and suitabilityfor meeting the 26 goals o f a quantitative cancer assessment. 27 28 Recommendations 29 30 Since the EPA nonlinear analysis only used studies in S-D rats that were 31 identified in Section 2 of the Report for potential noncancer dose-response 32 modeling, additional alternative PODs should be added. For example, Simon et 33 al. (2010), which was cited in EPA's Report, provided a number of alternative 34 PODs for a nonlinear approach that should be included in the EPA risk 35 assessment. 36 37 38 Charge Question 6. Feasibility of Quantitative Uncertainty Analysis 39 40 In its evaluation of EPA's 2003 Reassessment, the NAS committee recommended 41 that EPA improve the transparency, thoroughness, and clarity in quantitative uncertainty 42 analysis (QUA). Section 6 of EPA's Response to NAS Comments document addresses 43 NAS comments regarding QUA. The Panel was asked to comment on: whether Section 6 44 of EPA's Report was clearly presented and scientifically justified; EPA's conclusion that 40 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 a QUA is not feasible; the discussion of volitional uncertainty, and the utility of the 2 limited sensitivity studies presented by EPA. 3 4 6.1. Please comment on the discussion in this Section. Is the response clearly 5 presented and scientificallyjustified? 6 7 Response: 8 9 As discussed below, the Panel found that Section 6 of EPA's Report is clearly 10 presented, but it is not scientifically justified. In particular, the Panel disagrees with 11 EPA's argument that, since the most detailed and complete available methods for 12 conducting a quantitative uncertainty analysis (QUA) are unfeasible, no analysis can be 13 conducted at all. There are a number of approaches for conducting a QUA, some of 14 which are feasible given current knowledge and data. Specific methods that can be 15 implemented in a timely manner using available data and knowledge are suggested. 16 17 Clarity o f the EPA response to the NASpresented in Section 6 o f the Report 18 19 The EPA response is clearly presented. The Report addresses a broad range of 20 philosophical and methodological issues in conducting an uncertainty analysis for TCDD 21 toxicity, specifically for estimates of cancer oral slope factors and noncancer reference 22 doses. Section 6 is successful in identifying the challenges involved in assessing 23 uncertainty in toxicity estimates based on a small set of available models for 24 toxicokinetics, dose-response relationships, and low dose extrapolation, with limited 25 application, testing, and verification; and a small set of animal bioassay, epidemiological 26 or clinical/case studies, many with differing endpoints, dose metrics, and (in the case of 27 the human studies) uncertain exposure and subject data. 28 29 Section 6 of the Report provides many useful insights for the Agency's dioxin 30 reassessment. However, in its discussion of available methods, the Report is somewhat 31 biased in its treatment of certain statistical methods (discussed below) which could 32 address some of these issues (though the Report does note the potential contribution of 33 the methods at the end of Section 6, as part of ongoing or future studies) and overly 34 pessimistic regarding our ability provide improved quantitative estimates for certain 35 portions of the toxicity assessment. 36 37 Some Panel members indicated that the whole section should be rewritten to make 38 it more accessible to non-statisticians. As further discussed in the editorial comments on 39 Section 6 in Appendix C of this report, some phrasing and word choices in the text 40 should be reconsidered, in particular "exotic methods," "volitional uncertainty," and 41 "epistemic uncertainty." The Panel found that the definition of "quantitative uncertainty 42 analysis" was overly narrow and should be expanded to embrace other common and 43 useful methods discussed below. In a few other places, the Report's wording in Section 6 44 is strongly at variance with the literature on uncertainty analysis (see editorial comments 45 in Appendix C of this report). 41 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Scientificjustification o f the arguments presented in Section 6 3 4 The Panel found that the arguments in Section 6 are not scientifically justified. In 5 Section 6, EPA's decision to not do an integrated quantitative uncertainty analysis is 6 presented and a variety of theoretical issues are discussed, but EPA's decision may be 7 based primarily on grounds of practicality or timeliness. EPA indicates that a complete 8 quantitative uncertainty analysis would require data and resources not available. We 9 disagree with this logic. More limited evaluations can, and should, still be implemented 10 to inform critical issues in the dioxin reassessment. EPA should be methodical in 11 considering what variables and components of the assessment would be included in the 12 analysis. The Panel found that the uncertainty narratives and sensitivity analyses already 13 in the document are an excellent beginning and may constitute the lion's share of the 14 work necessary to implement quantitative uncertain analysis based on simple bounding. 15 16 The Panel does not concur with the specific argument EPA used to justify not 17 doing a unified QUA. If the answer to the question of why EPA did not undertake one is 18 that it was not possible to specify precise marginal distributions and dependence 19 functions from existing data, then the conclusion would be that EPA has not been 20 responsive to the NAS criticism, because there are many possible approaches that could 21 be used that do not depend on such specifications. If the argument is that EPA guidance 22 doesn't require a QUA, then one might agree that the NAS criticism is perhaps itself 23 unreasonable. If EPA had asserted that it actually had done an uncertainty analysis in the 24 form of uncertainty factors (UFs) and the limited sensitivity studies that were performed, 25 then that might be understandable, though not consistent with the current state-of-the-art 26 in risk and uncertainty analysis. Even if the argument had been that mounting a QUA is a 27 significant and controversial undertaking itself and that doing one shouldn't delay the 28 finalization of the Report, then such a practicality argument would be understandable 29 given the protracted delay in completing the dioxin reassessment. 30 31 Instead, EPA asserts that "Data are the ultimate arbiter of whether quantitative 32 uncertainty analysis ... has sufficient evidentiary support." This flies in the face of how 33 uncertainty analyses are normally conceived. Of course, the absence of data is never a 34 substantive reason not to conduct an uncertainty analysis; it is the reason to do one. 35 36 In its Report, EPA indicates that it needs an "underlying distribution from which 37 to sample" in order to conduct a quantitative uncertainty analysis. The Panel notes that 38 this is not necessarily true, and it is facile to shrug off a call to characterize and account 39 for important uncertainties in the assessment process on these grounds alone. If one can 40 estimate the value of a quantity, then one should be able to express the uncertainty about 41 the value, otherwise one does not really have a scientific measurement in the first place. 42 One is not forced to identify precise probability distributions and dependence functions 43 for everything that is to be characterized as uncertain. Even when the uncertainty is 44 volitional (or decisional or just model uncertainty), there can be relevant ranges that are 45 interesting to decision makers and stakeholders. In some cases, the analysis may be 42 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 formally closer to a sensitivity analysis, but some appropriate response is usually 2 possible, if not always practicable. To its credit, EPA has acknowledged the legitimacy 3 of the call for QUA by NAS and undertaken some efforts in this direction. 4 5 In the Report, EPA calls uncertainty analysis an "emerging area in science" and 6 this is inarguably true, but it does not seem reasonable to hold that methodological 7 research is necessary for EPA to do anything more comprehensive to respond to NAS's 8 criticism, even if we disallow the use of expert elicitation. Under a commitment to the 9 idea that analyses be data-driven, it is possible to do something that's useful, even if it is 10 not predicated on precise distributions. There are a variety of ways to conduct a 11 quantitative uncertainty analysis, even an entirely probabilistic one that obeys the 12 Kolmogorov axioms (Gillies, 2000) that require neither extensive data nor expert 13 elicitation. The response to Charge Question 6.2 below provides a list of various ways 14 (with references) to accomplish this. The list includes probability trees or model choice 15 trees that articulate the structure of the model and dependencies, sensitivity analyses, 16 simple interval analysis that just propagates the plausible ranges, and the supervaluation 17 approach that uses nested inner and outer intervals (with the inner range representing the 18 values that most everyone considers to be plausible values and the outer range 19 representing conservatively broad ranges). There is also a continuous and unbounded 20 version of nesting intervals in an approach known as info-gap analysis that would be 21 useful if one cannot develop finite bounds on some of the inputs. One can also propagate 22 bounds on distribution functions, so whatever imperfect information about each input 23 variable's distribution is available, one can fashion bounds on distribution functions and 24 propagate them through the calculations, with or without assumptions or information 25 about the dependencies among variables. 26 27 The Panel notes that the approaches mentioned above require EPA to make 28 certain modeling judgments, in the same way that developing any analysis requires 29 judgments. However, this does not mean that analysts would be required to make up 30 numbers or elicit any expert opinion. Such an analysis does not necessarily require a lot 31 of extra work by EPA. These methods can be simple to develop, and they are mostly 32 computationally trivial. Of course, the more comprehensive the analysis is, the harder it 33 is to complete. But the analysis does not have to be fully comprehensive to provide 34 useful insights. 35 36 We note that there was not perfect consensus among Panel members about the 37 value of a quantitative uncertainty analysis. Some on the Panel agree that an uncertainty 38 analysis is not an absolute good. For instance, if the final answer is already clear, an 39 uncertainty analysis can be a waste of time and resources. It would not be reasonable to 40 insist on another analysis which would merely waste time and resources. Likewise, if the 41 analysis is done poorly, or without appeal to available evidence from the real world, it 42 can be misleading. For instance, the idea, mentioned in footnote 66 on page 6-20 of 43 EPA's Report, of arbitrarily converting uncertainty factors to independent lognormal 44 random variables in a scattered attempt to mount a QUA would entail a suite of 45 unjustified and probably untenable assumptions rendering the exercise nearly pointless. 43 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Finally, if the analysis is used strategically to avoid rendering or finalizing a decision that 2 is proper, it can be counterproductive. However, most members of the Panel felt that 3 quantitative uncertainty analysis is an integral part of any good assessment, and that one 4 is essential to address the many empirically unresolved questions and issues that have 5 arisen in this assessment which beg for explicit consideration in the context of an 6 uncertainty analysis. In its discussion of the other charge questions, the Panel has 7 identified a number of important issues that should be addressed in an eventual 8 uncertainty analysis. 9 10 Other methods to be considered 11 12 The Panel found that relevant Bayesian methods have been inadequately 13 addressed and improperly dismissed in Section 6. In particular, methods that should be 14 given a more extensive and balanced discussion with more citations to the literature 15 include: 1) Bayesian hierarchical modeling (Axelrad et al., 2007; Choi et al., 2010; Coull 16 et al., 2003; Ryan, 2008) which is used for combining information from multiple studies, 17 and 2) Bayesian model averaging (Morales et al., 2006; Viallefont et al., 201l; Wheeler 18 and Bailer 2007, 2009) which would be useful for considering more than one dose19 response equation, while allowing the data to weight their relative likelihood and 20 contribution to the estimate. These Bayesian methods should not be referred to as 21 "exotic." For example, in agreeing with the Section 6 authors that these methods should 22 be pursued in ongoing and future case studies, White et al. (2009) refer to them as 23 "advanced," rather than exotic. Specifically, they recommend that health scientists 24 should explore statistical approaches to model selection and suggest that "improvements 25 to statistical approaches for model selection, such as model averaging, should be pursued. 26 Case study applications of these advanced statistical approaches will identify potential 27 strengths and weaknesses of the approaches and their significance for risk 28 characterization" (White et al., 2009). 29 30 Recommendations 31 32 The Panel recommends that EPA revise Section 6 of the Report because, as 33 discussed above, the arguments in this section are not scientifically justified. In 34 particular, EPA should consider revising its argument that quantitative uncertainty 35 analysis is unfeasible for the dioxin assessment. Specific suggestions regarding 36 feasible methods for quantitative uncertainty analysis are provided herein. 37 38 6.2. Please comment on EPA's overall conclusion that a comprehensive quantitative 39 uncertainty analysis is notfeasible. 40 41 Response: 42 43 The Panel rejects EPA's argument that a quantitative uncertainty analysis is 44 unfeasible. Although a quantitative uncertainty analysis is challenging, the Panel does 45 not agree that it is impossible or even impractical to undertake one. While it may well be 44 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 true that we lack an adequate empirical basis for full Monte-Carlo propagation of input 2 distributions, there are many other options available. Many on the Panel indicated that 3 the present circumstances warrant a compromise approach that would be simple and 4 achievable with modest effort by the Agency. Various bounding approaches, sensitivity 5 studies, uncertainty set analyses, and event trees (probability trees without the 6 probabilities) are suggested as possible approaches that could be used. With such 7 methods, legitimate and comprehensive uncertainty analyses (including even fully 8 probabilistic analyses) are possible. They would be useful and sufficient to respond to 9 NAS' criticism. 10 11 The Panel agrees with EPA's assertion that expert elicitation would be 12 problematic and should be "off the table." However, many on the Panel further 13 suggested that value-of-information methods would also be very useful, although 14 feedback from EPA included reservations about this idea. A discussion of value of 15 information methods is provided in Appendix B of this report. 16 17 The Panel considered the use of bounding approaches for quantitative uncertainty 18 analysis and asked EPA to provide information about the limitations of bounding 19 approaches. In response, EPA asked Dr. Roger Cooke to send the Panel a document on 20 bounding analysis. The short bounding analysis document provided to the Panel by Dr. 21 Cooke focused on the features of interval analysis, although this is not by any means the 22 only approach that might be useful in the context of the dioxin assessment. The bounding 23 analysis document mentions one issue that could be construed as a disadvantage of this 24 simplest bounding approach. It is the idea that the ranges are supposed to be absolute 25 bounds on the possible values of each input variable. So, for instance, the only thing one 26 can say about a percentage is that it is between zero and 100%, or the only thing one can 27 say about a dispersal distance is that it is between zero and the circumference of the Earth 28 (these are Dr. Cooke's examples). But the Panel finds that this criticism seems to 29 represent a misunderstanding of the word "absolute." Vacuous (e.g., physically limiting) 30 bounds are not the only bounds that can be used in interval analysis. In fact, they are 31 meant to be informed by observed study results. Furthermore, one is not necessarily 32 limited to interval ranges and interval analysis. 33 34 The Panel suggests that there are in fact a variety of methods that, with proper 35 application, could be useful and informative, including: 36 37 Sensitivity analysis studies (even if not completely comprehensive) (Saltelli et 38 al., 2000a,b; Frey and Patil, 2002), 39 Interval analysis (Moore 1966; Neumaier, 1990) which has been widely used for 40 decades and can be applied to complex models and even blackbox models (Trejo 41 and Kreinovich, 2001), 42 Nesting of intervals, e.g., two levels, wide and narrow can give conservative and 43 optimistic characterizations of overall uncertainty (van Frassen, 1966, 1980), 45 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Probability bounds analysis (Ferson and Long, 1995; Ferson et al., 2003) 2 including Bayesian p-boxes (Montgomery, 2009), which has been used in a 3 variety of applications (Aughenbaugh and Paredis, 2007; Dixon, 2007; Karanki et 4 al., 2009; Minnery et al., 2009; Regan et al., 2002a,b), including assessments at 5 two Superfund sites (EPA, 2007, 2002-2005), 6 Info-gap decision theory (Ben-Haim, 2006) which has been used in several 7 applications, (Davidovitch et al., 2009; Hall and Harvey, 2009; Regan et al., 2005; 8 Rout et al., 2009; Yokomizo, 2009), 9 Robust optimization (Bertsimas and Brown, 2009; Bertsimas et al., 2009; 10 Bertsimas et al., 2010; Ben-Tal et al., 2010), and 11 Probability trees, which are distributional methods for considering alternative 12 assumptions and models at various stages of the toxicity assessment. Small 13 (2008) explains that the distributional approach for characterizing uncertainty in 14 cancer risk assessment was developed by Evans, Sielken, and co-workers 15 beginning in the 1990s (Holland and Sielken, 1993; Evans et al., 1994a,b, 1995; 16 Sielken, 1990, 1993; Sielken and Valdez-Flores, 1996, 1999; Sielken et al., 1995) 17 and has also been referred to as information analysis, weight-of-evidence analysis, 18 the comprehensive methodology, and comprehensive realism (Sielken, 1990; 19 Sielken et al.,1995, 1996). The method has since been acknowledged in a number 20 of reviews of cancer risk assessment practice and research needs (Boyce, 1998; 21 Moschandreas and Karuchit, 2002; Zeise et al., 2002), and applied in various 22 forms for risk assessment of different chemical compounds (Humphreys et al., 23 2001; Rai et al., 2002; Kirman et al., 2004; Starr et al., 2006; David et al., 2006; 24 Crump, 1994). The distributional approach enables consideration of a "portfolio25 of-mechanisms" that may contribute to carcinogenesis (Cox, 2006). 26 27 These methods are nontrivial and potentially valuable alternatives to traditional 28 probabilistic uncertainty analysis, and they are able to provide insights on critical 29 uncertainties in the assessment endpoints and the ongoing and future research needed to 30 achieve their resolution. The motivation for all of these approaches is the recognition 31 that the use of a single set of assumptions for the components of a cancer risk assessment, 32 whether default, conservative, or otherwise, fails to capture the full range of plausible or 33 likely relationships, how these relationships depend upon our current state of knowledge, 34 the implications for computed values of potency or unit risk, and the opportunities for 35 improved estimates. The methods require modeling judgment as any analysis does, but 36 they can provide a basis for ongoing integration and value of information assessment as 37 new studies and knowledge accumulate over time (Brusick et al., 2008). These methods 38 can at least provide useful bounds on the plausible risks and on the value of information 39 (VOI) of reducing uncertainties further (especially, perhaps, on whether the dose40 response relation has a threshold). 41 42 There are, of course, many significant benefits to undertaking a quantitative 43 uncertainty analysis. Although a completely comprehensive analysis might indeed be too 44 much to expect, it is possible and practical to provide readers with much more useful 46 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 information about uncertainty. A policy maker might reasonably expect the Report to 2 provide insight into major uncertainties and questions such as the following: 3 4 How likely is it that TCDD is not a human carcinogen at current exposure levels? 5 Full discussion of this uncertainty may help to overcome probability neglect and 6 action bias (Patt and Zeckhauser, 2000). 7 How likely is it that TCDD at current exposure levels has health effects that have 8 not yet been identified in the toxicological or epidemiological literature 9 (Diamanti-Kandarakis et al., 2009; Soto and Sonnenschein, 2010)? 10 What is the probability that reducing TCDD exposures would not reduce cancer 11 risk at all, or only by amounts that would not be measurable, based on recent 12 epidemiological studies and updates such as Pesatori et al. (2009)? 13 What is the probability that reducing TCDD exposures would reduce cancer risk 14 in the whole U.S. population, or targeted subpopulations, by amounts significantly 15 greater than a prediction derived from the cancer slope factor estimated by EPA? 16 What is the probability that reducing TCDD exposures would increase cancer risk 17 (e.g., if the dose-response relation is J-shaped or U-shaped)? 18 What is the decision-analytic value of information (VoI) from collecting more 19 information on AhR kinetics and dose-response before making risk management 20 decisions? 21 What is the probability that TCDD interacts with other compounds to which U.S. 22 or targeted subpopulations are exposed, increasing cumulative risk for cancer or 23 other health effects (Carpenter et al., 2002)? 24 25 Although many members of the public believe that it is imprudent or even 26 morally wrong to delay tighter regulation of TCDD exposures (perhaps reflecting beliefs 27 that TCDD is a potent carcinogen, developmental toxin, etc.) many on the Panel felt that 28 EPA should provide a thorough quantitative decision analysis that makes explicit the 29 current uncertainties and trade-offs and that shows the conditions under which acting now 30 or postponing action are the optimal actions. Without such quantitative analysis, risk 31 management decisions for TCDD will not be adequately informed, and principles other 32 than those of rational decision making (e.g., the biases discussed in Sunstein and 33 Zeckhauser, 2010) may dominate risk management decisions for TCDD. EPA's 34 uncertainty analysis should provide the scientific basis for improved decision making. 35 The current decision, in effect, to "punt" on quantitative uncertainty analysis is not 36 adequate for informing responsible risk management decision and policy-making, and is 37 not justified. 38 39 Recommendations 40 41 The Panel recommends that EPA reconsider the argument for not doing a 42 quantitative uncertainty analysis, or undertake one. EPA could follow the 43 recommendation of the NAS on this point by using one or more of the techniques 44 suggested above. 47 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 6.2a. Please comment on the discussion in Section 6 regarding volitional uncertainty 3 and how this type of uncertainty limits the ability to conduct a quantitative 4 uncertainty analysis. 5 6 Response: 7 8 In the Report, EPA contrasts volitional uncertainty with cognitive uncertainty. 9 The Panel recommends that the term "volitional uncertainty," which might also have 10 been called "decisional uncertainty," should be dropped from the Report. EPA should 11 focus instead on uncertainties about the state of world and display the different modeling 12 choices and the consequences of making them. The decisions mentioned in the 13 discussion in Section 6 of volitional uncertainty are modeling choices, and they should be 14 dealt with using techniques for model uncertainty. Standard tools and techniques for 15 analysis of model uncertainty can be applied. 16 17 Recommendations 18 19 The Panel recommends that EPA delete from the Report the notion of "volitional 20 uncertainty." EPA should display the different modeling choices and the 21 consequences of making them. 22 23 6.3. Throughout the document (including the Appendices), EPA presents a number o f 24 limited sensitivity analyses (e.g., toxicokinetic modeling, RfD ranges, cancer OSF 25 ranges, cancer RfD development). Please comment on the approaches used, and 26 the utility o f these sensitivity analyses in clarifyingpotential significant 27 uncertainties. 28 29 Response: 30 31 The Panel congratulates EPA on the sensitivity studies that it has already done 32 and considers them to be very useful. The Panel felt these studies should be integrated 33 and unified in an overall uncertainty analysis. The Panel emphasizes that EPA has 34 already done the lion's share of the effort needed in their considerations described in the 35 uncertainty narratives. The Panel feels the agency should take credit for this hard work 36 and extend the sensitivity studies to respond fully to the NAS criticism. 37 38 The Panel is mindful of the need to minimize further delay of the finalization of 39 this already protracted dioxin assessment. The work the EPA has already done in the 40 sensitivity studies should be leveraged to hasten the completion of whatever uncertainty 41 analysis EPA elects to undertake. 42 43 44 45 48 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Recommendations 2 3 The Panel recommends that sensitivity studies that have already been completed 4 be integrated into whatever overall uncertainty analysis EPA elects to undertake. 5 6 7 8 9 49 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 REFERENCES 2 3 Abbaspour, K. C., R. Schulin., E. Schlappi and H. Fluhler 1996. A Bayesian approach for 4 incorporating uncertainty and data worth in environmental projects. Environmental 5 Modeling and Assessment 1: 151-158. 6 7 Anbalagan, J, A.M. Sashi, G. Vengatesh, J.A. Stanley, R. Neelamohan, and M.M. 8 Aruldhas. 2010. Mechanism underlying transient gestational-onset hypothyroidism9 induced impairment of posttesticular sperm maturation in adult rats. Fertility and Sterility 10 93(8): 2491-2497. 11 12 Andersen, M.E., and H.A. Barton. 1999. 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Several documents available online at 3 http://www.epa.gov/region1/ge/thesite/restofriver-reports.html describing the U.S. EPA's 4 use of probability bounds analysis in the "rest of river" component of the assessment for 5 the GE/Housatonic River Site in New England, including both the Ecological Risk 6 Assessment and the Human Health Risk Assessment. 7 8 EPA (U.S. Environmental Protection Agency). 2006. Aframeworkfor assessing health 9 risks of environmental exposures to children. EPA/600/R-05/093F, National Center for 10 Environmental Assessment, Office of Research and Development, Washington, D.C. 11 12 EPA (U. S. Environmental Protection Agency). 2007. Region 6 SuperfundProgram: 13 Calcasieu Estuary Initiative. http://www.epa.gov/earth1r6/6sf/sfsites/calcinit.htm, 14 [accessed July 2009] 15 16 EPA (U.S. Environmental Protection Agency). 2010. EPA's Reanalysis of key issues 17 related to dioxin toxicity and response to NAS comments. 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Murphy and R.W. Katz (eds.), 493 38 524, Westview Press, Boulder, CO, 39 40 Yokomizo, H., H.P. Possingham, M.B. Thomas, and Y.M. Buckley. 2009. Managing the 41 impact of invasive species: the value of knowing the density-impact curve. Ecological 42 Applications 19(2):376-386. 43 44 Yr, J. 2008. Neuro-developmental deficits in early-treated congenital hypothyroidism. 45 Annals of the Academy ofMedicine, Singapore 37,Supp. 12:42-43. 61 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Yoshizawa, K., A.E. Brix, DM. Sells, M.P. Jokinen, M. Wyde, DP. Orzech, G.E. 3 Kissling, N.J. Walker, and A. Nyska. 2009. Reproductive lesions in female Harlan 4 Sprague-Dawley rats following two-year oral treatment with dioxin and dioxin-like 5 compounds. Toxicologic Pathology 37(7):921-937. 6 7 Yoshizawa, K., N.J. Walker, A. Nyska, G.E. 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This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Appendix A: Dissenting Opinion from Karl Rozman, Ph.D. 2 The University of Kansas Medical Center Karl K. Rozman, Ph D. Professor School of Medicine Department of Pharmacology, Toxicology and Therapeutics Thomas Armitage, Ph.D. Designated Federal Officer USEPA Science Advisory Board (1400R) 1200 Pennsylvania Ave., N.W. Washington, D.C. 20460 December 9, 2010 RE: A Dissenting Opinion Dear Tom, As I have indicated in my previous written and oral opinions to this panel, I disagree with the panel conclusions regarding the carcinogenicity of TCDD and the adequacy o f the EPA response to the criticisms of the NAS report. There is at best equivocal evidence (statistically not significant) for the carcinogenicity of TCDD (or DLCs) in the occupational setting where the body burdens were at least 100 or 1000 times higher than the current or previous background levels. Therefore, the consideration of a practical threshold for any defined population requires acceptance of the compelling scientific conclusion that there is negligible (essentially zero) carcinogenic risk at current background levels which are much lower than past levels. Any other conclusion is incompatible with sound science and no amount of modeling or data manipulation will transform a non-existing effect at occupational exposure levels into a risk at current background levels other than the non scientific, policy-driven, non-threshold extrapolation by EPA. Further, it is my opinion that the EPA document (2010 Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments, 600/-10/038A) is deliberately non responsive to the recommendations of the NAS report. Respectfully, Karl K.Rozman, Ph.D., D.A.B.T. Professor 3901 Rainbow Blvd., MS1018, Kansas City, KS 66160 (913) 588-7717 FAX (913) 588-7501 krozman@kumc.edu 3 A-1 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Appendix B: Value of Information 2 3 When human health risk assessments include an explicit representation of 4 uncertainty, the potential value of new information (VOI) can be estimated by its ability 5 to reduce uncertainties that matter most to the assessment target. While methods for 6 determining VOI are most commonly associated with the decision analysis literature in 7 the context of informing management or regulatory decisions (Raiffa, 1968; Keeney, 8 1982; Winkler and Murphy, 1985; Finkel and Evans, 1987; Taylor et al., 1993; Clemen, 9 1996; Chao and Hobbs, 1997), there are many steps in a scientific assessment well before 10 (or even without subsequent) decision support and decision making where VOI 11 evaluations can be of benefit in characterizing current scientific knowledge and the 12 potential for its improvement. EPA should integrate these methods into their current and 13 ongoing assessments of dioxin toxicity. 14 When uncertainty in a scientific assessment is measured by the variance of model 15 predictions, a first measure of VOI is the extent to which this variance might be reduced 16 by new or additional data (e.g., Patwardhan and Small, 1992; Brand and Small, 1995; 17 Abbaspour et al., 1996; Chao and Hobbs, 1997; Sohn et al., 2000; Bosgra et al., 2005; 18 Cooke, 2009). The relative contribution of different model assumptions and parameter 19 uncertainties to the variance of the estimated effect (e.g., the BMD), or the cancer slope 20 factor) provides an indication of which of these uncertainties would be most beneficial to 21 address. In addition, a VOI assessment considers the potential for the component 22 uncertainties to be reduced, based on the feasibility, resource requirements (time and 23 funding), and likelihood of success of the studies that would be needed to achieve the 24 necessary improvement in scientific knowledge. 25 26 A scientific VOI study may also target a key classification inference that results 27 from a risk assessment, for example, whether a compound is genotoxic. Assuming the 28 current assessment leads one to assign an inconclusive probability to this outcome (e.g., 29 between 10% and 90%, so that neither inference can be rejected with a high degree of 30 confidence), then potentially valuable studies are those able to shift subsequent 31 probabilities to high values (e.g., above 90, 95, or 99%) with a positive result (e.g., 32 providing support for genotoxicity) and/or to low values (below 10, 5, or 1%) with a 33 negative result. 34 35 To illustrate, Small (2008) presents a simple probability tree model (a 36 "distributional approach") for assessing genotoxicity based on studies of DNA damage 37 response caused by naphthalene and its metabolites. In the proposed studies a series of 38 isogenic cell lines deficient in various DNA metabolism pathways are used to 39 characterize the DNA damage responses caused by the targeted compounds. Following 40 results from the cultured cells, mice deficient in the specific DNA damage responses 41 would be exposed to naphthalene. Possible inferences are identified based on the 42 assessed sensitivity and selectivity of study results to the genotoxicity of naphthalene. 43 Study outcomes considered include: i) DNA damage responses in the isogenic cells; ii) 44 increased numbers of stable DNA adducts in the DNA repair deficient mouse lung; and B-1 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 iii) heightened Clara cell toxicity in the DNA repair deficient mouse lung. Illustrative 2 results using Netica are presented as follows: 3 <[ (a) Prior probabilities )> Fig. 5. Illustrative consideration of selected experimental results for naphthalene Study IV (outcomes assumed independent, prior probability of genotoxicity set to 0.5. and sensitivities and selcctivities chosen by author solely for illustration of methodology): (A) Prior probability before study: (B) Positive outcomes for both study results; and (C) Positive results for cell DNA damage, but negative results for increased tumors in DNA repair-deficient mouse. <C (b) Both results positive 4 5 As noted, the results shown above are intended solely to demonstrate the way in which 6 study results can be combined to support or refute targeted inferences. 7 8 Even when the uncertainty tree method is only used to delineate the set of 9 possible outcomes and relationships among steps and assumptions in the risk assessment 10 (i.e., mode of action; dosimetry measures for exposure; the mathematical form of the 11 dose-response relationship; the experimental data set(s) used to fit the relationship; and 12 the procedure used for interspecies extrapolation) without the assignment o fprobabilities 13 to the tree branches, key assumptions and the experiments needed to support or refute 14 them can still be identified. These will typically involve elements of the assessment that, 15 depending on their resolution, effectively restrict the set of possible outcomes to either a 16 positive or a negative inference regarding the endpoint of the risk assessment. 17 Establishing a procedure of this type will allow the Agency to put in place a more formal 18 mechanism for identifying, conducting, and integrating the results of key studies for 19 future assessments. B-2 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Appendix C: Editorial Comments and Corrections 2 3 a. Section 2 4 5 Minor suggestions to further improve clarity regarding data set inclusion/exclusion 6 criteria 7 8 Page xxxvii, Lines 16-19. The sentence needs clarification. It currently gives the 9 impression that studies that were eliminated for further analysis would have NOAELs 10 available. 11 Pages 2-234 - 2-247. EPA should consider adding information to the appendices and/or 12 tables to provide readers with clarification regarding the exclusion of particular studies. 13 For example, an extra column in Table 2-7 listing, by numbered reference, the criteria 14 that were or were not met for each study would be helpful. 15 16 b. Section 6 17 18 Page 6-2. Add NRC (1996). 19 20 Page 6-3, bottom: The word "margins" should be "marginals." 21 22 Page 6-3, line 26: If EPA wants to use the adverb "always", the phrase "as a joint 23 distribution" should be "as some characterization of a joint distribution" to be correct. 24 25 Page 6-4, lines 9-12: This text is strange and off-putting. A reader might ask who wrote 26 this and why. It seems opinionated and unnecessary. 27 28 Page 6-4, line 9: The tone is too pedagogical ("This is not the place . . ."). 29 30 Footnote 54: The discussion of alternatives to strict, single-measure probability theory is 31 ham-handed. Neither interval probabilities nor imprecise probabilities (sensu Walley, 32 1991) depart from probability theory; they follow the Kolmogorov axioms. They are 33 motivationally and essentially equivalent to sensitivity analyses, except they do not make 34 use of sampling strategies and can be more comprehensive. 35 36 Lines 29-30: It is simply untrue that sensitivity analyses have to be systematic. The 37 word "systematic" might better be "comprehensive" and the word "essential" should be 38 weakened, perhaps to "advantageous". 39 40 Page 6-5, lines 4-7 and footnote 55: There seem to be only two axioms mentioned in the 41 text, but Kolmogorov needs three to make probability theory. 42 43 Page 6-5: The meaning of the phrase "epistemic uncertainty" given on this page is 44 plainly incorrect. Epistemic uncertainty is the uncertainty that arises from imperfect C-1 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 knowledge such as from limitations on the amount or quality of data available or 2 deficiencies in our causal understanding about a system. It is not true that a quantity 3 about which there is epistemic uncertainty is necessarily fixed. Although it is perhaps 4 clear how one might come to this mistaken impression, no researchers use the phrase to 5 imply that the underlying quantity has no variability (although all would admit that this 6 could be the case given our ignorance about it). Indeed, a variable can have both forms 7 of uncertainty. For example, when body weight varies across a population, but with a 8 distribution that is unknown, the variable has both aleatory and epistemic uncertainty. 9 This mistake echoes in a couple of other places throughout this section. 10 11 It is not clear what the authors take to be the difference between epistemic uncertainty 12 and what they call "cognitive uncertainty." It seems that the latter phrase was introduced 13 because the meaning of "epistemic uncertainty" had been misunderstood. Normally, the 14 phrase "cognitive uncertainty" would refer to an individual person's uncertainty about the 15 validity of the results of his or her own information processing. The assertion that 16 cognitive uncertainty may be represented by probability (i.e., by precise probability 17 measures) is unnecessary and may be misleading. In fact, researchers in human cognition 18 and neuroscience have shown that humans process this kind of uncertainty (which they 19 often call "ambiguity") separately and differently from what we think of as probability or 20 frequentist risk (Hsu et al., 2005; Glimcher, 2003). The section can omit the phrase 21 "cognitive uncertainty" altogether and use in its place "epistemic uncertainty." There are 22 slight differences between the two ideas (e.g., epistemic uncertainty could be shared by 23 members in a group, whereas cognitive uncertainty is always personal), but these appear 24 to be unimportant in this context. 25 26 Page 6-5: The words "aleatoric" and "aleatory" are both used on this page as 27 (synonymous) adjectives of uncertainty. Actually, in the engineering literature, only 28 "aleatory" is preferred for this use. In any case, please pick one to use. 29 30 Page 6-5, line 10: The assertion that the frequentist and Bayesian interpretations are not 31 mutually exclusive may be misleading. They are mutually exclusive in the sense that it 32 would be improper to mix and match components of each into an analysis. It would be 33 appropriate to omit the clause with the phrase "mutually exclusive," although it is surely 34 fair to say that subjective probabilities can and do track relative frequencies. 35 36 Page 6-5, lines 30-32: The text on the subject of dependence is strange here, and also in 37 section 6.I.3.3. It is incorrect that the "[i]ssues involving...epistemic and aleatory 38 uncertainty translate into issues of dependence." This is just wrong (even under their 39 unusual definition of "epistemic"). 40 41 Page 6-6: Section 6.1.3.2 starting on this page discusses a way to address uncertainty for 42 sample data. This Spartan treatment does not mention that sampling uncertainty is not 43 the only kind of uncertainty that can be associated with data, nor that it may not even be 44 the largest kind of uncertainty. Mensurational uncertainty (including the plus-minus part 45 of a measurement, and censoring) may be more important. In some cases, the family or C-2 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 shape of the marginal distribution may be unknown, which is a kind of model 2 uncertainty. As suggested on page 6-35, such uncertainties can be significant. The 3 section suggests only a resampling approach to expressing the uncertainty, but fails to 4 mention the often severe limitations of such approaches, and says nothing about what one 5 might do if there is no relevant sample data. 6 7 Page 6-6, line 20: Maybe the last word of the header should be plural. 8 9 Line 21: Modern practice has replaced "error" with "uncertainty" in this context. 10 11 Footnote 56: EPA could add "or subtracting" after "adding." 12 13 Page 6-7, line 14: "The role of dependence modeling" should be replaced with 14 "Dependence among variables." 15 16 Page 6-7. More examples of use of expert judgment for health assessment are available 17 and should be cited. 18 19 Page 6-7, last paragraph: This paragraph extending onto the next page should be 20 rewritten. The example is reasonable and important, but the discussion about it is 21 confused. The first sentence is incorrect. The uncertainty mentioned in the second 22 sentence may be epistemic, but the sentence is erroneous in its claim. In the following 23 sentences, the words "variable" and "fixed" (or "constant") should be used rather than 24 "aleatoric" and "epistemic." It is nonsense to say that a kinetic constant is "completely 25 correlated across individuals." It's not correlated; it is invariant. This case is not an 26 example of a dependence issue. There is no correlation between a distribution and a 27 fixed quantity (even if it's uncertain). Correlation is defined between varying quantities. 28 If the number is fixed, whether or not we know what it is, then one cannot say it is 29 correlated with anything. The authors may have come to this twisted language because 30 they're thinking of the uncertainties in terms of how they might plan to quantitatively 31 characterize them in a Monte Carlo simulation (repeatedly selecting a random deviate for 32 the kinetic constant but assigning it to every individual). Of course, variables such as 33 body fat, age, and smoking, on the other hand, can and do exhibit correlations that 34 definitely should be accounted for in the quantitative assessments. Likewise, it is also 35 important to keep track of the constancy of particular quantities about which we may not 36 know the precise value. These two issues should be untangled and discussed in a less 37 confusing way. 38 39 Page 6-8, line 12: The first paragraph of section 6.1.3.4 seems to be saying that one can 40 sometimes express model uncertainty as parametric uncertainty, which simplifies its 41 handling. This could be said more plainly. It would be helpful to mention that this trick 42 cannot always be used (as when the possible models cannot be listed). It might also be 43 especially helpful to mention that this trick is not so much a way to propagate model 44 uncertainty as a way to sweep it under the rug. Model averaging, including Bayesian 45 model averaging (which is mentioned in several places, including 6-36, lines 3ff), erases C-3 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 model uncertainty in the same way that averaging variable quantities erases their 2 variation. 3 4 Page 6-8. line 13: Omit the unnecessary fancy after the semicolon. 5 6 Lines 15-17: This sentence is nonsense, if we understand what a linear low-dose model 7 is. Parsing the sentence, it seems to say "uncertainty over a...slope...may be quantified, 8 but uncertainty...in slope...cannot be captured" which is self-contradictory. Perhaps 9 what the authors mean to say is that the linearity assumption is not itself subject to 10 uncertainty quantification. 11 12 Page 6-9, line 1: The mathematical symbol x should be italicized, as should all Roman 13 letters throughout the document that represent unknown quantities, i.e., are symbols 14 representing something else rather than names like "e" the base of the natural logarithms. 15 16 Lines 14 and 16: The prefixes "pseudo" and "quasi" are not words. Hyphens are needed. 17 18 Page 6-9, line 18: Provide citations for dependence modeling. 19 20 Page 6-9: Section 6.1.3.6 might also mention graphs, and other traditional 21 communication tools other than correlation indices. 22 23 Page 6-10, line 4: Add mention of methods that identify uncertain assumptions or 24 parameters that are important for determining whether the model is consistent with 25 observed data (Hornberger and Spear, 1983) and for affecting a decision that is made as a 26 result of the model (Merz et al., 2009). 27 28 Page 6-10, lines 29-30: Do the authors mean "this probabilistic language," referring to 29 the word "likely" in the quoted text? 30 31 Page 6-11, line 19: Of course there is no guarantee that linear will be protective. 32 33 Page 6-13, line 18: Of course it isn't really apodictic knowledge at all, but rather only an 34 opinion or an assumption. We see the authors' point and agree with it entirely, but 35 perhaps they should use a word other than "apodictic" here since it's not technically 36 correct. 37 38 Page 6-14, lines 33-34: The parenthetical phrase "volitional uncertainty" should be 39 expanded into a sentence that says what the authors mean to express. The phrase 40 "cognitive uncertainty" does not mean anything in this context. Perhaps if the authors 41 expanded it into a sentence too, maybe making it "epistemic uncertainty" along the way, 42 it would be possible to understand what they are trying to say here. 43 44 Footnote 62: "Effective" is misspelled, as is "cancer." 45 C-4 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Page 6-16, line 5: We note that it's not really a guarantee of course. 2 3 Line 8: The word "common" should be "predominant". 4 5 Page 6-16, line 20: Perhaps we can say that variability (and uncertainty) in the factors 6 that are used to determine a particular UF can be considered in choosing the particular 7 value of the UF. 8 9 Page 6-17, lines 3-14: This problem can be addressed using a Bayesian analysis with a 10 beta conjugate for the uncertain response probability, p, with uniformative (uniform) 11 prior forp. The probability that "an experiment with a null response might have yielded 12 a positive response" can be estimated from the predictive distribution (which will depend 13 on the number of test animals in the original study that yielded zero responses) for the 14 next experiment (with any number of exposed animals). 15 16 Page 6-17, line 28: The word "band" should be "limit". 17 18 Page 6-20, footnote 66: The text starting "each have an error factor" should be followed 19 by "o f rather than "or". 20 21 Page 6-21, line 6: It would be helpful to say something about what the concerns are. 22 23 Page 6-21, lines12-14: NAS was not suggesting that EPA use the uncertaintyfactors 24 approach to mount an uncertainty analysis, but rather a more modern approach. 25 26 Page 6-22, line 19: Would it be appropriate to note "and establishes a concomitant 27 reduction in some UFs?" 28 29 Line 29: The word "invokes" should perhaps be "would require". 30 31 Page 6-23, line 33 and passim: The word "exotic" is a poor choice that is unnecessarily 32 and transparently loaded. 33 34 Page 6-25, line 29: This sentence is ungrammatical. 35 36 Page 6-26, line 24 and Figure 6-1: Would it be helpful to draw the 45-degree line on the 37 graph? 38 39 Page 6-27, line 10: The word "epistemic" here is acceptable. 40 41 Line 14: The word "epistemic" here should be replaced by "fixed across individuals," 42 and " is estimated from" should be replace by "varies with." How does half life's 43 estimability from data imply that it is variable? 44 45 Page 6-28, lines 1-2: One would need the dependence between the variables to proceed. C-5 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Line 9: We suggest that "and" should be "although." 3 4 Page 6-29, line 1-2: There are bounding techniques based on the classical Frechet 5 inequality that do not require any knowledge of or any assumptions about dependencies. 6 7 Line 32: Omit "to." 8 9 Page 6-31, line 24: The pessimistic conclusion is a bit strong. Any estimate made from 10 data is amenable to a quantitative uncertainty analysis so, if one is measuring anything, 11 one can propagate uncertainties such as mensurational uncertainty, sampling uncertainty, 12 and perhaps even surrogacy uncertainty. It's not quite as hard to get quantitative models 13 as the text here seems to suggest. 14 15 Page 6-32, lines 13-14: The dour conclusion is confusing. One could do a sensitivity 16 analysis in this case, couldn't one? If so, it seems that some kind of uncertainty analysis 17 is clearly possible. 18 19 Page 6-33: The example in the text box is great, but the second table seems to say the 20 log-likelihood for LLD is 2.46 and for Hill is 2.16, which would make LLD's larger than 21 Hill's, which contradicts what's said in the text. 22 23 Page 6-34, line 4: Shouldn't "Delivereddose" be a new bullet? 24 25 Line 8: We don't think this statement is true. Perhaps "statistically more powerful" 26 should be "typically yield more sensitive". 27 28 Lines 24-25: We don't think it is necessary or helpful to persist with Box's platitude. 29 Model uncertainty is the uncertainty about a model's predictions that arises from doubt 30 about the relevance of that model for making such predictions. 31 32 Page 6-37, line 29: The caveat is overwrought. Exploring relevant alternative values in a 33 sensitivity analysis could constitute a quantitative uncertainty analysis, even if the 34 exploration is limited. 35 36 Page 6-37, line 30: This sentence is false. Analytical methods of propagation 37 (convolution) don't "sample" anything, and analyses based on intervals or imprecise 38 probabilities don't depend on uncertainty "distributions" (i.e., precise probability 39 distributions). 40 41 It is important to keep in mind that, in general, we are not necessarily limited to 42 identifying precise probability distributions for everything that is to be characterized as 43 uncertain (as seems to be suggested here). Simple intervals about uncertain quantities 44 can support a straightforward, albeit crude, interval analysis that propagates uncertainty 45 about parameters and other model choices to statements about the range of possible C-6 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 results. Similarly, an approach based on interval probabilities, probability boxes, or 2 general imprecise probabilities (Walley,1991) can combine such intervals with precise 3 distributions if they are known for some other inputs, and with structures that are 4 intermediate between coarse intervals and delicate probability distributions when some 5 but incomplete knowledge is available. If the inputs are profoundly uncertain, the results 6 from such analyses are likely to be wide in reflection of these uncertainties. In almost all 7 cases, it is possible to be entirely rigorous without necessarily being precise and without 8 completely specifying each probability distribution. 9 10 Page 6-37, line 31: There does not need to be a specified "underlying distribution from 11 which to sample" in order to conduct a quantitative uncertainty analysis. It is facile to 12 shrug off a call to characterize and account for important uncertainties in the assessment 13 process on these grounds alone. Even when the uncertainty is volitional, there can be 14 relevant ranges that are interesting to decision makers and stakeholders. In such cases, 15 the analysis may be formally closer to a sensitivity analysis, but some appropriate 16 response is usually possible, if not always practicable. To their credit, EPA has 17 acknowledged the legitimacy of the call and undertaken some efforts in this direction, 18 notably Tables 5-18 and 5-19 (although some kind of graphical summary of the results 19 might have been better). 20 21 Page 6-38, line 30 and passim: The adjective "data driven" needs a hyphen, as it has 22 elsewhere in the document. 23 24 Line 23-24: We think this sentence is true, but, again, sampling from a distribution is not 25 the only way to conduct a quantitative uncertainty analysis. 26 27 Line 26: What is "(2.a)?" 28 29 Page 6-41, line 23: Omitting the word "extra" would make the sentence more easily 30 understandable. 31 32 Line 31: What does "How Forward?" mean? Is this idiomatic? 33 34 Section 6.5.2: The assertions in this section are rather surprising and questionable. EPA 35 says that uncertainty quantification is an "emerging area in science" and that it is "an area 36 where research could be focused" because "the requisite knowledge does not yet exist" to 37 apply quantitative uncertainty analysis in assessments such as this one for dioxin. The 38 document peremptorily dismisses the utility of "convening a blue-ribbon panel" to 39 identify the proper approach and suggests instead that "multiple approaches should be 40 encouraged." Is the inference that the present review panel shouldn't try to say what the 41 proper approaches to uncertainty quantification are, even if we think the area is more 42 mature than emerging? It is hard to understand what these statements are suggesting. 43 Will the Agency support intramural and extramural research efforts in this direction? If 44 not, what do the statements mean? Is it impossible that EPA could benefit from some 45 tech transfer efforts as well as basic research on uncertainty quantification? The C-7 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 paragraph beginning on page 6-42 (line 3) mentions a European idea of bench-test 2 exercises to compare different approaches. It may be worth mentioning that this idea has 3 been implemented in the United States as well (Oberkampf et al., 2004; Ferson et al., 4 2004). 5 6 The document's reference list is alphabetically arranged, but seems to go from Z back to 7 A again on page R-33. C-8 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 Appendix D: EPA's Charge Questions UNITED STATES ENVIRONMENTAL PROTECTION AGENCY NATIONAL CENTER FOR ENVIRONMENTAL ASSESSMENT WASHINGTON, DC 20460 MEMORANDUM May 27,2010 OFFICE OF RESEARCH AND DEVELOPMENT SUBJECT: Request for Science Advisory Board Review of the Draft Report, "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments" FROM: Becki Clark, Deputy Director National Center for Environmental Assessment (860IP) Office o f Research and Development TO: Vanessa T. Vu, Ph.D., Director EPA Science Advisory Board (1400F) This is to request a review by the Science Advisory Board of the draft report entitled "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments" (EPA/600/R-10/038A). This draft report details the Environmental Protection Agency's (EPA) response to key comments and recommendations included in the 2006 NAS report ("Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment") on their review of the (EPA) 2003 draft dioxin reassessment. This draft report also includes significant new analyses on both the potential cancer and noncancer human health effects that may result from chronic exposures to dioxins. Attached is the Charge that provides background information as well as questions that are to be the focus of the Science Advisory Board review of this draft report. Please let me know if you have any questions. Thank you. Attachment: Charge for EPA's Science Advisory Board - Review of the Draft Report, "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments" cc: Peter W. Preuss Annette Gatchett Glenn Rice Cheryl Itkin 2 D-1 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 Proposed Charge to the Science Advisory Board for Peer Review Of Draft Report 3 "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity 4 and Response to NAS Comments" 5 May, 2010 6 7 EPA has been preparing an assessment of the potential health impacts of 2,3,7,88 Tetrachlorodibenzo-p-Dioxin (TCDD) for many years. In 2003, EPA released an 9 external review draft report entitled, Exposure and Human Health Reassessment of 10 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds (U.S. EPA, 2003) 11 (herein referred to as "2003 Reassessment") that was reviewed by the EPA Science 12 Advisory Board (SAB), and then by the National Academy of Sciences (NAS). In 2006, 13 the National Research Council (NRC) of the National Academies published their report 14 of EPA's reassessment, Health Risksfrom Dioxin and Related Compounds: Evaluation of 15 the EPA Reassessment (NRC, 2006). 16 17 The current Report EPA's Reanalysis ofKey Issues Related to Dioxin Toxicity and 18 Response to NAS Comments ( "Response to Comments") before the SAB is a response to 19 the review by the NRC, and includes new analyses completed in response to the NRC 20 recommendations and recently published literature, as well as a discussion of topics 21 where our views differed. The draft Response to Comments document is not an 22 assessment per se; it is designed to supplement the information provided in the 2003 23 Reassessment. However, the draft Response to Comments provides a noncancer reference 24 dose and updated cancer values. Detailed discussions of many of the issues addressed in 25 the draft Response to Comments are available in the 2003 Reassessment and have not 26 been reproduced in the current Report - whenever appropriate; the reader is directed to 27 the pertinent chapters of the 2003 Reassessment. 28 29 The NRC identified three key recommendations that they believed would result in 30 substantial improvement to the EPA 2003 Reassessment and thus support a scientifically 31 robust characterization of human responses to exposures to TCDD. These three key areas 32 are (1) improved transparency and clarity in the selection of key data sets for dose33 response analysis, (2) further justification of approaches to dose-response modeling for 34 cancer and noncancer endpoints, and (3) improved transparency, thoroughness, and 35 clarity in quantitative uncertainty analysis. The NRC Report also encouraged EPA to 36 calculate a reference dose (RfD), which had not been derived in the 2003 Reassessment. 37 The draft Response to Comments document addresses each of these issues. Please 38 consider the accuracy, objectivity, and transparency of EPA's reanalysis and responses in 39 your review. 40 41 General Charge Questions 42 43 1.1 Is the draft Response to Comments clear and logical? Has EPA objectively and 44 clearly presented the three key NRC recommendations? 45 D-2 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 1.2 Are there other critical studies that would make a significant impact on the 2 conclusions of the hazard characterization or dose-response assessment of the 3 chronic noncancer and cancer health effects of TCDD? 4 5 Specific Charge Questions 6 7 Section 2. Transparency and Clarity in the Selection of Key Data Sets for Dose8 Response Analysis 9 10 2.1. Is this Section responsive to the NAS concern about transparency and clarity in 11 data-set selection for dose-response analysis? 12 13 2.2. Are the epidemiology and animal bioassay study criteria/considerations 14 scientifically justified and clearly described? 15 16 2.3. Has EPA applied the epidemiology and animal bioassay study 17 criteria/considerations in a scientifically sound manner? If not, please identify and 18 provide a rationale for alternative approaches. 19 20 Section 3. The Use of Toxicokinetics in Dose-Response Modeling for Cancer and 21 Noncancer Endpoints 22 23 3.1 The 2003 Reassessment utilized first-order body burden as the dose metric. In the 24 draft Response to Comments document, EPA used a physiologically-based 25 pharmacokinetic (PBPK) model (Emond et al., 2004, 2005, 2006) with whole blood 26 concentration as the dose metric rather than first-order body burden. This PBPK 27 model was chosen, in part, because it includes a biological description of the dose28 dependent elimination rate of TCDD. EPA made specific modifications to the 29 published model based on more recent data. Although lipid-adjusted serum 30 concentrations (LASC) for TCDD are commonly used as a dose metric in the 31 literature, EPA chose whole blood TCDD concentrations as the relevant dose metric 32 because serum and serum lipid are not true compartments in the Emond PBPK 33 models (LASC is a side calculation proportional to blood concentration). 34 35 Please comment on: 36 37 3.1. a. The justification of applying a PBPK model with whole blood TCDD 38 concentration as a surrogate for tissue TCDD exposure in lieu of using 39 first-order body burden for the dose-response assessment of TCDD. 40 41 3.1. b. The scientific justification for using the Emond et al. model as opposed to 42 other available TCDD kinetic models. 43 44 3.1. c. The modifications implemented by EPA to the published Emond et al. 45 model. D-3 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 3.1. d. Whether EPA adequately characterized the uncertainty in the kinetic 3 models. 4 5 3.2. Several of the critical studies for both noncancer and cancer dose-response 6 assessment were conducted in mice. A mouse PBPK model was developed from an 7 existing rat model in order to estimate TCDD concentrations in mouse tissues, 8 including whole blood. 9 10 Please comment on: 11 12 3.2. a. The scientific rationale for the development of EPA's mouse model based 13 on the published rat model (Emond et al., 2004, 2005, 2006). 14 15 3.2. b. The performance of the mouse model in reference to the available data. 16 17 3.2. c. Whether EPA adequately characterized the uncertainty in the mouse and 18 rat kinetic models. Please comment specifically on the scientific 19 justification of the kinetic extrapolation factor from rodents to humans. 20 21 3.3 Please comment on the use of the Emond et al. PBPK model to estimate human 22 intakes based on internal exposure measures. 23 24 3.4. Please comment on the sensitivity analysis of the kinetic modeling (see Section 25 3.3.5). 26 27 3.5. Both EPA's noncancer and cancer dose-response assessments are based on a 28 lifetime average daily dose. Did EPA appropriately estimate lifetime average daily 29 dose? If not, please suggest alternative approaches that could be readily developed 30 based on existing data. 31 32 Section 4. Reference Dose 33 34 4.1. The Mocarelli et al. (2008) and Baccarelli et al. (2008) studies were selected as co 35 critical studies for the derivation of the RfD. Is the rationale for this selection 36 scientifically justified and clearly described? Please identify and provide the 37 rationale for any other studies that should be selected, including the rationale for 38 why the study would be considered a superior candidate for the derivation of the 39 RfD. In addition, male reproductive effects and changes in neonatal thyroid 40 hormone levels, respectively, were selected as the co-critical effects for the RfD. 41 Please comment on whether the selection of these critical effects is scientifically 42 justified and clearly described. Please identify and provide the rationale for any 43 other endpoints that should be selected as the critical effect. 44 45 4.2. In the Seveso cohort, the pattern of exposure to TCDD is different from the average D-4 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 daily exposure experienced by the general population. The explosion in Seveso 2 created a high dose pulse of TCDD followed by low level background dietary 3 exposure in the exposed population. In the population, this high dose pulse of 4 TCDD was slowly eliminated from body tissues over time. There is uncertainty 5 regarding the influence of the high-dose pulse exposure on the effects observed 6 later in life. 7 8 4.2. a. Mocarelli et al. (2008), reported male reproductive effects observed later 9 in life for boys exposed to the high dose pulse of TCDD between the ages 10 of 1 and 10. EPA identified a 10 year critical exposure window. In the 11 development of the candidate RfD, EPA used an exposure averaging 12 approach that differs from the typical approach utilized for animal 13 bioassays. EPA determined that the relevant exposure should be 14 calculated as the mean of the pulse exposure and the 10-year critical 15 exposure window average. Please comment on the following: 16 17 4.2. a.i. EPA's approach for identifying the exposure window and 18 calculating average exposure for this study. 19 20 4.2. a.ii. EPA's designation of a 20% decrease in sperm count (and an 21 11% decrease in sperm motility) as a LOAEL for Mocarelli et al. 22 (2008). 23 24 4.2. b. For Baccarelli et al. (2008), the critical exposure window occurs long 25 after the high-dose pulse exposure. Therefore, the variability in the 26 exposure over the critical exposure window is likely to be less than the 27 variability in the Mocarelli et al. subjects. EPA concluded that the 28 reported maternal exposures from the regression model developed by 29 Baccarelli et al. provide an appropriate estimate of the relevant effective 30 dose as opposed to extrapolating from the measured infant TCDD 31 concentrations to maternal exposure. Additionally, EPA selected a 32 LOAEL of 5 p-units TSH per ml blood in neonates; as this was 33 established by World Health Organization (WHO) as a level above which 34 there was concern about abnormal thyroid development later in life. 35 Please comment on the following: 36 37 4.2. b.i. EPA's decision to use the reported maternal levels and the 38 appropriateness of this exposure estimate for the Baccarelli et al. 39 study. 40 41 42 4.2.b.ii. EPA's designation of 5 p-units TSH per ml blood as a LOAEL 43 for Baccarelli et al. (2008). 44 45 4.3. Please comment on the rationale for the selection of the uncertainty factors (UFs) D-5 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 for the RfD. If changes to the selected UFs are proposed, please identify and 2 provide a rationale. 3 4 4.4. EPA did not consider biochemical endpoints (such as CYP induction, oxidative 5 stress, etc.) as potential critical effects for derivation of the RfD for TCDD due to 6 the uncertainties in the qualitative determination of adversity associated with such 7 endpoints and quantitative determination of appropriate response levels for these 8 types of endpoints in relation to TCDD exposure. Please comment on whether this 9 decision is scientifically justified and clearly described. 10 11 4.5. In using the animal bioassays, EPA averaged internal blood TCDD concentrations 12 over the entire dosing period, including 24 hours following the last exposure. 13 Please comment on EPA's approach for averaging exposures including intermittent 14 and one day gestation exposure protocols. 15 16 4.6. Please comment on the benchmark dose (BMD) modeling conducted by EPA to 17 analyze the animal bioassay data and EPA's choice of points of departure (PODs) 18 from these studies. 19 20 4.7. For the animal bioassay modeling, EPA applied the kinetic extrapolation at the 21 level of the POD prior to applying the uncertainty factors because EPA has less 22 confidence in the kinetic model output at lower doses reflective of the RfD. Please 23 comment on whether this approach was scientifically justified and clearly 24 described. 25 26 4.8. Please comment as to whether EPA's qualitative discussion of uncertainty in the 27 RfD is justified and clearly described. 28 29 Section 5. Cancer Assessment 30 31 5.1. Weight of Evidence Cancer Descriptor: The 2003 Reassessment concluded that 32 TCDD is a "known human carcinogen." In the current draft Response to Comments 33 document, EPA concluded that under the 2005 Guidelines for Carcinogen Risk 34 Assessment (U.S. EPA, 2005) TCDD is "carcinogenic to humans." Is the weight35 of-evidence characterization scientifically justified and clearly described? 36 37 5.2. Mode of Action: The mode of action of a carcinogen can inform identification of 38 hazards and approaches used for a dose-response assessment. The mode of 39 carcinogenic action for TCDD has not been elucidated for any tumor type. EPA 40 concluded that, while interaction with the Ah receptor is likely to be a necessary 41 early event in TCDD carcinogenicity in experimental animals, the downstream 42 events involved are unknown. 43 44 5.2.a. Are the available data related to mode(s) of action for the carcinogenicity 45 of TCDD appropriately characterized and clearly presented? D-6 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 5.2.b. Do the available data support EPA's conclusion that the overall mode(s) 3 of action for TCDD-induced carcinogenesis is largely unknown? Please 4 comment on whether this evaluation is clearly described. 5 6 5.3. Is EPA's approach for selecting data sets from the key epidemiologic studies and 7 animal bioassays identified for cancer dose response modeling scientifically 8 justified and clearly described? 9 10 5.4. For the animal bioassay data, potential cancer oral slope factors (OSFs) were 11 calculated by linear extrapolation (using a linear, nonthreshold cancer approach) 12 from the point of departure (POD). EPA also estimated the composite risk of the 13 occurrence of several tumor types from the animal cancer bioassay data. 14 15 5.4. a. Please comment on whether the approach for estimating cancer risk, 16 including the use of tumor modeling of the TCDD animal cancer 17 bioassay data, is scientifically justified and clearly described. 18 19 5.4. b. Please comment on the choice of using a BMDL01 as the POD for the 20 development of candidate oral slope factors derived from the TCDD 21 animal cancer bioassays. 22 23 5.5. EPA selected Cheng et al. (2006) - an analysis of the NIOSH occupational cohort 24 as the critical study for oral slope factor (OSF) development. This study was 25 chosen because it considers dose-dependent elimination of TCDD rather than first 26 order kinetics. 27 28 5.5. a. Please comment on whether the rationale for this selection is scientifically 29 justified and clearly described. Please identify and provide the rationale 30 for any other studies that should be considered and provide a critical 31 evaluation of the study and of its suitability for meeting the goals of a 32 quantitatively cancer assessment. 33 34 5.5. b. Cheng et al. (2006) analyzed all-cancer mortality. Please comment on the 35 use of all-cancer mortality as the basis of the OSF. 36 37 5.5. c. Please comment on whether the use of the Emond PBPK model in the 38 estimation of risk-specific doses from the Cheng et al. dose-response 39 modeling results is scientifically justified and clearly described. 40 41 5.5. d. EPA elected to use the log linear relationship of fat concentration and rate 42 ratio to estimate risk-specific doses at all risk levels. EPA could have 43 estimated a POD for cancer risk itself at a single risk level (BMR) for 44 extrapolation to the origin. Please comment on EPA's choice of 45 extrapolation approach. D-7 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 2 5.5.e. The slope factor derived from Cheng et al. (2006) was extrapolated below 3 the background TCDD exposure levels experienced by the NIOSH 4 cohort. Please comment on this extrapolation. 5 6 5.6. Please comment on whether EPA has clearly described the major qualitative 7 uncertainties in the derivation of the OSF. 8 9 5.7. EPA did not consider dioxin-like compounds (DLCs) in the cancer dose-response 10 modeling because the occupational exposures in the available cohorts were 11 primarily to TCDD. Background DLC exposures were not incorporated in the 12 dose-response modeling because EPA judged that it was not possible to 13 disaggregate the responses from background exposure to DLCs and occupational 14 exposure to TCDD. Please comment on whether this approach is scientifically 15 justified and clearly described. 16 17 5.8. The NRC suggested that EPA consider nonlinear approaches for the assessment of 18 TCDD carcinogenicity. In the Response to Comments, EPA presents two 19 illustrative nonlinear approaches for cancer, but considers both inappropriate to use 20 because of the lack of MOA information. 21 22 5.8. a. Please comment on these two illustrative nonlinear approaches including 23 EPA's conclusions regarding the limitations of these approaches. 24 25 5.8. b. Are there other nonlinear approaches that could be readily developed 26 based on existing data for the assessment of TCDD carcinogenicity? If 27 so, please suggest alternative approaches and describe their utility and 28 suitability for meeting the goals of a quantitative cancer assessment. 29 30 Section 6. Feasibility of Quantitative Uncertainty Analysis from NAS Evaluation of 31 the 2003 Reassessment 32 33 6.1. Please comment on the discussion in this Section. Is the response clearly presented 34 and scientifically justified? 35 36 6.2. Please comment on EPA's overall conclusion that a comprehensive quantitative 37 uncertainty analysis is not feasible. 38 39 6.2.a. Please comment on the discussion in Section 6 regarding volitional 40 uncertainty and how this type of uncertainty limits the ability to conduct a 41 quantitative uncertainty analysis. 42 43 6.3. Throughout the document (including the Appendices), EPA presents a number of 44 limited sensitivity analyses (e.g., toxicokinetic modeling, RfD ranges, cancer OSF 45 ranges, cancer RfD development). Please comment on the approaches used, and the D-8 Science Advisory Board (SAB) 5/4/11 Draft. Do not cite or quote. This draft SAB Panel report has been prepared for quality review and approval by the chartered SAB. This draft does not represent EPA policy. 1 utility of these sensitivity analyses in clarifying potential significant uncertainties. D-9