Document QJb833nrL003da1oYYDnNbEK5

From: Sent: To: Subject: Attach: Matt Todd <ToddM@api.org> Friday, December 12, 2003 10:02 PM (GMT) BHRC Oversight Committee (E-mail) <benzconsort-oc@listserve.api.org>; BHRC Technical Committee (E-mail) <benzconsort-tc@listserve.api.org>; BHRC Communications Committee (E-mail) <benzconsort-cc@listserve.api.org> Shanghai Health Study Update: December 12, 2003 2003-12-01_shs_stakeholder~lan.doc; shs_overview. doc; shs_technical_overview.doc; shs_erpJoles_summary.doc; shs_srpJoles_summary. doc; 2003_shs_annual_meeting_summary. doc Please click on the following link, then click on "SHS Update" in the left hand navigation bar to view this week's update. http://www.shanghaihealthstudy.org Announcements: The Shanghai Health Study Launch Ceremony took place and is reported to have been a successful event. The Oversight and Communications Committees will have a joint conference call on Monday, December 15th from 3-5 pm EST (see attached Stakeholder Engagement document) The Oversight Committee will have a conference call on Wednesday, December 17th from 2-5 pm EST. The 3Q03 budget spreadsheet is available and located on the Financials page on the SHS website. Attached to this email are the following documents that have been approved and finalized for SHS outreach efforts: o SHS Overview o SHS Technical Overview o ERP Summary o SRP Summary o 2003 SHS Annual Meeting Summary If you have any announcements that you would like to be posted, please send an email to Matthew Todd, toddm@api.org. Matthew Todd Regulatory Analysis and Scientific Affairs American Petroleum Institute 1220 L Street NW Washington, DC 20005 p: (202)682-8319 f: (202)682-8031 www.api.org SHELL-MCCLURG-054218 SHANGHAI HEALTH STUDY First Annual Meeting August 25-27, 2003 Asilomar Conference Center Monterey, California The First Annual Meeting of the Shanghai Health Study was held August 25-27,2003 at the Asilomar Conference Center in Monterey, California. The meeting was the first faceto-face gathering all the various groups involved with the study: the Principal Investigators (both Chinese and American research team members), Scientific and Ethical Review Panel members and the project sponsors. Beginning with the welcome reception and dinner on August 25th and throughout the two full days of meetings that followed, the participants took advantage of the time to engage in an open and informative exchange of ideas related to the study. The opening plenary session began with a welcome from Chair of the Benzene Health Research Consortium Oversight Committee, Dr. Donald Burnett ofBP. In his brief remarks, Dr. Burnett set the tone for the meeting by inviting all of the participants to join in the discussions and freely engage in question and answer sessions with the panel members. Dr. Burnett then introduced the moderator for the plenary session and Chair of the Benzene Health Research Consortium Technical Committee, Dr. Patrick Beatty of ChevronTexaco. Dr. Beatty laid out the expectations for the day, noting that panelists representing the Scientific and Ethics Review Panels would be providing summaries of their work to date and that the Principal Investigators involved in the research would provide an up-to-date look at their progress in Shanghai. Each of the presentations was followed by a dynamic question and answer period in which the presenters and the audience members exchanged comments and views. Ethics and Scientific Review Panel Activities The first panelist was Dr. Jerry Rice, Chair of the study's Scientific Review Panel (SRP) and recently retired from the International Agency for Research on Cancer (IARC). Dr. Rice spoke on behalf of his colleague and Chair of the study's Ethics Review Panel (ERP), Dr. Baruch Brody of the Baylor College of Medicine, who was unable to attend. Dr. Rice noted that the role of the ERP is to ensure that the research conducted under the study meets internationally accepted ethics standards and reflects relevant cultural norms in Shanghai. He highlighted the fact that the current study is based on standards set forth by the Council for International Organizations of Medical Science (CIOMS) - the only internationally accepted ethical standards for studies on human subjects. Dr. Rice also focused on key elements of the ERP review including: 11113/2003 SHELL-MCCLURG-054219 SHANGHAI HEALTH STUDY First Annual Meeting Payment to subjects - adequate, but to avoid concerns over a perception of exploitation, scalable (depending on the subjects level of participation); Informed consent - importance of forms in local languages; Information about HIV - HIV status is important to validate as another potential cause/risk factor for hematopoetic disease; HIV is included in the informed consent; Subject confidentiality; and Publication of the study results - study sponsors will have an opportunity to review and comment on the findings, but the principal investigators have sole control over and responsibility for any published papers. To underscore the fact that the research is being done under the highest international ethical standards, Dr. Rice introduced another member of the ERP, Dr. Juhana IdanpaanHeikkila of the World Health Organization and Secretary General ofCIOMS. Dr. Idanpaan-Heikkila briefed the meeting on the recently revised/updated International Ethical Guidelinesfor Biomedical Research Involving Human Subjects - the guidelines upon which the Shanghai study is based. Dr. Rice then resumed his role as Chair of the SRP and provided an overview of the panel and its role in the Shanghai Health Study. Dr. Rice noted that SRP was charged with reviewing and approving the initial research protocol and continues to review all significant proposed protocol changes and issues that might impact the protocol. In addition, he noted that the SRP also intended to review scientific manuscripts and abstracts related to the study prior to presentation or submission to appropriate journals. In this regard, he explained that the SRP also serves in an Editorial Board-like capacity to provide "quality assurance" and help ensure that papers are more easily publishable. An Update on the Study - Reports From the Researchers Collaboration Between Academic and Governmental Agencies in China One of the study's biggest strengths is in the level of cooperation and collaboration among the academic and health communities and the Chinese government in Shanghai. Professor Fu Hua, Deputy Dean of the Fudan University School of Public Health and one of the Co-Principal Investigators of the Case-Control Study of AML and NHL in Shanghai, provided a detailed overview of the Shanghai Health Study and the interrelationships and support structure that has been developed for the project in Shanghai. Professor Fu provided an extremely informative introduction to the various hospitals, academic institutions and medical societies, and government agencies that currently playa role in the study, including: Fudan University and the School of Public Health; Medical Center of Fudan University (and more than 20 other hospitals located throughout Shanghai); Shanghai Municipal Center for Disease Preventions and Control (Shanghai CDPC); 11113/2003 SH ELL-MCCLU RG-OS4220 SHANGHAI HEALTH STUDY First Annual Meeting Shanghai Municipal Institute for Public Health Supervision (Shanghai IPHS); Shanghai Hemotological Society; Lymphoma Society; and Society of Occupational Medicine Professor Fu also explained the three-pronged approach of the study including a casecontrol study, a disease progression study, and a molecular epidemiological study of benzene exposure. All three elements of the study are supported by a single, state-of-theart laboratory - the Joint Sino-US Clinical and Molecular Laboratory - based at Fudan University. Case Control Study ofAML and NHL in Shanghai Dr. Otto Wong of Applied Health Sciences then provided an overview of the design and a status report on the case-control study in Shanghai. As one of the Co-Investigators in the study, Dr. Wong described in detail the hospital-based case-control study now underway in Shanghai. Prospective enrollment for the study began in June of 2003 and will continue in an effort to develop up to 2 individually matched controls for each acute myeloid leukemia (AML) and non-Hodgkin's lymphoma (NHL) case identified in the study. Dr. Wong described the identification process for study cases and controls, including the interview process and the patient consent procedures. He noted that all of the forms and the participant questionnaires were carefully pilot-tested for language and clarity and extensive training was provided to the interviewers. Dr. Wong also provided an overview of the various information sources for data on exposure levels and how the data would be used to inform the exposure assessment in the current study. Molecular Epidemiology Studies in Shanghai Next, Dr. Robert Schnatter, the senior scientific advisor for Occupational Health at ExxonMobil Biomedical Sciences, Inc. and a Co-Investigator in the Shanghai Study, described the two-phased molecular epidemiology study and its role in the project. Dr. Schnatter described the first phase as a retrospective study intended to define dose response relationships for past benzene exposure and identify the most sensitive measures of effect for items recorded in routine exams. Dr. Schnatter added that the study will initially focus on shoe workers but will be expanded to include a variety of workplace environments and sites where benzene is used. He described the second phase as exposure response analyses coupled with a study of the effects of current or recent benzene exposure and a measurement of the effects on blood and bone marrow. Dr. Schnatter concluded by describing a pilot test of the procedures and the worker questionnaire where 48 of 49 of the tested company's workers participated and the results were viewed as "very successful". Exposure Assessmentfor Shanghai Studies Stepping in for his colleague Tom Armstrong, an industrial hygienist at ExxonMobil Biomedical Sciences, Inc. who was unable to attend the meeting, Dr. Schnatter also provided an overview of the exposure assessment processes and procedures to be used in the study. He described the two level process for exposure questionnaires - the first 11113/2003 SHELL-MCCLURG-OS4221 SHANGHAI HEALTH STUDY First Annual Meeting explores the work history and potential workplace exposures and is provided to all workers who agree to participate; the second is triggered by specific pre-identified job categories to measure the exposure level in particular industries. The resulting data will be added to the database of the JCML at Fudan University. China and OEL Standards The final speaker for the morning was Dr. Liang You-xin of the Fudan University School of Public Health. Dr. Liang provided very interesting insights into the current state of occupational health improvement efforts in China. Dr. Liang reported that significant progress has been made in improving occupational health in China since the 1980's, particularly in the regulation and reduction of exposure to potentially hazardous materials in the workplace. He noted that the systematic development of occupational exposure limits began in 1981 with the establishment of two national standards-setting bodies: the National Technological Committee of Health Standards Setting (NTCHSS) and the Subcommittee of Occupational Health Standards Setting (SCOHSS). Dr. Liang also highlighted the Occupational Diseases Prevention and Control Act, P.R. China, 2001 (ODPCAct) - the first comprehensive law on occupational health in China - which he compared to the Occupational Health and Safety Act (OSHA) in the US. Dr. Liang also discussed the historical changes to benzene Occupational Exposure Limits (OELs) both internationally and in China. He also pointed out that while the standards exist in China, workplace measurements, licensing and enforcement of government standards is less rigorous there, and Chinese workers continue to be exposed to higher levels of benzene. In closing, Dr. Liang stressed that increased enforcement ofOELs "may be of equal or even greater importance than lowering the standard". The Clinical and Molecular Laboratory - From Concept to Case Accrual The final speaker for the plenary session was Dr. Richard Irons, Director of the Molecular Toxicology and Environmental Health Sciences program at the University of Colorado Health Science Center, and Principal Investigator and Laboratory Director for the Shanghai Heath Study. Building on the information from previous presentations, Dr. Irons began by providing an integrated overview of the study and its goals. He described the overarching goal of the study as an effort to "characterize the relationship between benzene exposure and the development of specific hematopoietic diseases." He provided a detailed outline of the study and the specific disease states that it would address. Dr. Irons then offered a unique first look at the new state-of-the-art laboratory facility that has been built, and is now up and running, at Fudan University. He described in detail the process to transform the original workspace at Fudan into the laboratory as it exists today (a process which began in early 2001). Dr. Irons was pleased to report that training for key clinical and laboratory personnel was complete and that the laboratory was fully functional. Asked to describe the current status of the study, Dr. Irons said that it had moved from the developmental stage into operational activities and the study has begun to accrue cases. 11113/2003 SH ELL-MCCLU RG-OS4222 SHANGHAI HEALTH STUDY First Annual Meeting The remainder of the meeting provided time for the various committees and panels associated with the study to meet and to discuss both progress and future actions. By all accounts, this First Annual Meeting was a complete success, providing an invaluable opportunity for everyone involved in the study to meet face-to-face and openly exchange information and ideas. 11113/2003 SH ELL-MCCLU RG-OS4223 SHANGHAI HEALTH STUDY Summary of Scientific Review Panel Roles and Responsibilities SCIENTIFIC REVIEW PANEL (SRP) The Scientific Review Panel consists of recognized, independent experts in scientific/medical fields relevant to the research program of the consortium. Initial membership was approved by the Business Oversight Committee. The SRP is responsible for naming additional qualified members. The SRP reviewed and approved the initial research protocols and would review any significant protocol changes proposed by the investigators, the Ethics Review Panel, or others. It determines what protocol changes are significant enough to require review. The SRP will review all manuscripts for publications and all abstracts for presentation. Their comments will be communicated to the investigators for their consideration. SRP Members: General Toxicology and Biochemistry Dr. Jerry M. Rice, (Chair), IARC (Retired) Dr. Helmut Greim, Technical University of Munich Epidemiology Dr. Harvey Checkoway, Washington University Statistics Dr. Howard Rockette, University of Pittsburgh Industrial Hygiene Hematology Genetic Toxicology Dr. John Cherrie, Aberdeen University, Institute of Occupational Medicine Dr. Robert F. Herrick, Harvard University, School of Public Health Dr. Richard Larson, University of Chicago Medical School Dr. Mark Minden, University of Toronto Dr. Li Guilan, Chinese Academy of Preventive Medicine Dr. Richard Albertini, University of Vermont, College of Medicine November 20, 2003 lofl SH ELL-MCCLU RG-OS4224 SHANGHAI HEALTH STUDY Summary of Ethics Review Panel Roles and Responsibilities ETHICS REVIEW PANEL (ERP) Initial membership of the ERP was determined by the Business Oversight Committee. Members are experts in bioethics. The ERP members are responsible for adding appropriate members as appropriate. It should consist, at a minimum, of members drawn from the U.S., from Europe, and from China. The ERP makes recommendations to ensure that the research meets internationally accepted ethics standards and reflects relevant cultural or other patterns in Shanghai. It reviewed the protocols, recommending changes that were incorporated to meet international guidelines. It has also reviewed the consent forms, and other aspects of the research ethics, to ensure that recommendations of the ethics review process had been incorporated. It will review any relevant changes before they are implemented. It will also periodically review the conduct and progress of the research to see that the ethics standards are being followed. ERP members are available to respond as needed to issues raised by the investigators, the Scientific Review Panel or the company sponsors. ERP members: Dr. Xu Zong-Liang, Dean, Faculty of Humanities and Social Sciences, Fudan University Medical Center; Director, Bioethics Research Center, Fudan University Medical Center Dr. Juhana Idanpaan-Heikkila, World Health Organization, Geneva, Switzerland November 20, 2003 1 SH ELL-MCCLU RG-OS422S SHANGHAI HEALTH STUDY Technical Overview This document describes studies underway to investigate the potential dose-response and mechanistic aspects of the hematological effects of benzene exposure in a population of workers in Shanghai, China. The project described below includes parallel case control studies of Non-Hodgkin's lymphoma (NHL) and acute myelogenous leukemia (AML), an investigation of the potential role of non-neoplastic diseases such as aplastic anemia (AA) and myelodysplastic syndrome (MDS) in a progression to AML, and determination of the dose-response relationship between benzene exposure and selected biomarkers of both exposure and effect. Data Gaps and Uncertainties There are a number of areas of uncertainty regarding hematopoietic disease and benzene that, if answered, have the potential to improve the accuracy of estimates of benzenerelated risks. These are: 1.) The shape of the dose-response relationship between benzene exposure and certain hematological diseases (including the possibility of a true threshold). 2.) Clearly identifying those types of hematopoietic cancer that can be causally related to benzene exposure. Currently, only acute myeloid leukemia has a demonstrated relationship, but regulatory agencies still assume that all leukemias can result from benzene exposure, basing risk estimates on this assumption. 3.) Clarification of the role, if any, of non-cancer hematological diseases in the etiology of benzene-induced leukemia. Ifbone marrow toxicity is a prerequisite for subsequent leukemia, then there must a priori be a threshold below which leukemia cannot be induced. 4.) Identification of any similarities between leukemia secondary to benzene exposure and the much better understood leukemias secondary to administration of certain chemotherapeutic drugs used to treat some primary cancers. This category of uncertainty includes the ability to identify a marker or other characteristic of leukemia induced by exposure to benzene, rather than those resulting from errors in DNA repair or other causes. 5.) Clarification of any quantitative relationship between benzene exposure and potential indicators of exposure or of effect. This includes determining which of these two categories potential indicators actually represent. Project Description The project consists of three highly integrated aspects: 1.) A population-based case-control study investigating the potential relationship between benzene exposure and both NHL and AML, including an attempt to define a quantitative potency for the AML response. 11119/03 - 1- SH ELL-MCCLU RG-OS4226 SHANGHAI HEALTH STUDY Technical Overview 2.) A hospital/clinic-based investigation of the relationship between non-neoplastic diseases of the bone marrow and AML to determine if there is a progression through stages of bone marrow cytotoxicity to an ultimate leukemogenic response. This disease progression study is attempting to define both potency and the shape of the dose-response for these "precursor" diseases. 3.) A molecular epidemiology study investigating the quantitative relationships between benzene exposure and potential early indicators of both exposure and effect in a focused population of benzene-exposed manufacturing workers. All three study aspects are highly integrated, in that a central laboratory has been created through which all clinical samples will be analyzed. This state-of-the-art hematology/oncology laboratory provides the diagnostic information to determine the subtype and viral status for the potential cases for the case control studies, ensuring accurate and consistent categorization of all the cases, and conducts the cytogenetic analyses, which are part of the molecular epidemiology project. The progression study, the second portion of the project, uses the shared laboratory facilities, and many of the cases in the AML case-control study may also be included in the progression study. Case-Control studies This project is a case-control epidemiology study ofNHL and AML in the population of Shanghai. The case-control design allows a focused examination of the hypothesis that benzene exposure can cause NHL. NHL is not a single disease but, rather, is a collective of over a dozen phenotypically distinct hematopoietic cancers. The consortium study design includes subtyping each individual case to determine if any positive response is associated with any of the NHL subtypes. In addition, the viral status of each case is being determined because it is known that a number of viruses are associated with the increased risk ofNHL. This portion of the project, as well as the other two listed above, includes independent analysis of benzene exposures. If the quality of the exposure data permits, an estimate of any quantitative potency (slope factor) will be made for any cancer type with a positive association with benzene exposure. This study is being done in collaboration with the Departments of Public Health and Hematology of Fudan University Medical School. There is also a close working relationship between the investigators and the Shanghai Tumor Registry at the Shanghai Center for Disease Control, which is the governmental repository for workplace exposure information. And the investigators have the cooperation of the Institute for Public Health Supervision in Shanghai, which can provide investigators with access to factories in Shanghai for industrial hygiene monitoring. The Principle Investigator on this study is Dr. Otto Wong of Applied Health Sciences. Disease Progression/Molecular Epidemiology Study This project utilizes individuals identified as part of the case-control epidemiology study to investigate genetic effects and disruption of regulatory processes on the hematopoietic system. This study also allows an independent evaluation of the exposure-response 11119/03 -2- SH ELL-MCCLU RG-OS4227 SHANGHAI HEALTH STUDY Technical Overview nature of these effects in a concentrated population that has been more highly exposed to benzene than populations in the U.S. or Europe. This study identifies those individuals with hematopoietic disease, myelodysplastic syndromes (MDS) or AML, which can be reliably associated with benzene exposure, in order to identify unique characteristics of benzene-induced disease. Due to the highly controlled nature of benzene exposure in North America and Western Europe, researchers have not had the opportunity to bring modern medical and molecular biological techniques to bear on a single case of AML, MDS or aplastic anemia in which benzene could be considered the probable causative factor. This study may allow a definitive identification of hematopoietic effects unique to benzene exposure, and may establish a link between benzene-induced leukemias and other leukemias secondary to chemical exposure (mainly alkylation chemotherapy) about which much is already known. The study is being performed by Dr. Richard Irons of the University of Colorado, with the collaboration and assistance of investigators from the Departments of Hematology and Public Health of Fudan University Medical School and from ExxonMobil Biomedical Sciences. The above investigators are also involved in an examination of the relationship between AML and other non-neoplastic hematopoietic diseases. The presence of a population that is relatively stable geographically combined with both hospital and occupational records of bone marrow related disease has created the possibility of investigating this relationship. Workers in benzene-related areas have been monitored for excessive exposure (reported to the Shanghai Center for Disease Control and Prevention as "benzene poisoning") by means of annual blood counts. It has been hypothesized that AML must be preceded by some degree of toxicity to the hematopoietic system. Validation of this hypothesis would provide critical support for a nonlinear (sublinear) dose response of hematopoietic effects due to benzene exposure, and would imply a nonzero threshold exposure to benzene below which there would be no risk of AML, etc. It is not clear at this time how reliably individuals with benzene poisoning can be located, but cases ofMDS or aplastic anemia (AA) treated in hospitals may be more easily located. These issues will be resolved during the course of the investigations. Transitional Study of the Manufacturing Industry One area of benzene research that has received a lot of attention in the last few years is the attempt to identify early biological indicators that predict a later event such as AML or serious forms of bone marrow toxicity such as MDS or AA. These early indicators have also been referred to as "biomarkers." Some endpoints which have been measured, such as protein adducts of benzene metabolites, are clearly indicators only of exposure to benzene (although there may be some complicated relationship with biological responses). Some endpoints, such as certain cytogenetic abnormalities, have been claimed to be indicators of future effect. One challenge is distinguishing between the two types of indicators. At this time no biological predictor of benzene-induced leukemia has been unequivocally identified. And to date there is no publication in the scientific literature that has attempted to establish an exposure response relationship for genetic 11119/03 -3- SH ELL-MCCLU RG-OS4228 SHANGHAI HEALTH STUDY Technical Overview effects that is based upon several sets of data points. This study is designed to address both points. The objective of this series of studies is to investigate the relationship between benzene and various blood dyscrasias and cytogenetic abnormalities as demonstrated by the Shanghai manufacturing industry. Sites included in the study are being selected based on existing exposure and clinical records. The dose-response is being investigated in relation to various types of benzene exposure metrics. This integrated Shanghai Health Study will include of the wide range of benzene exposures in the Shanghai manufacturing sector, which will maximize the possibility of seeing non-linearity of any dose response that exists. Specific aims of this facet of the overall project are: 1.) To define benzene dose-response patterns for alterations in blood cell counts, bone marrow cytotoxicity and selected chromosomal alterations; 2.) To define the most relevant exposure indicators for each of the effects noted above; 3.) To assess if the dose response patterns are affected by the presence of other environmental compounds such as toluene or xylene, which commonly are coexposures with benzene; 4.) To assess if the dose response patterns are altered by the presence of reported susceptibility factors in exposed individuals; and 5.) To define the relationship between external benzene exposure and selected internal measures of exposure. Location The location for the project is Shanghai, China. Shanghai is a major population center with approximately 14 million individuals living in the local area. Shanghai presents the unique situation of a large number of workers with documented exposures to benzene at levels that have not existed in North America or Western Europe since the 1940's or 50's. A feasibility study has shown records of industrial hygiene monitoring of work areas where benzene was routinely used. Although many air samples indicated exposures of less than 10 ppm, concentrations in the range of 10 - 50 ppm were also found. The regional agency in charge of maintaining occupational health records, the Shanghai Center for Disease Control and Prevention (SCDC), has a computerized database of industrial hygiene (IH) monitoring data extending back to the mid 1980's. In addition to air monitoring data, blood counts of exposed workers are routinely made on an annual basis. These data are also maintained in computerized form by the local SCDC offices. Shanghai also contains a major medical school, Fudan University Medical School, with a School of Public Health and Hematology Department associated with a teaching hospital. This hospital is one of the major hospitals in Shanghai and is serving as a source for identifying potential cases for the studies. 11119/03 -4- SH ELL-MCCLU RG-OS4229 SHANGHAI HEALTH STUDY Technical Overview The Investigators The principal co-investigators leading the project are: Epidemiology Otto Wong, D. Sc. - Applied Health Sciences, San Mateo, CA Robert Schnatter, Ph.D. - ExxonIMobil Biomedical Sciences, Annandale, NJ Fu Hua - Deputy Dean, Fudan University Medical School, School of Public Health, Shanghai, PRC HematologylMolecular Biology Richard Irons, Ph.D. - University of Colorado Health Sciences Center, Denver, CO Lin Guowei, M.D. - Director, Center of Clinical Epidemiology, Hua Shan Hospital, Shanghai, PRC Industrial Hygiene Lu Wei - Deputy Director General, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, PRC Thomas Armstrong, C.I.H. - Exxon/Mobil Biomedical Sciences, Inc., Annandale, NJ Roy Rando, Ph.D., C.I.H. - Professor ofIndustrial Hygiene, Tulane University. 11119/03 -5- SH ELL-MCCLU RG-OS4230 SHANGHAI HEALTH STUDY Overview Purpose: To gain an accurate understanding of the relationship between benzene exposure and the risk of certain hematopoietic diseases. This study is an important element in the product stewardship programs of participating companies. It could also lead to improved, health-based regulatory (e.g., ambient air, water & occupational) standards worldwide, by providing the regulatory and scientific communities with additional information for more accurate assessment of the risks from exposure to benzene. A unique set of circumstances exists at this point in time in Shanghai to conduct benzene research. These include a database of occupational exposures, and qualified co-investigators influential in local scientific medical, and regulatory establishments. Therefore, questions that have complicated benzene health risk assessment for decades may be addressed in Shanghai. The Studies: The program involves three inter-related studies: Case-Control Study - A hospital-based case control study investigating the potential relationship between benzene exposure and both Non-Hodgkins Lymphoma (NHL) and Acute Myelogenous Leukemia (AML), including an attempt to quantify the potency of the AML response. Disease Progression Study - A hospital/clinic-based investigation of the potential relationship between non-cancer diseases of the bone marrow and AML to determine if effects on bone marrow progress through non-cancer stages to an ultimate leukemia. This study is also attempting to define the shape of the dose response for possible "precursor" diseases and could result in characterization of unique identifiers of benzene-induced AML. Molecular Epidemiology Study - Investigating if there is a quantitative relationship between benzene exposure and potential early indicators of both exposure and effect in a focused population of workers. The investigators are leading experts in their fields, coming from such well-known institutions as the University of Colorado Health Sciences Center and Fudan University Medical Center. The combined studies apply cutting-edge, 21 st century technologies in ways that will not only advance our understanding of benzene-induced disease, but may also identify potential prevention strategies for benzene-induced disease in individuals. Benefits: Information gained from this project may have direct relevance for worldwide regulatory standards designed to protect workers and the general population from benzeneinduced disease. These include air and water quality standards, as well as hazardous waste and site remediation standards. These studies will assist contributing companies in achieving the highest product stewardship goals and in oversight of their risk management programs. Challenges: The proposed studies meet several technical, ethical, and cultural/political challenges. Technical - In order to stand up to scientific scrutiny, studies must be large, well-managed, and incorporate the latest technology. State-of-the-art research is absolutely necessary to make real progress in developing sound benzene risk assessments. To that end, a Scientific Review Panel made up of leading experts from a number of fields relevant to these studies has reviewed and endorsed the research protocols. Additionally, the protocols have been reviewed by Use of Human Subjects Committees (lRB) both in the US and China. November 13, 2003 - 1- SH ELL-MCCLU RG-OS4231 SHANGHAI HEALTH STUDY Overview Ethical - To address ethical issues posed by the study, the protocols have undergone a thorough analysis to ensure that they meet international standards for research involving humans, including for example insuring that the subjects and the communities benefit from participating in the study; that confidentiality is preserved, and that participants are fully informed about the research to give their informed consent. An Ethics Panel is part of the oversight for the project. It includes bioethicists from the U.S., China and Europe. Cultural/Political- A key to this program's success is local partnerships. Collaborators on these studies include researchers from the Medical School at Fudan University, the Institute for Public Health Supervision, and the Shanghai Municipal Centers for Disease Control and Prevention (the latter two are governmental agencies responsible for occupational exposure monitoring and enforcement in Shanghai). Funding: Funding for the project is being provided by a consortium of interested oil and chemical companies. It is anticipated to take five years to complete the project, and that the costs are highest in the first years of the project. For More Information: Please contact anyone of the following individuals. Don Burnett, PhD Patrick Beatty, PhD Myron Harrison, MD Chris Roythorne, MD Lorraine Twerdok, PhD Bruce Jarnot, PhD BP ChevronTexaco ExxonMobil BP API API Q!!m~1tQm@lm_,~_Qm patrickbeatty(al,chevrontexaco.com myron. c.harrison@exxonmobil.com ~h!:i_~_,[QythQm~@_ll_k.Jm_,~_Qm twerdokl@aQi.org iarnotb(al,aoi.org 630-420-5093 510-242-7037 972-444-1673 44 (0)20 74964126 202-682-8344 202-682-8473 November 13, 2003 - 2- SH ELL-MCCLU RG-OS4232 12/01/2003 Draft DRAFT STAKEHOLDER ENGAGEMENT PLAN Objectives Promote understanding of science and project design among key stakeholders who can provide substantive input to the study and contribute to understanding and acceptance of the study in the scientific community. Work within established Communications Committee objectives: - Assist in meeting responsible standards - Ensure any public dialogue is well informed - Contribute to acceptance of published study results Approach Agree on process to evaluate, decide on and implement discussions with key stakeholders. Determine clear lines of responsibility and communication within the consortium. Begin with stakeholders most familiar with benzene science, broadening approaches as study nears conclusion. In general communications in China are managed by the PI's. (Communications Committee to discuss process for understanding those interactions and for additional considering consortium/company outreach.) Use available communications materials (short and long overviews, Adaptable Presentation, annual meeting summary, etc.) with Communications Committee available to develop new materials or Questions/Answers as needed. Note: Recruitment contacts with other companies are not addressed in this plan. Guidelines Assign clear responsibilities (name individual to contact named organization or individual). Prompt feedback on contacts/next steps, including responses to requests for information, etc. One on one communications are preferred, with judgment on best approach left to responsible individual/company. (Exception is scientists/researchers where a symposium or society forum may be more appropriate.) SH ELL-MCCLU RG-OS4233 12/01/2003 Draft Developing an Outreach Plan Establish following categories to assign responsibilities, develop outreach plan: Scientists/researchers/P I peers Government regulators Other officials Other stakeholders/NGO's China Technical Committee Technical Committee Technical/Oversight Committees Communications Committee Communications Committee A discussion tool for assigning priorities is in the matrix below, where the vertical axis is an organization's ability to influence the acceptance and use of the SHS in risk assessments and rule makings and the horizontal access is their understanding of and interest in benzene health issues. Highest priority is to reach the upper right quadrant--those with an interest in and ability to actively engage in scientific discussion of the study. Influence Interest Factors to consider in planning outreach: - What is the organization's (or individual's) interest in the SHS? + What subject areas will they be most interested in? + What key points should be made? - What is the individual's background in and understanding of the scientific concepts in the study? - Who is the most appropriate contact with the organization? + Familiarity, previous interactions + Knowledge/interests - What relevant activities is the organization/individual involved with? + Other benzene research? + For government officials, pending regulatory action, risk assessment? SH ELL-MCCLU RG-OS4234 12/01/2003 Draft - What issues/questions are likely to be raised and how would they be addressed/answered? - What do we want the organization to do? + Attend annual meeting + Monitor progress through periodic contacts + Provide comments/input + Information exchange only It is important that feedback to others in the group be thorough and prompt. For example: - Overall assessment - Recommended follow-up items or next steps - Report on questions/issues were raised - Suggestions on other contacts that could be made - Revisions to the materials used API (Matt Todd) will develop and maintain a reporting format to summarize the concepts, highlighting key new items in his SHS updates. In addition, the Technical Committee should schedule a quarterly review of progress, inviting the Communications and Oversight Committees to participate in that agenda item. Actions to consider 1. Approve plan as discussed/amended. 2. Agree to Committee assignments. 3. Commit to feedback as a priority process step. SH ELL-MCCLU RG-054235