Document 102VLwGk5OqgQnbRMK6bM8z6j

To: Lorraine Twerdok Subject: RE: BHRC ACTION REQUESTED - BALLOT for OC CHAIR/Co-chair Approve. ~garcfs) Patsy Patsy Clegg Product Steward Shell Chemical LP One Shell Plaza, 910 Louisiana, Houston, TX 77002-4916 Tel: +1 713241 2521 Fax: 3325 Email: patsy.clegg@shell.com Internet: http://www.shell.com/chemicals -----Original Message----From: Lorraine Twerdok [mailto:Twerdokl@api.org] Sent: Friday, January 09,2004 1:41 PM To: Benzene OC listserve (E-mail) Subject: BHRC ACTION REQUESTED - BALLOT for OC CHAIR/Co-chair Importance: High To BHRC Oversight Committee: Don Burnett is rotating off as OC Chair, effective january 15,2004. Patsy Clegg is willing to move from CoChair to Chair, and Brian Doll is willing to assume the Co-Chair position. Please indicate by return email your vote (approve/reject) Patsy and Brian as Oversight Committee Chair and Co-Chair, respectively. Ballots are due next Wednesday, january 14. Also, for your information, Lynn Russo and Patrick Beatty will continue on as Chair of the Communications and Technical Committees, respectively. And as approved in August 2003, Stuart Cagen will serve as Vice Chair of the Technical Committee and Chair the Technical Committee Budget Workgroup. Thankyou for your prompt response to this email. Regcwds, La VYCl LV\,e Lorraine E. Twerdok, PhD., DABT Manager, Health Sciences Regulatory and Scientific Affairs American Petroleum Institute 1220 L Street, N.W. Washington, DC 20005 tel: 202-682-8344 email: twerdokl@api.org fax: 202-682-8031 SH ELL-MCCLU RG-067427 The Shanghai Health Study Benzene Health Research Consortium www.shanghaihealthstudy.org Final 11122102 1 SH ELL-MCCLU RG-067428 Presentation Topics ~:::itl:~::t::::~:mm:~:::: Shangha-I Health Study Overv-Iew :~fJ~t.':t~~{:~i~~r Current Benzene SC-Ience ~:~::.:~:~ Shanghai Health Study Elements ::;::: Shanghai Health Study Sponsors ::;::: Shanghai Health Study Funding Structure ~:::itl:~::t::::~:~~~~~~:f: TermsI Sources and Resources Final 11122102 2 SH ELL-MCCLU RG-067429 What is the Shanghai Health Study? ::~:I:~: A long-term clinical study to investigate the potential cause and development of Iymphohematopoietic diseases (diseases of the lymphoid organs, blood and bone marrow) ::~:I:~::~ A project of Fudan University Medical Center; Colorado Health Sciences Center, University of Colorado; Applied Health Sciences - an independent U.S. research firm; Chinese public health agencies; and Shanghai hospitals Final 11122102 3 SH ELL-MCCLU RG-067430 Shanghai Health Study Purpose Ct To gain a quantifiable understanding of the relationship between benzene exposure and potential associated cancer risks ~:~:H:~:~ Researchers will use cutting-edge technologies to advance the understanding of benzene-induced disease Final 11122102 4 SH ELL-MCCLU RG-067431 Benzene Is ... ::~:~.:~:: A chemical found primarily in solvents, glues and petroleum fuels ::~:~.:~:: A recognized human carcinogen ::::;=::::1 Acute Myelogenous Leukemia (AML) !:::.~::~: Tightly regulated although worldwide standards vary ::~:.~::~: What is currently not known: tH::: benzene's impact on a molecular level; tI:: if a safe level of exposure exists (threshold effect); t{:: whether and how associated cancers or other related diseases may be caused; and }!{:: the role genetic susceptibility may play in adding to existing knowledge Final 11122102 5 SH ELL-MCCLU RG-067432 Benzene Toxicity C') The effects of exposure to any hazardous substance depend on: ~:~:H:~:~ dose, durati n,0i:i::i,:i::i:i :i:}-!:i:i: how exposure occurs, :ti:t:i: personal traits and habits, ~i:i:!i~ genetic susceptibility C') Co-exposure to other chemicals can also influence toxicity Final 11122102 6 SH ELL-MCCLU RG-067433 Why is Understanding Benzene Important? ~t:~t:~:::;::::~:mm:~:::: Benzene exposure -IS un-Iversal C~ Advancing current scientific understanding of benzene exposure would be a significant contribution to health and worker safety c") Understanding heaIth effects of lowlevel benzene exposures would improve benzene risk assessments Final 11122102 7 SH ELL-MCCLU RG-067434 Why Shanghai? C') Unique Study Environment I:;"I: Databases documenting exposure :Ii'I: Exposure across industries I}I: Range of exposure levels Committed Collaboration =;::1111:1:::111::;; Ch-Inese government:r::::r::::::::::::: iii::!':::::: University and hospital based researchers I:;"I: Community hospitals :Ii'I: Shanghai Municipal Center for Disease Control and Prevention iii::;,::::: Institute for Public Health Supervision Final 11/22102 8 SH ELL-MCCLU RG-067435 Unparalleled Collaboration "Th-IS::::~:l:::~::::t~r::: study -IS an enormous collaborative effort, unlike anything America nand Chinese resea rchers have ever done. II - Dr. Richard Irons, PhD, SHS principal investigator, professor and director of the University of Colorado's Molecular Toxicology and Environmental Health Sciences Program Final 11122102 9 SH ELL-MCCLU RG-067436 Shanghai Health Study Background i:~::i:~:~: Most environmental and occupational standards for benzene are based on mathematical extrapolations of cancer risk from high-level exposures to environmental concentrations ::~:I:~:: These extrapolations are based on almost no knowledge of how benzene functions at a molecular level in humans Final 11122102 10 SH ELL-MCCLU RG-067437 Slides: Histology/Biology Ct Optional insert: slide examples of histological tissues and biological tissues Final 11122102 11 SH ELL-MCCLU RG-067438 Difficulties in Past Benzene Research c") Animal models do not replicate human benzene-related diseases RetrosQect-lve resea rch:::!U~:t:.. ..:~::;;~~;~~;:::: -----+---~~::~~ Review case files of people who have died :~::!:: Rely on inexact diagnoses ::::::::!::::: Accuracy of reconstructed exposure data :~:=::: Guess at lifestyle and dietary habits :i::!~i:i: Data difficult to isolate ::~::: Exposure limits; cultural/political issues Final 11122102 12 SH ELL-MCCLU RG-067439 How is the SHS Distinct? ProsQect-lve resea rch::::~:}:1t~.::::;;~;;;;;::::. -----+---:~:i:~: Patients at participating hospitals suspected of having a lymphoid, blood or bone marrow disease will be referred to the SHS :~:i:~: Patients' diets, environmental exposures and family histories will be recorded :iI:i::::i:i: Patient disease progression followed at supporting hospitals Final 11122102 13 SH ELL-MCCLU RG-067440 Clinical Laboratory Support Sino-U.S. Joint Clinical & Molecular Lab Referral Hospitals Outside Benzene Cases Consultation SUJCML Ex osure SMCDCP ~--~~~~~~ Laboratory IPHS Case 1.0. Institute for Public Health Study Data Supervision Shanghai Municipal Centers for Disease Control & Prevention Case Disease Molecular Control Progression Epidemiology Final 11122102 14 SH ELL-MCCLU RG-067441 How is the SHS Distinct? C. Study will be able to examine primary diagnostic and medical data in real time C. First-hand exposure reports are considered more reliable than secondhand reconstructed information :~:iI:!:I:i; State-owned databases document worker histories Final 11122102 15 SH ELL-MCCLU RG-067442 Shanghai Health Study Background Ct The SHS is designed to provide mechanistic data on AML development in humans :~:iI:!:I:i; A more reliable basis for the extrapolation of leukemia risk associated with low-level benzene exposure can be made with that information Final 11122102 16 SH ELL-MCCLU RG-067443 Shanghai Solutions i:::i::~: Unique Study Environment i:::i::~: Unparalleled Collaboration i:::I::~: Shanghai Health Study Genesis ~::::I:::: Ra re 0 pportu nity i::::::::::::::::: Shanghai Health Study Partners :~::i:::i Shanghai Health Study Hospital Partners :~::i:::i Sino-U.S. Joint Clinical & Molecular Lab Final 11122102 17 SH ELL-MCCLU RG-067444 Unique Study Environment: Shanghai :~::I:~: Robust data set ::;::: State-maintained benzene exposure and health effects databases documented from 1970s i:[::::i:i Benzene related health effects are #2 in reported chronic occupational health hazards in China in 2001 (Source: Ministry ofPublic Health) I}I~ Large range of exposure levels from a variety of occupational sources :If~:~: Regulatory authorities interest in improving benzene exposure regulation and enforcement Final 11122102 18 SH ELL-MCCLU RG-067445 Unique Study Environment: Shanghai :::::::::!::::::: China interested in scientific basis for improved worker-safety regulations :~:::I Chinese occupational standards based on measurable human health effects ::::::1::1:::::: Chinese Occupational Diseases Protection Law (effective May 1/ 2002) :::;::::I Increases worker protections I~{~:~ Specifies company mandates for workers afflicted with health problems due to occupational exposures :t::!I Benzene receiving additional scrutiny Final 11122102 19 SH ELL-MCCLU RG-067446 Unique Study Environment: Shanghai c" High interest in collaborating on research ~!:.::~~ Technology transfers :~;I:{~:~: International health standards :::::::\::::::I::': State-of-the-art lab/ equlpment ~:;:::~i Sha nghai hematology/pathology communities support and expertise ~!:::~~ Strong research program supports China's regulatory understanding and objectives Final 11122102 20 SH ELL-MCCLU RG-067447 Unique Study Environment: Shanghai Ct Fudan University Medical Center :~::l:~l Research partnership Commun-Ity part-Ic-Ipat-Ion.::~t~3t::.;:::~~l;fi~l~f~' ~:::!:~l 16 hospitals will refer patients to the SHS :t!:~::; Shanghai Municipal Center for Disease Prevention and Control :r::~Il Shanghai Institute for Public Health and Supervision Final 11122102 21 SH ELL-MCCLU RG-067448 Unparalleled Collaboration Insert quote from Fu Hua or Fudan:::::::::~;:~:;1lm:;:;}::~::::t University OfficiaI Final 11122102 22 SH ELL-MCCLU RG-067449 SHS Genesis ::~I:~:: NCIjCAPM study ::::::<:::: Retrospective study published 1997 ::::: Raised new questions on effects of low-level benzene exposure :~::I:~: 1999 Shanghai feasibility assessed :Ir:::: Respected scientific collaborators ::t::::::: Well-documented occupational exposure levels across variety of industries I}I: Detailed health and historical records :::::r:::: Sufficient incidences of disease Conclusion:::::::<:::: full study feasible ::~!:~:: Three distinct, highly integrated studies designed Final 11122102 23 SH ELL-MCCLU RG-067450 C") Insert quote from Dr. Wong re: opportunity to conduct rare research in China Final 11122102 24 SHELL-MCCLURG-067451 Rare Opportunity co Unique data set co Technological advances C') Earlier, consistent detection and diagnosis of leukemias and related diseases in Shanghai ~:i:I:!I:i:; Identification of more sensitive benzene exposure biological markers Final 11122102 25 SH ELL-MCCLU RG-067452 Shanghai Partners Ct Fudan University Medical Center f) Institute for Public Health Supervision Shanghai Public Health Bureau .;:~t~3t::;.;~;~lIn;~l~;;:;: Shangha-I Hematology Soc-Iety Shangha-I Pathology Soc-Iety;:;~:::;tmlf}Mt;:r:~;'. ~) Shanghai Municipal Centers for Disease Control and Prevention Final 11122102 26 SH ELL-MCCLU RG-067453 SHS Hospital Partners Changha-I Hosp-Ital;:~:::~:;,'~:::~:i:~:~:::;' Changn-Ing Central;:~:::~:;,'~:ti:~i~:::;' District Hospital ::~:~:~:~:: Changzheng Hospital :i:::::::::::i: First Municipal Hospital ;~tf:\~~~~:::::::;;;' F-Ifth Mun-Ic-Ipal Hosp-Ital ;~tf:\~~~~:::::::;;;' S-Ixth Mun-Ic-Ipal Hosp-Ital ;~ttt:~~~~:::::::;;;' N-Inth Mun-Ic-Ipal Hosp-Ital Huadong Hosp-Ital;;:f\t~~~~:::::::;;;' ::~:;.~::i: Huangpu Central District Hospital Huashan Hosp-Ital;~f}t,~::::::::::::., Re nJ- HosPta I~(t)~;':~~:::::=!;;;: -I -I Shuguang Hosp-ItalAff:~;':~~:::::=!;;;: T-Ielu Hosp-Ital::WJ~::;~:::\::::::::., TongJ--1 Hosp-Ital;~f}t,~:::\::::::::., X-Inhua Hosp-Ital;~f}t,~::::::::::::., Zhongshan Hosp-Ital~(t)~;':~~:::::=!;;;: Final 11122102 27 SH ELL-MCCLU RG-067454 Sino-U.S. Joint Clinical and Molecular Laboratory c~> Insert pictures of laboratory under construction and when complete :~::iwU~:t: V-I rtua I la b tou r?_ Final 11122102 28 SH ELL-MCCLU RG-067455 Benzene Basics What Benzene-IS',t:~t~:if}~tl:r"r Final 11122102 29 SH ELL-MCCLU RG-067456 What is Benzene? C~) A colorless, volatile, flammable liquid with a sweet aromatic odor; c") A natural component of many substances including crude oil; v.;:~r:.:t~::; A by- product of combust-IonI c") A chemical building block; and .) One of top-20 most-produced u.s. chemicals Final 11122102 30 SH ELL-MCCLU RG-067457 Benzene Uses ::~I:I:~: Benzene is a basic petrochemical building block, widely used in the manufacture of products such as: ::::g:::: Dyes and laundry detergents Lubr-Icants:tit::::::::::: I:::!I Nylon and synthetic fibers (carpet, clothing) ::::::::I Pharmaceuticals Pest-Ic-Idesr)I::::::::::: I::::I Plastics and resins ::':: Some types of rubbers (tires) Final 11122102 31 SH ELL-MCCLU RG-067458 Benzene Uses Ct Element of crude oil; found in small amounts in petroleum products Ct As a chemical building block, is transformed in the manufacturing process Eliminated:::::1:1:1'1:::1:::: as an unconverted additive to solvents and adhesives Final 11122102 32 SH ELL-MCCLU RG-067459 Existing Benzene Knowledge tl Conclusions pre-1997 ~, U.S. Regulatory Interpretation t) Recent Epidemiological Studies Co) Challenges Observat-Ions on EX-Ist-Ing SC-Ience:tf}!:::t::;;~;l;!l;~;~:::: Final 11122102 33 SH ELL-MCCLU RG-067460 Epidemiology Conclusions pre-1997 :::::::::!::::::: Acute Myelogenous Leukemia (AML) associated with benzene ::,:: No risk at exposures < 1ppm I:,:::::: Clear risk at exposures > 20 ppm :!:::{!:! Insufficient data at 1-20 ppm to assess risk :~::I:i~: Some steps are not dose-dependent and are governed by a threshold mechanism :::::::::!::::::: All steps required for induction of cancer have not been determined Final 11122102 34 SHELL-MCCLURG-067461 u.s. Regulatory Interpretation co Regulatory decisions based on no- threshold assumption Ct This assumption does not fit the science with respect to benzene Final 11122102 35 SH ELL-MCCLU RG-067462 Challenges Ct Accounting for multiple exposures Ct Addressing confounding factors Ct Quality control C') Accuracy of diagnosis c") Analysis of results Final 11122102 36 SH ELL-MCCLU RG-067463 Recent Epidemiological Studies Ct National Cancer Institute Shanghai Study (NCI) - case-control study published in 1997 iiii:;:::iiii Benzene associated with AML and Non Hodgkin's Lymphoma (NHL): association with a non-AML cancer II:Il Study design did not add to understanding of threshold (lowest exposure group was 10 ppm or less) Final 11122102 37 SH ELL-MCCLU RG-067464 Recent Epidemiological Studies C. Australian Institute of Petroleum's (AlP) Health Watch Study - case-control study released in 2001 :~:::~: Association with all leukemias, including chronic lymphocytic leukemia ::::::H::::; No association with NHL or multiple myeloma Final 11122102 38 SH ELL-MCCLU RG-067465 Observations on Current Science Ct No definitive epidemiological evidence to define a th reshold :::::1:1:1,,1::1:1:; NCI and AlP studies conflict with earlier studies by associating benzene exposure with non-AML cancers Ct SHS designed to quantitatively address these issues Final 11122102 39 SH ELL-MCCLU RG-067466 SHS Elements Ct Case Control Study :ir~}t~:~~tt~i1/?' D-Isease Progress-Ion Study Molecular Ep-Idem-Iology.,::mt:t~:~.'~:;~mil;m;::~; Qua I-Ity Sc -I ence,:;~:::f;:m1fJMt~:r:~:'. :~:iI:!:I:i; Scientific Review Panels Cu rrent Status.:;::;~~ltI~r3~t;:~l:~r.' Final 11122102 40 SH ELL-MCCLU RG-067467 Specific Study Goals :~i:~:I:~:i:~ Understand relationship, if any, between benzene exposure and development of specific hematopoietic diseases: AA, MDS, AML and NHL :::::i::::: Causation of specific diseases/subtypes i:nIi Mechanism of disease progression iIiIi Dose-response relationships iIl':Ii Identification of cofactors and confounders iI!':Ii Identification of biomarkers of exposure and disease progression Final 11122102 41 SH ELL-MCCLU RG-067468 Study #1 - Case Control Study ::~:I:~::i Traditional epidemiology study to determine risk of AML, and potential NHL among benzene exposed workers :i:~:I:~::~ Data collection allow analysis of other causal factors for NHL besides potential benzene exposure ~::~:!:~:: Estimate 4 to 5 years to obtain 450 new AML and 450 new NHL cases ::~:!:~::~ Improved exposure assessment based on historical and concurrent workplace monitoring and questionnaire Final 11122102 42 SH ELL-MCCLU RG-067469 Study #2 - Disease Progression !:~:~:I:~:~ Prospective study on relationship of non-cancer bone marrow disease and benzene-induced AML :lE:::: Is benzene-induced AML different from spontaneous AML by unique cellular markers? i1E::i: Does AML involve a progression through one or more non-cancer states? !:~:~:i:~:~: Research methods: questionnaires, interviews, review work histories; examine blood, breath, urine; study/evaluate potential biomarkers Final 11122102 43 SH ELL-MCCLU RG-067470 Study #3 - Molecular Epidemiology !:~:~:I:~:~ Prospective study to establish quantitative relationship between exposure and effect :;g:~: Do benzene exposures as low as 5-7 ppm (AlP & NCI study) cause blood effects? :;HI: Is there an association of blood effects and genetic susceptibility? ilEi:i: Do biomarkers of exposure accurately reflect workplace exposures? :~:~:I:~::! Healthy workers at sites with varying levels of benzene exposure will participate; extensive lab work, including genetic tests, will be conducted Final 11122102 44 SHELL-MCCLURG-067471 Qualify Science :~::.:~:~ All protocols reviewed and approved by external Institutional Review Boards (IRB's) :!:::=:I: Govern use of human subjects :;:: u.s. and China independently ::~t:t~::'~t~~~:1:i~~::::' Shangha-I Health Study panels t:::I: International Independent Ethics Expert Panel ::::i{::: International Independent Scientific Expert Panel 12 members 6 scientific disciplines ::;::: Expert panels will participate during entire course of studies Final 11122102 45 SH ELL-MCCLU RG-067472 Scientific Review Panels General Toxicology and Biochemistry Epidemiology Statistics Dr. Jerry M. Rice, ( Chair), IARC; Dr. Helmut Greim, Technical U. of Munich Dr. Nancy Mueller (Vice Chair), Harvard U., Public Health; Dr. Harvey Checkoway, WA U. Dr. Howard Rockette, U. of Pittsburgh Industrial Hygiene Dr. John Cherrie, Aberdeen U., Inst. Of Occ. Medicine; Dr. Robert F. Herrick, Ha rva rd U., Pu bl ic HeaIth Hematology Genetic Toxicology Ethics Review Panel Dr. Richard Larson, U. of Chicago Medical School; Dr. Mark Minden, U. of Toronto Dr. Li Guilan, Chinese Academy of Preventive Medicine; Dr. Richard Albertini, U. of VT, College of Medicine Dr. Baruch Brody (Chair), Baylor College of Medicine; Dr. Xu Zong-Liang, Fudan University Final 11122102 46 SH ELL-MCCLU RG-067473 Current SHS Status i:~:!.:!:~:i State-of-the-art laboratory constructed on Fudan University campus I::::I Sustainable technology transfer an important project design component I:'i::~: Equipment imported from u.S. I:':::::: Built according to international standards ::{: Lab will support the project, Shanghai medical community and remain at Fudan ::~I:I:~: Technology transfers :::::=t::: Chinese staff receiving training at University of Colorado ::::::::I U.S. researchers collaborate with Chinese colleagues Final 11122102 47 SH ELL-MCCLU RG-067474 Scientific and Ethical Review Status Disease Progression/Molecular Epidemiology ::;::: Fudan University IRB - final approval Nov 01 ::;::: External International Scientific Review Panel - final approval Jan 02 :~::.:~:~ External Ethics Review Panel - final approval Feb 02 ::~:I:~:: University of CO IRB - final approval May 02 ~::~:~::~:i Applied Health Sciences - review pending Final 11122102 48 SH ELL-MCCLU RG-067475 SHS Projected Timeline :::;:: Questionnaire development, pilot testing in progress, 2002 ::;::: Key laboratory personnel trained, 2002 ,~:::iiftit. Laboratory complete early 2003 :~:~:.::~:i Case recruitment begins - 1st quarter, 2003 :1,:::;::::: 1600 benzene exposed workers, 400 controls :1,::=;:::: Time necessary to identify qualified patients :;;:'f,:::: Length of study may be extended if required ,Laboratory open-Ing.~::::)}i:i::: spr-Ing 2003 t:~:;::~::i Research, analysis expected 2003-2007 :~:~:.::~:i Results published upon project completion Final 11122102 49 SH ELL-MCCLU RG-067476 SHS Sponsors Final 11122102 50 SH ELL-MCCLU RG-067477 Who is Sponsoring the SHS? :~:~:!.:~::~ A consortium of petroleum and chemical companies concerned about understanding the human health effects of benzene :i:H:!:! British Petroleum, ChevronTexaco, ConocoPhillips, ExxonMobil, Shell :In:::: Other members being recruited :lI,::::: American Petroleum Institute, project administrator ~:~::.!:~: Individual company product stewardship and corporate responsibility programs Final 11122102 51 SH ELL-MCCLU RG-067478 Why Industry Sponsors? SHS goal to provlde an accurate';~:::~~i~i~(~:j1}:i:~:~::;:.' understanding of how benzene works on a molecular level in humans :If:::::: Advanced understanding of benzene-induced disease could lead to development of effective disease prevention strategies ::;.:: Would allow a more finely calibrated assessment of potential health effects !:!::;;::!:! Provide best protection for workers and public Final 11122102 52 SH ELL-MCCLU RG-067479 Why Industry Sponsors? Worldw-Ide:::::::I::tm!:r::::::::t I benzene occu pat-lana I exposure regulatory standards vary widely ~I::I: Examples: O.5ppm in Malaysia; lOppm in Japan; China in the middle range :::::!"!:::::: American Conference of Governmental Industrial Hygienists recommends O.5ppm f'Industry has long sponsored benzene research Final 11122102 53 SH ELL-MCCLU RG-067480 SHS Funding Structure Final 11122102 54 SH ELL-MCCLU RG-067481 SHS Funding Structure :t::::::::: $22.8 million program total for all costs over 5 years I:;'I: $16.5 million confirmed as of October 2002 :I;:~:~: Current funding through October Q3 03 :::::::::1::::::: Costs projected to be highest during first yrs. ::;::: Payment scheduIe :Ii:!:!: August 2001 I:;{:!: January 2002 I:;'I: August 2002 :IiI: August 2003 I}I! August 2004 August 2005:::::!::::::: 15% 15% 25% 15% 15% 15% Final 11122102 55 SH ELL-MCCLU RG-067482 SHS Funding Structure :~:~:I:~::~ Funding shares determined by size and sector ::~t}t:.'~::~~~~~:1:i~~::;:' Formula used to asslgn 1 to 3 shares ::;.:: Refiners: 1 to 3 shares based on u.s. capacity :IiI: Chemical companies: 2 shares iIiIi Other companies: 1 share ::~:!:~::~ One share currently equals $1.5 million Final 11122102 56 SH ELL-MCCLU RG-067483 SHS Funding Structure D-Irect costs;::fJt:;:~tf~~i~~::;: ::::g:::: Data collection and analysis with procedures to protect pri-vacy; t:{::: Procedures and training for data collection in participating clinics; :::: Constructing, training, staffing state-of-the-art hematology laboratory; :::;:'i;:::: Laboratory operations for research and clinical tests; and I:':;;::: Operations for 5 years estimated to identify study cases i:~:!;i!:~:i Administrative costs ::{: Internal and external communications and coordination; :;:{: API project administration, travel; off-site meetings Final 11122102 57 SH ELL-MCCLU RG-067484 Terms, Sources and Resources Final 11122102 58 SH ELL-MCCLU RG-067485 Terminology ::iiilil:i::::iliii:~AA ::::iili:i:!:lii:::;AML B-10m arke r.:t:~:}t:,:~;;t1tr:' EP-I dem-I alogy.::if)t~:.::;mfi~;m;::' H-Istology.:.i:li:~i~~~:f~l~t~:i:~f.: NHL::ili:!:i:ili:~ Final 11122102 59 SH ELL-MCCLU RG-067486 Acronyms :~::.::~: API - American Petroleum Institute :~::i:::~: AlP - Australia Institute of Petroleum :~::i:i::~: IRB - Institutional Review Board :~::.:::~: CAPM - Chinese Academy of Preventive Medicine :t::::::::: IPHS - Institute for Public Health Supervision (China) :~::.::~: NCI - National Cancer Institute (U.S.) :~::i:::~: SUJCML - Sino-U.S. Joint Clinical and Molecular Lab :~::i:i::~: SMCDCP - Shanghai Municipal Center for Disease Control and Prevention :~::.::~: USEPA - U.S. Environmental Protection Agency Final 11122102 60 SH ELL-MCCLU RG-067487 Sources i:~:!:~::i American Council of Government Industrial Hygienists :~:~:I:~:~ Agency for Toxic Substances and Disease Registry ToxFAQs, U.S. Department of Health and Human Services ~:~:I:~::~ American Petroleum Institute i:~:!:~::i International Agency for Research on Cancer :~:~:i:~:~: United States Environmental Protection Agency :~:~:I:~:~ University of Colorado Cancer Center, Denver, CO Final 11122102 61 SH ELL-MCCLU RG-067488 For More Information Cm'Template: Add your and your team's contact information here. :::::i::::;::::::: Lorraine Twerdok, BHRC Administrator 202.682.8319i:i::i,:i::i:i Twe rd kl@ apl. rg0i!i!:;:::::!i!i 0 Final 11122102 62 SH ELL-MCCLU RG-067489 For More Information f~ Patrick Beatty, Chair, Technical Committee f'Don Burnett, Chair, Oversight Committee :~:I:i:!:I~:: Bill Frick C~, Lorraine Twerdok, BHRC Administrator Final 11122102 63 SH ELL-MCCLU RG-067490 The Shanghai Health Study Lorraine Twerdok American Petroleum Institute twerdokl@api.org SHELL-MCCLURG-067491 Conclusions from pre-1997 Epidemiology :~:~:i:::~ Only acute myelogenous leukemia (AML) associated with benzene <No r-Isk at exposures 1ppmt\:::::=:::::':::::= :I;:~:~: Clear risk at exposures > 20 ppm :I!':I: Insufficient data at 1-20 ppm to assess risk :~:~:i:::~ Some steps are not dose-dependent and are governed by a threshold mechanism ~::~:i:~:~: All steps required for induction of cancer have not been determined SH ELL-MCCLU RG-067492 Regulatory Interpretation c") Regulatory risk assessment default of linear, no threshold model does not fit the science Ct Current regulatory decisions imply recog nition of a th reshold or a no observed adverse effect level (NOAEL) SH ELL-MCCLU RG-067493 Recent Epidemiological Results c") National Cancer Institute Shanghai Study - published in 1997 itl::::::i:i Benzene associated with AML and Non Hodgkin's Lymphoma (NHL) - first association with a non-AML cancer iiii:;::!:iiii No threshold observed (effects observed in lowest exposure group of 10 ppm or less) Ct NCI Exposure Methods Criticized in published literature SH ELL-MCCLU RG-067494 Recent Epidemiological Results ::;::: Australian Institute of Petroleum's (AlP) Health Watch Study: Case-control study published in 2001 :::;:: Strong association with all leukemias, including chronic lymphocytic leukemia :I;:~:~: No association with NHL or multiple myeloma Low exposures 2 ppm) wlth no;;fJ~~;: 1':~t~{:~i~~~::;' - apparent threshold ::;::: Significant methodological problems SH ELL-MCCLU RG-067495 Observations on Current Science Ct No definitive epidemiological evidence to support or refute a threshold :::::1:1:1,,1::1:1:; NCI and AlP studies conflict with earlier studies by associating benzene exposure with AML and non-AML cancers ::::1:11:;::11::1) Effects descri bed at lower doses tha n previously seen; no apparent threshold SH ELL-MCCLU RG-067496 Genesis ofShanghai Health Study C") Feasibility studies in Shanghai in 1999 documented :::::1'::::: High exposure levels; good records :I;{::: Sufficient numbers of cases of disease for valid study :Ii:::::: Willing scientific collaborators in Shanghai Ct Three closely related studies were designed SH ELL-MCCLU RG-067497 Study #1 - Case Control Study :::::::;::!::::::: Traditional epidemiology study to determine risk of AML, NHL among benzene exposed workers i:~::.!:~:: Should identify other causal factors for NHL besides benzene exposure ::~:!.::~:i Estimate 4 years to obtain 450 new AML and 450 new NHL cases i:~::.!:~:: Improved Exposure Assessment based on historical and concurrent workplace monitoring and questionnaire SH ELL-MCCLU RG-067498 Study #2 - Disease Progression ::;::: Prospective study on relationship of noncancer bone marrow disease and benzene induced AML :Ii:I: Is benzene induced AML different from spontaneous AML? :I!':I: Are there unique markers for benzene induced AML? i:~::.:~:: Questionnaire, interviews, review work histories; examine blood, breath, urine, evaluation of biomarkers of exposure SH ELL-MCCLU RG-067499 Study #3 - Molecular Epidemiology Study !:~:~:I:~:~ Prospective study to establish quantitative relationship between exposure and effect r!{::~ Do benzene exposures as low as 7 ppm (as in NCI study) cause blood effects? t{::: Is there an association of blood effects and genetics t{::: Do biomarkers of exposure accurately reflect workplace exposures? :~:~:I:~::~ Healthy workers exposed to varying levels of benzene will participate; extensive lab work including genetic tests will be conducted SH ELL-MCCLU RG-067S00 Highest Quality ofScience ;:it:~:;:;.':'::~:i:/f' All protocols revlewed and approved by ~Ii:I~ Use of Human Subjects Committees (IRS's) in US and China :Ii'I: International Independent Ethics Expert Panel IJI: International Independent Scientific Expert Panel 12 members 6 scientific disciplines :::::::i"!::::::: Expert Panels will participate during entire course of studies SHELL-MCCLURG-067501 Scientific Review Panels General Toxicology and Biochemistry Epidemiology Statistics Industrial Hygiene Hematology Genetic Toxicology Dr. Jerry M. Rice, ( Chair), IARC Dr. Helmut Greim, Technical University of Munich Dr. Nancy Mueller (Vice Chair), Harvard School of Public Health Dr. Harvey Checkoway, University of Washington Dr. Howard Rockette, University of Pittsburgh Dr. John Cherrie, Aberdeen University, Inst. Of Occ. Medicine Dr. Robert F. Herrick, Harvard 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 Ethics Review Panel Dr. Baruch Brody (Chair), Baylor College of Medicine Dr. XuZong-Liang, Fudan University SH ELL-MCCLU RG-067502 Current Status ofProgram ::::::::::i::::::: Consortium of 5 companies have committed $16.5 million dollars of a $22.5 million budget for estimated 5 year program I:;':~: BP, ChevronTexaco, Conoco, ExxonMobil, Shell I:!::::: Other members being recruited i:~::'i:~:~: State-of-the-art science facility is under development in Shanghai :~:~:i::~:i Questionnaire development and pilot testing In progress i:~::'i:~:~: Case recruitment - 1st quarter of 2003 SH ELL-MCCLU RG-067503 In Summary . .. :~:~:i:::~ These studies are an opportunity to obtain a better understanding of the mechanism of benzene induced disease in humans. ~:~::I:~:: Completion of these studies should have a significant impact on benzene risk assessment These stud-Ies:::::::~tti}lt::::::. ::::::I: esCm.iepnlocey state-of-the-art biological and epidemiological II::: represent sound product stewardship IH:::: exemplify best practices in research ethics ::::::I: depend upon partnership of industry, governments, academia and public SH ELL-MCCLU RG-067504 For More Information Patr-I ck Beatty.:t:~:}t:,:~;;t1tr:' pwbe@chevrontexaco. com Stuart Cagen.::~tt\:~~~:j}~tl:rt, szcagen@shell.com La rra -I ne Twe rd ak,:::~:::~t~tli{Mtr:::::' twerdokl@api.org .': :". B-II Fri-c k.::::~;:mffUi:~:;:m~;::~:::' 1 frick@api.org SH ELL-MCCLU RG-067505 The Shanghai Health Study Patsy Clegg Chair, Oversight Committee Shell Chemicals LP June 2005 SH ELL-MCCLU RG-067506 What is the Shanghai Health Study? :~::.::~: A long-term clinical study to investigate the potential causes and development of Iympho-hematopoietic diseases (diseases of the lymphoid organs, blood and bone marrow) as related to benzene A pro1iect of:'~:~~~/::I::t;:;. J }{::~ Fudan University Medical Center - Shanghai, China }{:: University of Colorado Health Sciences Center t::::::: Applied Health Sciences - an independent U.S. research firm t:t::: Chinese public health agencies t{::: Shanghai hospitals SH ELL-MCCLU RG-067507 Path to developing the study: ~::::) Pre-97: :::::) 97: Benzene exposure associated with AML NCI published conclusions from China study that: y AML develops at exposures lower than previously known - no th reshold observed y Benzene is associated with NHL NCI Methodology criticized Feasibility studies in Shanghai Australian Institute of Petroleum's (AlP) Health Watch Study y Association with all leukemias, including chronic lymphocytic leukemia y No association with NHL or multiple myeloma Benzene Health Research Consortium formed to: y do a study to test conclusions y address questions of disease progression and biomarkers SH ELL-MCCLU RG-067508 The Shanghai Health Study is 3 studies 1. Case Control Study Traditional, prospective epidemiology study to determine risk of AML, NHL among benzene exposed workers - 450 AML and 450 NHL patients into study 2. Disease Progression Study Prospective study on relationship of non-cancer bone marrow disease and benzene induced AML 3. Molecular Epidemiology Study Prospective study seeking to establish quantitative relationship between exposure and effect SH ELL-MCCLU RG-067509 The Shanghai Health Study 1. Case Control Study - Update Traditional, prospective epidemiology study to determine risk of AML, NHL among benzene exposed workers - 450 AML and 450 NHL patients into study As of YE04: DDisease recruitment on track [This is much too detailed for this audience, and are non-vetted numbers -- suggest something like "disease recruitment on track"] SHELL-MCCLURG-067510 The Shanghai Health Study 2. Disease Progression Study - Update Prospective study on relationship of non-cancer bone marrow disease and benzene induced AML Unique profile of MDS (myelodysplastic syndrome) identified fin high-benzene exposed workers 30-200 ppm, 6-20 years I ~ Characterized as BIMDS (benzene-induced myelodysplastic syndrome) ~ MDS subtype profile was established acros~ 100 consecutive I MDS cases ~ provided a unique profile for this genetic pool and geographic reqion ~ both BIMDS and MDS-subtvping will appear as manuscripts [Suggestion -- eliminate concentrations/numbers, since tll1s is unpublished data (100 is incorrect anyway). Reference to BIMDS is OK. The bottom line from this is mechanistic: "Suggests that immune parameters have a much larger influence than originally thought" (which is better than the alternative genetic parameters). ] SHELL-MCCLURG-067511 The Shanghai Health Study 3. Molecular Epidemiology Study - Update Prospective study seeking to establish quantitative relationship between exposure and effect ME Phase I ~ 400 medical records from 48 factories had been reviewed (of 1800 total medical records from 84 factories) ME ~hase L.A ~ Analyses performed on blood/urine from 231 high-exposure workers ME Phase 28 ~ Worker recruitment issues remain ... only 3 bone marrow samples obtained [Numbers from phase 1 are incorrect (84 factories/1800 med records???) , rest is theoretically OK. -- "have successfully recruited several factories and records for over 1000 cases have been abstracted to dat, SHELL-MCCLURG-067512 Uniqueness ofShanghai Study :i:~:I:~:i: Prospective resea rch iI;:Ii Patients at participating hospitals suspected of having a lymphoid, blood or bone marrow disease are referred to the SHS ill: Patients1 diets, lenvironmental exposures and family histories are recorded :in:i:i: Patient disease progression followed at supporting hospitals [Leave out "DIETS"] SHELL-MCCLURG-067513 Uniqueness ofShanghai Study ::~:I:~:: Study examines primary diagnostic and medical data in real time ::~:I:~:: First-hand exposure reports are more reliable than second-hand or reconstructed information i::~:~:i:~::~: a e-owne a a ases ocumen wor er histories exposure readings from some tions [We are NOT going into every factory of patients' to get "first hand" exposure reports. Nor can the IPHS database be used for every patient. We DO have to re-construct exposure, especially for CC and ME-I studies. The 'state-owned' databases don't document worker histories, they document exposure readings for some jobs/locations. ] SHELL-MCCLURG-067514 Why Shanghai? i::::::::::::::::: Benzene related health effects are #2 in reported chronic occupational health hazards in China in 2001 (Source: Ministry ofPublic Health) :::::::::1::::::: Large range of exposure levels from a variety of occupational sources :::::::::::::::::i Regulatory authorities interest in improving benzene exposure regulation and enforcement SHELL-MCCLURG-067515 Quality, Independent Science :::::i:::::::: All protocols reviewed and approved by external Institutional Review Boards (IRB's) II::: Govern use of human subjects t{::: u.s. and China independently :i:::i::i:::i: Shanghai Health Study independent review panels ::::::I: International Ethics Review Panel 13 members - 1 each from China, Europe, and US t{::: International Scientific Review Panel 12 members 6 scientific disciplines ::}Ii Involved during entire project [Should read "4 members - 1 each from China, Europe, 2 from US"] SHELL-MCCLURG-067516 Benzene Health Research Consortium Sponsoring Companies ~ BP ~ ChevronTexaco ~ ConocoPhillips ~ ExxonMobil ~ Shell Chemical LP Marathon/Ashland providing additional support SHELL-MCCLURG-067517 Benzene Health Research Consortium Organization Oversight Committee Technical/Btdget CommU~ication ~eJewlScientific Panel Ethics Review Panel API Administrative Support [Suggest leaving out the arrow for SRPjERP...they are independent] SHELL-MCCLURG-067518 Shanghai Health Study Study Participants Principal Investigators: Dr. Richard Irons, U of Colorado Health Sciences Center Dr. Otto Wong, Applied Health Sciences Dr. Fu Hua, Fudan University Collaborators: ExxonMobil Biomedical Sciences Chinese Participants: Fudan University School of Medicine 31 area Shanghai hospitals Shanghai Municipal Center for Disease Prevention Shanghai Hematology Society Shanghai Pathology Institute for Public Health Supervision Sha nghai Pu blic HeaIth Bu rea u Internal Review Boards U of Colorado, Fudan University, AHS SHELL-MCCLURG-067519 Shanghai Health Study Aug 01 3/4Q01 2002 3Q03 Aug 03 4Q03 Aug 04 Oct 04 Nov 05 2007/8 Study Time Line Consortium Formed Protocols Reviewed JCML Lab constructed, equipped at Fudan; technicians trained Began accruing cases First Annual Meeting Opening Ceremony in Shanghai Second Annual Meeting International Benzene Symposium Third Annual Meeting Report/Publications in scientific journals SH ELL-MCCLU RG-067520 Shanghai Health Study .:. Budget .:. Funding Costs $ 26M $ 26M SHELL-MCCLURG-067521 Shanghai Health Study Summary :~:;:{:~: Opportunity to obtain a better understanding of the mechanism of benzene induced disease in humans. =:i:f,f::i:= Potential significant impact on benzene risk assessment. =~{:;:~: Highest Quality of Science: esCm.iepnlocyes state-of-the-art biological and epidemiological represents sound product stewardship exemplifies best practices in research ethics depends upon partnership of industry, governments, academia and public SH ELL-MCCLU RG-067S22 SH ELL-MCCLU RG-067523 The Shanghai Health Study Patsy Clegg Chair, Oversight Committee Shell Chemicals LP July 2005 SH ELL-MCCLU RG-067S24 What is the Shanghai Health Study? ::i:::i"!::} A long-term clinical study to investigate the potential causes and development of Iympho-hematopoietic diseases (diseases of the lymphoid organs, blood and bone marrow) as related to benzene :.::{;W::;::t.,: A pro1J iect of II:l Fudan University Medical Center - Shanghai, China n~] University of Colorado Health Sciences Center IIi: Applied Health Sciences - an independent U.S. research firm tIl Chinese public health agencies ii:Il Shanghai hospitals SH ELL-MCCLU RG-067525 Shanghai Health Study Purpose C) To gain a quantifiable understanding of the relationship between benzene exposure and potential associated cancer risks SH ELL-MCCLU RG-067526 Path to developing the study: t:;::::~:: Pre-9 7: 97::~: :;:;: : : Benzene exposure associated with AML NCI published conclusions from China study that: y AML develops at exposures lower than previously known - no th reshold observed y Benzene is associated with NHL NCI Methodology criticized Feasibility studies in Shanghai Australian Institute of Petroleum's (AlP) Health Watch Study y Association with all leukemias, including chronic lymphocytic leukemia y No association with NHL or multiple myeloma Benzene Health Research Consortium formed to: y do a study to test conclusions y address questions of disease progression and biomarkers SH ELL-MCCLU RG-067S27 The Shanghai Health Study is 3 studies 1. Case Control Study Traditional, prospective epidemiology study to determine risk of AML, NHL among benzene exposed workers - 450 AML and 450 NHL patients into study 2. Disease Progression Study Prospective study on relationship of non-cancer bone marrow disease and benzene induced AML 3. Molecular Epidemiology Study Prospective study seeking to establish quantitative relationship between exposure and effect SH ELL-MCCLU RG-067528 The Shanghai Health Study 1. Case Control Study - Update Traditional, prospective epidemiology study to determine risk of AML, NHL among benzene exposed workers - 450 AML and 450 NHL patients into study As of YE04: y 437 AML cases had been accrued y 155 NHL cases had been accrued ~ Expect 300-325 thru 2005; 450-500 thru 2006 2 controls per case were also processed through JCML lab analysis SH ELL-MCCLU RG-067529 The Shanghai Health Study 2. Disease Progression Study - Update Prospective study on relationship of non-cancer bone marrow disease and benzene induced AML Unique profile of MDS (myelodysplastic syndrome) identified in high-benzene exposed workers - 30-200 ppm, 6-20 years ~ Characterized as BIMDS (benzene-induced myelodysplastic syndrome) ~ MDS subtype profile was established across 100 consecutive MDS cases ~ provided a unique profile for this genetic pool and geographic region both BIMDS and MDS-subtyping will appear as manuscripts SH ELL-MCCLU RG-067S30 The Shanghai Health Study 3. Molecular Epidemiology Study - Update Prospective study seeking to establish quantitative relationship between exposure and effect ME Phase I ~ 400 medical records from 48 factories had been reviewed (of 1800 total medical records from 84 factories) ME Phase 2A ~ Analyses performed on blood/urine from 231 high-exposure workers ME Phase 28 ~ Worker recruitment issues remain ... only 3 bone marrow samples obtained SH ELL-MCCLU RG-067S31 Uniqueness ofShanghai Study Prospective resea rch::::I!:;;!I::::: Ii'::::l Patients at participating hospitals suspected of having a lymphoid, blood or bone marrow disease are referred to the SHS ::::g:::l Patients' diets, environmental exposures and family histories are recorded If::::l Patient disease progression followed at supporting hospitals SH ELL-MCCLU RG-067S32 Uniqueness ofShanghai Study C~, Study examines primary diagnostic and medical data in real time C~, First-hand exposure reports are more reliable than second-hand or reconstructed information ::::1:1:1:1::11:::: State-owned databases document worker histories SH ELL-MCCLU RG-067S33 Why Shanghai? :~:~:;:~:i: Benzene related health effects are #2 in reported chronic occupational health hazards in China in 2001 (Source: Ministry ofPublic Health) i :i:::i::il::i::: : Large range of exposure levels from a variety of occupational sources ':~:I!i:~: Regulatory authorities interest in improving benzene exposure regulation and enforcement SH ELL-MCCLU RG-067S34 Quality, Independent Science :~t:;:!:: All protocols reviewed and approved by external Institutional Review Boards (IRB's) IIi Govern use of human subjects [m u.s. and China independently :::!::i!i!} Shanghai Health Study independent review panels nm International Ethics Review Panel 3 members - 1 each from China, Europe, and US rm International Scientific Review Panel 12 members 6 scientific disciplines n~] Involved during entire project SH ELL-MCCLU RG-067535 Benzene Health Research Consortium Sponsoring Companies ~ BP ~ ChevronTexaco ~ ConocoPhillips ~ ExxonMobil ~ Shell Chemical LP Marathon/Ashland providing additional support SH ELL-MCCLU RG-067S36 Benzene Health Research Consortium Organization Oversight Committee 11 Technical/Budget Communication Scientific Review Panel Ethics Review Panel API Administrative Support SH ELL-MCCLU RG-067S37 Shanghai Health Study Study Participants Principal Investigators: Dr. Richard Irons, U of Colorado Health Sciences Center Dr. Otto Wong, Applied Health Sciences Dr. Fu Hua, Fudan University Collaborators: ExxonMobil Biomedical Sciences Chinese Participants: Fudan University School of Medicine 31 area Shanghai hospitals Shanghai Municipal Center for Disease Prevention Shanghai Hematology Society Shanghai Pathology Institute for Public Health Supervision Sha nghai Pu blic HeaIth Bu rea u Internal Review Boards U of Colorado, Fudan University, AHS SH ELL-MCCLU RG-067S38 Shanghai Health Study Aug 01 3/4Q01 2002 3Q03 Aug 03 4Q03 Aug 04 Oct 04 Nov 05 2007/8 Study Time Line Consortium Formed Protocols Reviewed JCML Lab constructed, equipped at Fudan; technicians trained Began accruing cases First Annual Meeting Opening Ceremony in Shanghai Second Annual Meeting International Benzene Symposium Third Annual Meeting Report/Publications in scientific journals SH ELL-MCCLU RG-067S39 Shanghai Health Study .:. Budget .:. Funding Costs $ 26M $ 26M SH ELL-MCCLU RG-067540 Shanghai Health Study Summary :~:\:.::~: Opportunity to obtain a better understanding of the mechanism of benzene induced disease in humans. ti,:,::i::: Potential significant impact on benzene risk assessment. :~:;:i} Highest Quality of Science: esCm.iepnlocyes state-of-the-art biological and epidemiological represents sound product stewardship exemplifies best practices in research ethics depends upon partnership of industry, governments, academia and public SH ELL-MCCLU RG-067S41 The Shanghai Health Study Patsy Clegg October 2002 SH ELL-MCCLU RG-067S42 The Shanghai Health Study :~::.::~: Path to developing the study: IJ Pre-97: 97::::H::::: Benzene exposure associated with AML NCI published conclusions from China study that: - Benzene can cause NHL - AML develops at exposures lower than previously known - no threshold observed NCI Methodology criticized Feasibility studies in Shanghai Benzene Health Study Consortium formed to: - do a study to test conclusions - answer questions of disease progression and biomarkers SH ELL-MCCLU RG-067543 Benzene exposure and cancer Conclusions from pre-1997 Epidemiology :~:~:I:~::~ Only acute myelogenous leukemia (AML) associated with benzene :t!::I: No risk at exposures < 1ppm III: Clear risk at exposures > 20 ppm I:i::::: Insufficient data at 1-20 ppm to assess risk SH ELL-MCCLU RG-067S44 The Shanghai Health Study 1. Case Control Study Traditional epidemiology study to determine risk of AML, NHL among benzene exposed workers 2. Disease Progression Study Prospective study on relationship of non-cancer bone marrow disease and benzene induced AML 3. Molecular Epidemiology Study Prospective study to establish quantitative relationship between exposure and effect SH ELL-MCCLU RG-067545 Benzene Health Research Consortium Sponsoring Companies 'Y BP 'Y ChevronTexaco 'Y ConocoPhillips 'Y ExxonMobil 'Y Shell Chemicals, LP SH ELL-MCCLU RG-067546 Benzene Health Research Consortium Organization Oversight Committee Technic~mmtnication Jecruitment Legal 11 Scientific Review Panel APeD Ethics Review Panel API Administrative Support SH ELL-MCCLU RG-067S47 Shanghai Health Study Study Participants Principal Investigators: Dr. Richard Irons, U of Colorado Health Sciences Center Dr. Otto Wong, Applied Health Sciences Dr. Fu Hua, Fudan University Collaborators: ExxonMobil Biomedical Sciences Chinese Participants: Fudan University School of Medicine 16 area Shanghai hospitals Shanghai Municipal Center for Disease Prevention Shanghai Hematology Society Shanghai Pathology Institute for Public Health Supervision Sha nghai Pu blic HeaIth Bu rea u Internal Review Boards U of Colorado, Fudan University SH ELL-MCCLU RG-067548 Shanghai Health Study Aug 2001 3/4Q01 2002 1Q03 2Q03 Aug 03 2007 Study Ti me Li ne Consortium Formed Protocols Reviewed Lab Constructed and Equipped at Fudan Begin accepting cases Opening Ceremony in Shanghai First Annual Meeting Report SH ELL-MCCLU RG-067549 Shanghai Health Study .:. Budget Costs $22.5M .:. Funding $16.5M .:. Recruitment Plan to gain additional support SH ELL-MCCLU RG-067550 Shanghai Health Study Summary :~:;:{:~: Opportunity to obtain a better understanding of the mechanism of benzene induced disease in humans. =:!i:f'f::!:= Significant impact on benzene risk assessment. =~{:;:~: Highest Quality of Science: tHI employ state-of-the-art biological and epidemiological science :!}I represent sound product stewardship t{!: exemplify best practices in research ethics }{!: depend upon partnership of industry, governments, academia and public SHELL-MCCLURG-067551 Shanghai Health Study Overview Purpose: To gain an accurate understanding of the true 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 can also lead to improved benzene-driven, health-based regulatory (e.g., ambient air, water & occupational) standards worldwide, by providing the regulatory and scientific communities with 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 meaningful benzene research. These include a database of occupational exposures in a different regulatory environment, and willing and qualified co-investigators influential in local scientific medical, and regulatory establishments. Therefore, questions that have plagued benzene health risk assessment for decades appear to be answerable in Shanghai. The Studies: The program involves three inter-related studies: Case-Control Study - A hospital-based case control study to investigate 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 benzene for the AML response. Disease Progression Study - A hospital/clinic-based investigation of the relationship between non-cancer diseases ofthe bone marrow and AML (cancer) to determine if effects on bone marrow progress through non-cancer stages to an ultimate leukemia. This study would also attempt to define the shape ofthe dose response for possible "precursor" diseases and could result in characterization of unique identifiers of benzene-induced AML. Molecular Epidemiology Study - Investigate 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 benzene-induced disease in individuals. Benefits: Information gained from this project will have a 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 make 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. Ethical - To address the ethical issues, the study protocols have all undergone a thorough analysis to ensure that they meet international standards for research involving humans, including that the subjects and participating communities benefit from having participated in April 3, 2002 -I - SH ELL-MCCLU RG-067SS2 Shanghai Health Study Overview the study; that confidentiality is preserved, and that researchers are working with local regulatory authorities to improve worker safety. An Ethics Panel is part of the oversight for the project and includes a Chinese bioethicist. 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 responsible for occupational exposure monitoring and enforcement in Shanghai). Funding: Funding for the project will be handled by a consortium of interested stakeholders, with shares determined by size of the benzene related operations of the contributing organization. The proposed funding formula was devised based on the assumption that most of the support will come from the petroleum and petrochemical industries. It is anticipated to take five years to complete the project, and that the costs will be highest in the first years of the project. For More Information: Please contact anyone of the following individuals. Patrick Beatty Bill Frick Myron Harrison Chris Roythome Lorraine Twerdok Chevron Texaco API ExxonMobil BP API Dwbe(iv.chevrontexaco. com fricktQlaJ)i .org mvron.c.Harrison@exxonmobil.com roythorc(aJ,bQ.com tvverdokltQla])i .org + 1 510-242-7037 + 1 202-682-8240 + 1 972-444-1673 + 44 (0)20 7496 4126 +1 202-682-8344 April 3, 2002 - 2- SH ELL-MCCLU RG-067553