Document oew9G1JYN4rR6kOMr43dqxVv7

UNIVERSITY OF CALIFORNIA, BERKELEY SCHOOL OF PtJBUCHEALTii DIVISION OF ENIRONMENTAL :jif.AL1H SOENCES modem facsimile transmiKal from Martyn T. Smith room number: fax number: phone number: emai~ 7f7 University Hall (510) 642-5815 (510) 642-8770 martyntshclink4.berkeley.edu Dt. Grover 'Bagby Ox. Patrick 'Beattv Dt. Frederic BoiS Dr. John Budtoe Dl. Tony Cox Dl. David Eastmcnd Dr. Alessandta Forni Dt. Jennifer Galvin Dt. Donald Ga\'er Dt. Bernard Goldstein Dt. Rogene Hendetscn Dr. Richard Irons Dr. Troyce Jones Dr. George Kalf date: February 81 1996 (503) 494-4285 (510) 242-7022 (510) 540-2695 (510) 540-2923 (303)3~9 (SQ9) 7W1-3087 011 39 25518 7172 (918) 662-1139 (408) 656-2595 (906) 445 0131 (505) 645-1169 (303) 270-7223 (423) 576-7651 (215) 955-5393 Dr. Charles Lapin Dr. Richatd LaiSDn Dr. Tom McDonald- Dr. Miche1e Medinsky Dr. Sutesh Mool$avkat Dr. Y...-aria Palla\'lcini Dr. Mary Paxton Dr.AzraR.au Dr. David Ross Dr. Robert Snyder !k William Suk Dr. F. Benjamin Thomas Dr. David Ting Dt. LaurenZeise (213) 486-2021 (312) 702~963 (510) 540-2695 (919) 558-lnl (206) 667-7004 (415) 476-8218 / - (202) 682-8270 ~ (312) 455-8479 (303) 270-6281 (908) 445-0119 (919) 541-2843 (713)7~.0195 (510) 540-2695 (510) 540=2695 number of pages: 7 (including this cover sheet) OAttached is the final Program Agenda along-with the Aims and QuestioM that 1have dtafted for the upcommg workshop. 1 would like you to_think about these aims/quesmns before coming to the meeting. Please feel free to bring slides or overheads of any hot new data pertaining to these questions. In addition, it you haven't sent your 2 page Clmiwlum Vitat please do so at your earliest RtJSSible convenience. CV's should be submitted preferably via email (either as an attachment or in the body of the message) or by fax at the nwnber above. Please send email submissions- to Maura Starace at c:maura~udink2.berkeley.edu:.. If you have any last minute questions or concerns please contact Susan Neal at (510) 64.3-9815 or Maura Storace at (510) 643-5100. Best Regazds, ~~~' .Maztyl\ smith BP-00020757 Lunch-Reception 12:00 - 2:00 pm Afternoon 2:00- 2:40 pm 2:40-3:15 pm 3:15-4:00 pm 1:00-4:15 pm 4:15- 4:50 pm 4:50- 5:ll pm Evening 6:30pm Sunday.-Febmmy 1I Introductory Remarks Coals of the workshop M. Smith, NIEHS perspective: W. Sd Cal EPA perspectialteadytive: P. Btlltty Benzene TolCicoloSY Session Chairs: R. Snyder, M. -smiih Overview of Benzene Toxicology: M. Smith Altered Differentiation in Benzene Teicity: .R. Irons Discussion led by R. S11yder, D. Eastmond, A Forni, B. Goldstti11 Break Pharmacokinetics of Benzene: M. Mtdins1cy Discussion led by F.llois, G. KAlf, D. Ross, R. Henderson Buffet Recep6oll (spouses tmd puts wtlcome) BP-00020758 Morning 8:00- 8:35 am &35-9:10am 9:10 - :9:40 am 9:40- 10:00 am 10:00 -10:35 am 10:35 - 11:10 am 11:10 -12:00 pm 12:00 -1:00 pm Afternoon 1:00 -1:40 pm 1:40- 2:15 pm 2:15- 2:50 pm 2:50 - 3:15 pm 3:15 -3:55_ pm Evening 5:00pm Biology of I.wkemia Session Cha.iJ:s: G. K!J.lf, R. Larson Hematoto"icity_ and LeukenUa: G. &gby Apoptosis and leukemia: A. Raza Discussion led by R. Irons, G. Mlf, T.]onts, D. Ross Break Genetic Changes in Leukemia: M. Ptllltwir:irri Seconda%)' Leukemias: R. Lmon Discussion led by D. Eutmond, M. Smith, B. Golrlstm, A. Forni, T.Co.r Lunch Mitliematical Modelling Session Chairs: B. Goldstein, S. Moolgmr Overview of Carcinosenesis Models: S. Moo!gavw A Model of Benmne Hematotoxicity: L. Cox Lessons from Modelling the Effects of Radiation: T./onts Break Discussion led by F. BoJS, D. Gmr, A.. .Raza, L. Zeis~. R.lrottS, G. Bagby, M. ~di~~&ky BP-00020759 Morning 8:00- 8:35am 8:35-9:00am 9:00 -10:10am 10:10 -lO:~m 10:.30 -12:00pm 12:00 -1:30pm Afternoon 1:30 5:00pm Special Ledure Chait: M. Smith Chromosome Aberratioas as Predictors of Risk from Benzene Exposure: A. Forni Discussion Jed-by B. Goldsttin, R. Lan:o11. M. P,dlavicm~ F. 'Bois, L. Zh4ng Group-consensus Consensus Meeting I Break, informal discussion Consensus Meeting II Lunch- Closing Remarks Write-_up (organi2er61Uld invitee6 Oftly) Write-Up Participants from U.C. Berkeley, CalEFA. !ftdustry and selected invitees will work together to write up the proceedings of the workshop, to create a meeting report that summarizes the key conclusions that have ematged.. Points of consensus and key points of dissent will be included. BP-00020760 U!UKfMIA WORKSHOP AlMS Ovall Goals The general workshop aim is to evaluate the current state of lu\owledse of benzene-itlduceclleukemia Ia determine whether and howihe ptocess can be modeled mathematically, given what we bow about benzene's bone marrow effects, leukemogenesis, and available modelitlg techniques. We hope to address the overall questions: 1. What is the current state of knowledge of the mechanistic events that IXCUI in benzetle-induced AML? 2. What is the cUirent state of knowledge of phannacoitinetics of leukemogenic metabolites of benzene? 3. What is bown about the toxic effects a benz.ene metabolites on hematopoietic cells? 4. What options are available for modeling the dose-response relationships between henzene and Ior metabolites and leukemia and/ or other 'biological endpoints? 5. What are the best sour-ees of data available to validate models of benzene toxicity and leukemogenicity and to determine parameters of such models? 6. What are the most critical gaps in data. knewledge and computing ability that limit modeling_options, and how c:an they be addressed? The workshop will produce a write-up document summarizing points of consensus and dissentun the above issues, and recommendations to the workshop sponsors about the feasibility of biologicallybased modeling applied to 'benzene. This workshop will 1tot address the fol1owing: l The ability of benune to produce---l}mphocytic leukemias, lymphomas cr solid tissue cancers. The workshop will foeus solely on AMl. and myelcdysplastic syndromes which drive the risk assessment prore;;s; 2. Epidemiological studies of benzene exposure, except biomarker studies; 3. Long-term rodent bioassays of benzene carcinogenicity. Session Coals Each session will focus on questions proposed by the orpnizers that are considered to be important to achieving the overall aims of the wcrkshap. In discussions, we will define consensus answers to these questicms, and raise ether questions that particip;mts WDSidet critical to the lopk under discusiian. It is hoped that there will be extensive crass-talk between biologists ud modelers Ia facilitate the evaluation_of IJ\l:IMling possibilities. Some questions will be first addressed in scheduled presentations, and others only during the following discussions, -but aU participants should keep these questions in mind as guidelines. -====================================================-~==~----==~:B:P~-00020761 SessiDn 2: Bl?!Zme Toxicology 'Biological effects ot toxic metabolites: Which benzene metabolites are most relevant to a model of bone mauow toxicity /leukemogenesis? What are the target s:ells of the critical benzene metabolites, ud what a!e the resultins biological effects on tliose cells (such as cell death, recom.binati:ln, altered regulalo!y processes etcJ? How can "epigenet-ic" eifects be modeled? Which biological eifects of benzene contribute to leukemogenesis, and do we agree on which are most important? Are there susceptibilities to these effects that can be included in a model? How do the-above effects on hematopoietic cells and regulatory processes vary with dose and the dosing schedule? Given the summary of biological effects, can we propose a mechanistic description of benzene-induced leukemia in tams of a series of changes in the cell 'billogy of the bone mamw.'? Pharmacokinetics: All questions ate posed for humans and animals. What ate the critical enzymes involved? What do we know about interaction and competition among metabolites? What do we know about spatial enzymatic distributions and first pass effects? What are the relative contributions of in situ formation of metabolites and transport of metabolites to the bone marrow'? What is the extent of ncm-linearities in the above processes? What are the 'best quantitative estimates of rates of formation and transport of benzene metabolites? StssiDPI 2: Ltukmtza Biology(Discussion should be limited to the AML subtypes and MDS associated with benzene exposute) Which stages of hematopoiesis are altered in A.ML and how? Can we identify the cell "compartments'~with alterati:Jns, and describe-their dynamics? k there a role for chemical effects on stromal tissue in the causal pathway? Which cytokine/growth factor "'ulato'f pathways are mcsl critical in trying to describe nonnal and leukemic hematopoiesis?, Can we propose a simplified description a key feedback mechanisms fot modelitlg purposes, CDn$i.dering the ccmpll!lcities aac1 unknowns involved? -Is apoptotic block likely to be a general mechanism in ..o\Ml? Should we consider it as part of producing the first leukemic cell or as an aspectof diSease prosression? Are genetic changes necessary to cause AML? If !iiO. which ones? BP-00020762  How does tlie leukemogenic medianiim of benz.ene compa~:e to the ~J~~Chanism of other leukemcgens?- Should the myelodysplastic syndmmes be considered as part of the pathway to AML? If there are k!IDWn CO!Iditions that can be interpreted as iAtermediate wstages" iA leukemogenesis, then what additional "event(s)" must occur to cause AML? What is the best bio1ogical explanation of lag time betweea exposure and disease, and the difference in lag time for different leukemogens or exposure scenarios? How can this be i.nrorporated illto a model? How- much quantitative data are available concerning the number of cells in each "compartment", percent of cycling cells, approximate cell cycle time, cell division rates, cell maturation rates, total transit time, etc.? Is it possible to model the genesis of AML as some discrete numl!er of "stages" or "events''? How many different scenarios/pathways are likely? Are SOilU! more likely to occur than others? Is there any particular sequence within each possible pathway? Smion 3: iMDdeling. Are the assumptions made by the two-stage model consistent with what is known about benzene-induced leukemia? Caa the two-stage modeL or an adaptation of it., describe the-key alterations in cell behavior ud/ or regulation that are respott~ihle for c:ausing AML? If there is consensus about the key eveals/changes that we need to modeL and the two-stage model can he adapted to describe these events, are there sufficient data from which 1o estimate..relevant parameters? If not, what further information is needed? How can existing models of human/ animal hematopoiesis and hona marrow toxicity be adapted lc model the cancer process? Can they describe the biological effects we concluded were critical for benzene AML? Do they model the correct cell types'? Can they be adapted to describe human data? Can the genetic alterations that contribute to leukemogenesis be incorporated? Are there issues to resolve concerning the feasibility of linking a pharmac:okinetic model for benzene to a cancer model? Are there similar computational issues for adapting a cytotoll:icity /hematopoiesis model into a cancer model? S~cillsusicn: B1omarkm Can chromosome abeuations be used as predictors of leukemogenic risk from benmne? If so, can we extrapolate chromcsome aberratacn data to predict leu.kemia risk at doses below 10 ppm in air? BP-00020763