Document ba6rbkg3wr9GKDzN36EGo87y

C-B6-1996 16:20 F.ROM 202 582 8586 ~PI-HESD-WAS~INGTON DC TO Pages: Seven (including this cover sheet) 612165868314-7005 P.0V'07 1220 n. 5m\lllt ~WISt 'W!l$fllii!l'iM, D.C. 2!!005..!J07ll ~2-0000 To: ' IF:rom: December 6, 1996 Pat Beatty (510)242-7022 }ennif@X" Galvin (918)662-1139 Dave Steup (713)241-3325 Gerhard K. Raab (215)862-3551 Rob Schnatter (908)873-6009 Don Burnett (31Z)616-0985 Dale Strother (216)586-8314 Barbara Devine (713)752-41652. George Shevlin Benzene Task Force Draft Le~er Dr. Mary Burr Paxton has asked me to forward the attached draft letter to you for your comments. She would like to receive your input by the close of business Thursday, December f 12,1996. ). ' ..0 ~- If you have any questions regarding this matter, please direct them to Dr..Paxton. Her ,. telephone number is (202)682-8338. ,~-. . I' .' ,l>. . Thank you. l ' ,l . .._ BP-00017923 ~ 202 682 8586 C-06-1~96 16:20 FROM API-HESD-WASHINGTON DC TO 612165868314-7005 P.02/07 12201. SIJm, Norbw6t Wa!ShingiDn, DC 2.000S4070 iol: :al2-m~ Fw: :li02~ E-Ml!lll: d~@:Jj)i.Oftil ~IH. ~. PhJ). Oin!l;lor, I'IBilllll il!ld Slwirohr110111al Scienc;os l)apartmonl ]December 3, 1996 Dr. Jeffrey Foran Risk Science Institu~ Int.ema.tional Sciences Instiru~e 1126 Sixieenm Street. N.W. Washington .D.C. 20036 Dear Dr. Fo.rnn: . Last year, the Benzene Task Force (BTJF) of tlle American Petroleum Institute (APJO decided to undertake a project enlisting the aid ef-several experts to address t.b.e issue of &dld.itional data needs involving the genetic tmticology of benzene. The BTF decided to focus on ihe generic issue ofhow genetic toxicology diJta could be used to augment or clarify issues identified in epidemiology stl4dies of benzene lel!kemogem:sis. A second objective was a consideration of genetic toxicology data that would be MSejul in addressing those issues identified by beYI:l.en<: epidemiology stMdies. After initial discus.~ions wiih Dr. Gino Scarano of !LSI; APK agreed to help fund an JIJLSI workshop on genetic toxicology andYisk assessment in which benzene would be one of a limited numbe.rof illustrative example compounds. At that time, the Task Force's desire to focus on the use of genetic toxicology as an adjwact io epidemiology data was made very clear to Dr. Scarano in an initial meeting and in subsequent discussions with Dr. Mary Paxton of API staff. APll is becoming concerned tllat during the development of the plans for the U.Sl! Workshop program. the initial focus of the API wroject is evolving away from API's initial expectations and desires. Based on the September 27, 1996 memormdwn from Dr. Scarano. it ap~s that the major intent is now to use the case study chemicaJ!s in-a .risk assessment based upon EPA's recently released CBncer Assessment Guidelines. We agree that the proposed guideline." are an imponant framewortc for the consider.Won of human health risk: as.~. ment. because they (or an amended form of them) will be whaLt we will probably live with for the next decade. However, APK has some serious concerns about some aspect." of the charge to authors of the discussion papers as pui forth in the 9127/96 memo. While the issiWlee of the proposed guidelines by IEPA clearly supplies a fn.meworlt: in which genetic toxicology data are important, the initial API intent was broader_ Previous epidemiology studies of benzene expose<! worker popwations have identified a number of questions or. - -~ ..... ....... BP-00017924 l't:':""'tli". -:. C-06-1996 16=21 FROM 202 682 8586 DCAPI-~SD-WASHINGTON TO 612165868314-7005 P.03/07 associations ~pon whicn the results of appropriate genetic ro::ticology data could! possibly shed light As well as the issue of shape of~ dose-response relationship, a major question is the choice of the appliopriate exposure-response model, e.g., lifetime cumulative dose vs. a measure of peak exposure. Undler tlne current guid&lce in Dr. Scanmo's lettei', such an issue would probably not be addressed. Another_area of concern stemming from the use of recent guiootines as a. framework for the workshop is the charge to the auihors ~o ad<kess tlle issue of non-tumor data, i.e., genetic toxicology data, ~o e:Jttend the dose-response relationship. We feel that this topic alone is of suffiCient complexity and controversy to justify consideration in a separate worlrshoJP md that Us inclusion in this worltshop would detrnct from an adequate level of consideration of other ri.slt assessment issues. if this issue is to be included, anything beyond a discussion of the generic conditions tha~ must be met for consideratioo M a biomarlk:er would clearly go beyond tlhe initially agreed upon fonnat upon which Al?I based its support of the workshop. The third concern is that of using the non-rumor data as a basis for extrapolation of beyond the observable tumor response range (found in section 3 of JDr. Scarano's memo). It should be made expllicit to me authors that this section is not intended to generate a dose-response model for extrapOlation of the tumor response but. if inclluded at all, should be limited to generic considerations of the pros and cons ofibis type of activity. This is another area that has already been the-subject of separnte symposia. ~md wo.rkshops. It is API's belief that ttlis topic be dropped from the worlcshop. The other component of the AP'lproject was to identify genetic to~i.city data gaps that would provide valuable information if filled. While the intent was not to geJllerate specific testing recommendations, we did desire to identify those data that would answer specific questions or allow choices to be made between aliemative hypotheses. This issue does not appear in the 9127196 memo. API requests that !LSI address the concerns listed above and respond to Dr. Mary lP'axton indicating how the inst.Jruetions to the authors will ~ modified. If you have ;my questions or need clarification of any of the points m&de above, please contact Dr. Paxton at API or JDr. Patrick Bea~., chair of the &nzene 'flllSk lForce, at (510)-242-7037. Sincerely, Robert T. Drew, Ph.D; ' =c o--c::.;: .. .-~ d" BP-00017925 202 582 8586 C-06-1996 16=21 FROM API-HESD-WASHINGTON DC TO 612165868314-7005 P.04/07 RisK SciENCE INSTITUTE ernational Life_ Sciences Institute 0 TO: Dr. Richard Albertini, U. of Vermont Mr. Harvey Clewell, lCF Kaiser Dr. Vickie Dellarco, U.S. EPA Dr. Sheila Galloway, Merck Dr. D. Jacobson-Kram, Microbial. Assoc. Dr. Mary Paxton, API Dr. Julian Preston, CliT Dr. Steve Robison, Procter & Gamble Dr. Michael Shelby, NIEHS Dr. James Swenberg, UNC FROM: Dr. Curtis Travis, Informatica lnt-1. InstittJ~Dr. Gino Scanmo, lLSI Risk Science RE: Beginning ofthe Use ofNon-Tumor Data in Cancer Risk Assessment Proj~ DATE: September 27, 1996 0 The-purpose ofthis memorandum is to let you know that "the project" ( Uu ofNon-TumoP Data in Cancer Risk Assessment, formerly called the ..genoto>ticity projeet..), is fma.lly getting-off the ground. For your inform~tion, I am providing you with the names ofthe individuals invited to. partic;ipate in the project and details on how the project is expected to proceed. Jrndividumns lixwiacedl ~o Pam~.:ni!)ate ~!Ill ttlh!e -IP'rcjed The individuals listed have been contacted and have expressed an interest in participating in the project. Invitation letters have ~ sent to all individuals. Chemical Benzene Butadiene Vinyl Chloride Primarv Auxhor Dr. Martyn Smith (U.Cal-Berkeley) Dr. Richard AJbenini (U. Vermont) Dr. Jim Swenberg (U. North Carolina) Secondai.Y Auth01: Dr. Richard Irons (U. Colorado) Dr. J. Thornton-Manning (!nhal. Tox. Res. Inst.) Mr. Harvey Clewall (ICF Kaiser) Dr. R~y Tice (Integr. Lab.Sys.) <Dcr.nJnulian Preston Dr. Curtis Travis (Infonnatica Int'l.) There will be two_pmpl~e involved in the development of a draft documen~ on each chemical (a primary -a.'"'!d secondary author) with o~ person reviewing the draft in-ddail after it-is completed. lt-is:anticipated that the primary and secondary authors will agree upon writing assignments and will I 26 Sixteenth Sr.. N. w.. Washington, D.C. 20036-4804 Phone: (202) 659-3306 Fax: (202) 659-3617 E-mail: rsi@dc.ilsi.org BP-00017926 202 582 8586 C-06-1996 16:22 FROM API-HESD-WASHINGTON DC TO 612165868314-7005 write a first dlaft of the case study. It will be the responsibility of the primary author to prepare the first full draft of the document. Case Study The starting point foil' each case study will be ihe cancer potency estimaie derived according to the 1986 U.S. EPA cancer risk assessment guidelines. The estimate will be provicled to project participan~. From that point, their charge is to develop the following: cancer1. A cancer potency estimate derived using the dose-response def~Suli approaches incJuded in the 1996 proposed revisions to the U.S. EPA risk assessment guidclines (Attachment 3). This will involve-modeling 1!\\!l!liWOr i!lla~~t& in the observed range to detcnnine whether the effective dose corresponding to the lower 95% limit on a dose associated with ~ ! 0% response (LED 111) should be . used as a point ofdeparture for either extrapolation to the origin as the linear default, or Yo detemrine a margin of exposure (MOE) as the non-linear default. Information on such issues as species differences. the slope of the dose-response curve at the point ofdeparture. and other pertinent factors should be discussed. 2. A cancer potency es~e that reflects tlleuse and-modeling ofllllInHl"tll!lll!liiCI!i" lll!:m~ (e.g.;!DN.A adducts. mutation. chromosomal abe!l'li'ation, cellular proliferatian, hormonal OK' physiologic& changes, receptor binding). !11 the modeling of non-tumor data, the following should be inclooed and/or discussed: the evidence that supports the role of the non-tumor data a\5 m element of the agent's carcinogenicity; o support for selecting a linear versus non-linear exirapolation procedure using ihe def~aul2s (straight line from LED10 or MOE) described in the_proposed 1996 guidelines or, if available, a biologically based or case-specific model; o discussion of whether non-tumor data ml!y be used to extend the tumor response below the range of observation and thus guiae the assessmeni below ibe observed tumor i11nge; mcl discussion of why it may be more appropriate to model the combined non-tumor an& tumor data as an integrated data set, if the non-tumor data are believed to be part of a continuum that leads to the tumor response. 3. A discussion ofwhy. or why not, the tumor precursor response should be modeled and wed for extrapolation instead. of, or along -wiilf, the available twnor data: The discussion should include ~ationaJe on why the precursor response is believed to be either obligatOry in fue carcinogenic process, or more informative of the agent's carcinogenicity. 2 .....___ BP-00017927 ,f?.~r~-:nr,.;.;~;~. . .: . .!: . -06-1 '3'36 16: 22 FROM 202 682 8586 API -HESD-WASH I NGTON DC TO 61216~868314-700~ P.06/07 Following is sorne oilier useful infonnation: o Con~ RS~ witn coordinate periodic conference calls to monitor the: progress of the activney and assure the meeting ofall deadlines. o Iirru; line.. The first conference call will be held in the middle ofOctom. The development ofthe ase srudies shou!d take approximately five monihs.witll an additional month for the mreview. Therefore, the working group meeting wiU likely take place the ifi mid-1997. If you have any questions &iliout the project. please contact me-by phone (202-659-3306), fa~K (202-659-3617). cr e-mail (gino@dc.ilsi.org). r ~""'"~L=....... 4 BP-00017928 202 682 8586 C-06-1396 16:23 FROM RPI-HESD-WASHINGTON DC TO 612165868314-7005 P.B?/07 4. A discussion of the relative imponance of non-tumor endpoints that may be available and used in the exercise. For example. if both DNA adduct data and chromosomal abemltion datm au-e available for a chemical, should one endpoint ~ given more "weight.. than the other in a ~cer risk assessment? nsl!R ~rri&ii~zn allnEJtl Rlhl$r\e lb~ til d~aur dlnsmssnoi!D !lll!r ttllne lrZ~iionnSJR\\: lUlS<!!Illl ff@lr i!!zdn S!J!Djplll"O:Blil:lll azJltelll duUiliDg ~ftne JPlirOj~ Logistics The project will consist ofthe foUowing steps: o Identification of~ run wiU conduct a literature search on each ofthe chemiCl!\ls and send the results to each author and reviewer of that particular chemical. A conference call win! be held among the at!thors and reviewer to agree upon the data (human and animal) to be used in the project. 0 DAta Coliection md Identification gf Assignments.. RSI'will make sure th&t a.ll authors/reviewers receive the a~ upon literatw"e. RSI will then coordinate a-conference call betv.reen the primmy and secondary authors to facilitate the identifiCE~tion ~f wr-iting/analysis Msigrunents. 0 G~on of Fjmr>mft. Authors will begin work on their re~tive sections. Any computer xuns thl!l~ may need to be performed (e.g., calculation of cancer poteillcy factors) will b2 conducWd by ICF Kaiser and will be coordinated by RSI. Once the secondary &uthor has completed his/her section, it is to be given to the primary author. who will be responsible for fmali~ng the &ma " Reyiew of First Draft, The reviewer will then examine the fust draft generated by the authors. Comments will be provided to authors and revisions iJlcorporated as appropriate. Meetingofthe AutJlloKs..Revieweys and Working. GrougMembets. Once drafts for all ~ chemicals have b<len reviewed and revised. a meeting of all authors, revievvers md Working Group Members will take place. The purpose of the meeting will be to: 1) discuss the "lessons leamoo" ~om the case studies; 2) develop recommendations on the use of nonQ tumor data in cancer risk assessment; and 3) identify research needs regaroing the use ofnon 1. tumor data in cancer risk assessment. The product ofthis project is anticipated to be a repon published in the peer-reviewed literature or a stand-alone monograph on abe quantitative application of genotmdci~ and other data in cancer risk assessment. TOTAL P.07 BP-00017929