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Vol. 9 No. 23 June 10, 1983 P.O. Bo+c 2370 Reston, Viroinia 22090 Telephone 703-620-4646 DCCP BOARD APPROVES CONCEPTS FOR NEARLY $20 MILLION IN GRANTS, CONTRACTS, INCLUDING NEW INHIBITORS STUDY A grants program for the study of new natural and synthetic inhibit- ors of carcinogenesis was given concept approval this week by the Board of Scientific Counselors of NCI's Div. of Cancer Cause & Prevention. The Board agreed to earinark S P million for first year fui+ding of the (Continued to page 2) In Brief JOHN CAMPBELL. NIDA CONTRACTS CHIEF, NEW HEAD OF NCI CONTRACTS BAANCH; PHS HONORS SEVEN AT NCI JOHN CAMPBELL, chief of the Contracts Management Branch at the National Institute on Dtug Abuse, has been appointed chief of the NCI Research Contracts Branch. Campbell, 4 1, was an NCI/RCB staff member from 1973-76. He as agraduaAe of the Uni.: of Tennessee. Campbell will assume his new position later this month, relieving Robert Namovicz. NCI ereputy executive officer who has been acting chief of RCB.... SEVEN NCl STAFF members were recognized for outstanding achiever;tents in the annual Public Health Service Honor Awards made last month. Distinguished service medhls went to Director Vincent DeVita "For development of curative combinations of anti- cancer drugs resulting in hope and life for thousands of cancer patients and for decisive leadership of NCI;" arld to Joseph Fraurq'teni, director of the Field Studies & Statistics Program in the Div. of Cancer Cause & Prevention, "For outstanding leadership in developing ardd directing a highly productive program of epidemiologic research designed to clarify the environmental and hast determinants of cancer." Michael Goldrich, administrative officer of the Div. of Cancer Treatment, received a superior service award "For skillful and irmovative administrative management of DCT." Gilbert Beebe, an expert with the Clinical Epidemiology Branch, received a special recoptition award for his analysis of the health effect~ of ionizing radiation. Three members of the Div. of Cancer Biology & Diagnosis were honored: Thomas Wald- mann, chief of the Metabolism Branch, received a distinguished service medal for contributions to the understanding of immune response. Ira Pastan, chief of the lahoratory of Molecular Biology, received a mentorious sen•ice :nedal for his work in thyroid biochemistry, gene reFulation and molecular mechanisms of malignant transformatren. Gan• Peck, senior investigator in the Dermatology Branch, received a meritorious senice medal for "pioneering work" demonstrating effect- iceness of retinoid tn:atntent of cystic acne and skin cancer. Not only did DCBD Director Alan Rahson see three of his people honored, he alsosaH• his wife, Ruth hirsthstein, director of the National Institute of General Medical Sciences, win the P}1S equal opportunity achievement a\S'ard. I 0 Co ps,ngM 1983 The Cancer Leuer Inc. I SubSC.ophon $72S vede North Arner.43 5150 rear ersc~vhere Four DCCP Contracts Costing $9 Million Approved By Board For Recompetition ...Paga4

DCCP BOARD TABLES STUDY OF MUT4GENS IN HUMAN FOODS, OKAYS RECOMPETITIONS (Contir•,ued from page 1) grants, which probably will be four year awards. The DCCP Board also gave concept r,:proyal to three nem. contract supported proiects ti'th eal.'_'5 million in estimated first year awards and $4.18 million in total project costs; to the recompetition of four contract supported projects with $2.55 million in estimated first year awarcis and 58.9 million in total project costs; and to a variety of noncompeting contract programs with an estimated S' million in first year awards and total project costs of $6.82 miihon. The Board tabled a staff proposal for a four year grants program, with an estitnated $500,000 a year in awards. to study mutagens in human foods: and de- terred a proposal for a noncompetitive one year con- tract for a study of lung caneer monahty among coke oven workers at an es'timated cost of 575,00t1. DCCP will issue a request for applications for the natural and synthetic inhibitors study. Carl Smith, program director in the Chemical & Physical Car- cinogenesis Branch of the CArcinogenesis Extramural Program, presented the justification for the study: Fpidemiologre studies have implicated diet and nutrition as important factors in the occurrence of human cancer. with both positive and negative eonelations indicated for incidence or mortality at many sites with consumption of particular nutnents or food items. Hrgh intakes of legumes and rer-a's such as corn, rice and beans have been associated with re• duced risk for breast, colon and prostatr, cancers, for example, and an increased consumption of crucrferous vegetables such as cabbage, broccoli. Brussels sprouts and tumrps has been associated with decreased cancer frequencies for colon. rec- tum and bladder. Expenmental stadres in several animal models have demonstrated in direct feeding studies that cer- tain food or crude food components provide siFmf.can, pro• tection against chemcally induced or radratuon ind:rec.i tumorigmesis. Examples include the cructferous vegetables. celery, orange oil, beverage sources and edible legumes such as soybeans or soybean concentrates. Diverse types of chem- tcal compounds presrnt in these foods have also been shown to inhibit the neoplastrc process. including phenols, coumanns, rsothrocvanates, flavonoids and indoles. The extent of occur- rence of naturally occumng inhibitors of carcmogenesis. their role and potential as cancer preventrve agentsJ anJ hon pro- tective effects might be enhanced by dretaq• manipulation are lrttle known at the present ume. Research emphasrsin the proposed RFA will seek to ex- pand knowledge and understanding of naturally occurnng mhibrtors of carcrnugenests and therr potennal for human cancer preventtcn. HoUever. tt is not the rnrent of rhn RFA to stimulate studtes on reunotds un,ludmg natwal utamrn A). vtitamrns C and E, and selemums aFph.anrns de,lurc vuth these agents will be considered nonrespuns~%e. Areas for em- phasis include (1) Identrftcatton of nea• naturalh occurnnE rnhtbrt{in Ntth special attention to approf+nate methwd~ of rsolaurn of spectfic constituents or :hemt.al forms. (') thmouch studies on mechanisms of acnon of aeml% t6entrficd mhrbuors and their pharntacoktneucs,( 3) rrnpro%ement in current systems for identrfN •mg andstudYmc naturalh OccurnnF mhrhnors. . ^ !. , (4) broad determinations o: the range of conditrohs lrridc>' w•1trtK effrcacy is demonstrable including prevention of carcinogen production cr actn•atron, enhancement of detoxtficatron path- ways. blocking of ultimate carunogens• and antrpromotron actrvrues. This latter includes dose response studres, species and carcinogen promoters in which efficacy is demonstrable. and potential addttrve or synergisttc effects which may occur ' by use of more than one agent. Board member Dietrich Hoffmann commented that a previous RFA on the mechanisms of the bio- logical prevention of cancer brought out "a tremen- dous response. Not all of the good ones could be funded." DCCP Director Richard Adamson said that those focused on the mechanisms of action and in- claded selenium and vitamins A, C and E, which are excluded from the new RFA. "The epidemiology is clear," Board member Allan Conney said. "Green and yellow vegetables prevent cancer. The question is, what? Beta carotene and vitamin A are being looked at. What else is important? My feeling is that with cabbage and brussels sprouts, it may be other things." • "This will elaborate on the search for new test sys- terns," Board member Donald Davies said. "This is breaking new ground." However, Board member Gilbert Omenn expressed some reservations. "I'm quite unsettled about this. Objective number one is inappropriate. I don't think we should use NCI money to start a far-ranging screening program. That is not the function of the Cancer Institute. The National Toxicology Program would be more appropriate. Also, I'm not aware of infonnation on a large body of work on vitamins A, C and E, or on selenium. The mechanisms are not clear there either. We may be rushing off in search for lesser inhibitors before the mechanisms have been establishcd in the more important ones. ... If we're going into a drug development program, okay." "That's not the intent; " Adamson said "This is for the identification of new inhibitors. The Div. of Resources, Centers Rr Community Activities may set up a rapid screen• We'll stay more with basic mechan- isms." Omenn asked that only those applications Hhich are under the NCI pa)•line be funded• evrt if it meant that the entire SI million not be used. Adamson agreed, and the vote to approve the concept was un- anrrnous. The Board approved \Cl's contribution of 5500.- 000 a year to a four year contract admmutered jornt- lv with tite National ln>trtutc of Allercv & lnfc'ctrru!. Diseases to stucly the natural history of acqurred un• mane dcfuiency syndrome in homosexual men. NIAII) hzs committed a total ol' $..2 million to the st udv. John Cooper. actrng, director of the Carcrnot:enest.. Evtramur.rl Progr.rm. presentc•cf the ~tat7 lv.q•o~al. Smcc Jur,e of I ybl m%esu~ators ha~e identified an eprd emrc of acqurred tmmunodefrocn:. +~ndr{+mc in tl,c t mtc.' 'rhe Cencer Letter Page 2 1 June 10, 1983

States. As of May S. 1983. 1,410 cases of this svndrpme had been reported to the Centers for I)iseace Control. Althourh the preponderence of the reports have come from the t'.~-~ an additional 103 cases had been reported Srom 16 other countries. Since the recognition of this entny, the rrse in new cases has been exponential with hrgh case fatality rates within two years of onset. The underlying immune defect in these patients is complicated by the advent of Kaposi's sarcom;J, andlor any of a vanet% of opporiumsnc rnfecttons, the most common of Nhrch is pneumocysirs carmn pneumonia. Among the U.S. cases, 70 percent have been among homosexual ot bisexual males, 17 percent among IV drug users and five per• cent among Haitians with no history of homosexuahty or IV drug use. The epidemic pattern observed to date suggests an mfec- tiousetrology for the underlyingsyndronte with transmission by sexual contact or by exposure to blood or blood products. The case fataltry rate is high, survival after the onset of symp• toms is short and no known therapeuttc measures itave been effective. Under the circumstances, it would seem prudent )o rndke a serious attempt to collect and store mformatton and mat- enal from high risk irrdtviduals, which would permit study of the natural history of the disease and the future testing of etiologic hypotheses. Ideally this should be done in a popu• lation based manner. Sufficient individuals should be included in the sample so that adequate numbers may fall into various categories: 1) uninfected: 2) infected but without symptdms; 3) infected but w;:h minimal symptomatology; 4) trifecte;d with chnically evident disease. Penodic fo0owup and storage of materials would then provide a resource for rnvestigatior of both natural history and etiology. Since nothing is presently known with respect to the interval between mfectroh and thc development of immune dcpressron, and subsequent 01 ot KS, it rrught be advisable to cauy out such an acuvrty iqtwo ltigh nsk connnumties, one in which AIDS is aresently oCcurnng with high incidence and one where it is now occurrtng with low• incidence. Concept approval is requested to enter tnto a coll3borative project with the National Institute of Allergy and Infectious Diseases. Funds from ttus division uill be used to supplement the $2,'00,000 committed by KIAID in their recently issued RFP (with this title) to increase the maenitude and power of the acttvrties tden:ified. The purpose of this RFP is to estab- hsh a sufficiently large cohort of homosexual men ai nsk of AIDS to study its epidemiology, etiology ard na:ural history. Emphasis will be placed on collecting adequate clinical and eprdemrologre data and biolopc specimens for future analysis. If only a single t^clrnically acceptable response is forthcornmg, our assistance would be utilized to expand the,aze of the co• hort !o be examined and to increase tlte frequency of sur%ei4 lance. If multiple techme;alh acceptable sesponses are re- ceived, an attempt would be made to implement two such activities in cornmunrues h.evrnc hrgh and lou current attack rates. The Board approveci the concept of a new project for record ltnkage studtec utilizing resources in popu- latron based ttunor registnes, to be supported through the ntaster agreement mechanism. Under thad mech- ani>rn, nCCP would identtty ort:anrzations deemed capable of perfcr*mrnp the work. then w-hen sp°cific prc>.iects are initiated. RFPs would be circulated only among that grrup as task orders, %,.tth cornpetittve aw-.trd> tc follusti. Board members objected more to the medramsm than to the studtes, "I'm not s•urc µc should give you the ..c} to Fort l:nox," Board member Carl :'hy !ctd. referring to the tot.rl project estrtnatefJ cu.t of 5,. lI million over three years. "Yrn not sure wr shoul,f leave it up to staff to procced wrthoui an\ further revrew by• an outside review group." Adamson suggested that approcal be Fnen ;o pro- ceed with the understanding that feastbthty studies not to e\ceed 550.00i1 each could he unJertakrn. with proPosals for fullo.cup suhstanu%e srudres to hc brought back to the Board for conccpt ahpro\.rl. ~1 total limit of 5300,000 was placed on the leastlahty studies. The Board agreed. John Boice, of the Field Studies & Statistics Pro- gram, presented the staff p:oposal: Population based cancer repstnes provrd'e unique opfot• tuniues to conduct record linkage and feasibility studies of cancer euologl. The existence of records Nnh detadcd rnfi,r- matuon on cancer morphology, topography and stage. coupled with the availabibtv of additional detailed information on treatment, occupation and demongraphic charactenstres. makes these registnes valuable resources for epidemiologic research. The NCI (FSS) currently supports nine such reps- tries in the U.S., and it is frequently rccomrhended that they be used more often for analytical stud:es. Record linkage studies have been conducted successfully rqsercral re4stnes in the U.S. and around the world.e.g.. to study theeffcct> of occupational exposures, drug exposures, and radratren treat- ment. Such studies are often expanded by abstracttrtg ad• ditional information from existing records. This btanchwide project would provide managenai, data collectrun. and process• ing support to address issues where resources from populatton based tumor repstnes could be best ulthzed. The sMrces would be used for support of crllaboratrve research. tncludutg support of investrgators in SEk.R and other populatron b.tsed registries. The contract would be in the form of master agree- ments where master agreement recipients wr,uld compete for awards after a MA order RFP has been issued. It is envisioned that between 15 and 25 national and international cancer registnes would compete for these awards. Because of thz large number of cancers reported in peputa- uon based registries, small effects or rare caotcer wn be studied effecticely by combing results from several repsnres. bt ad• drtion, since existing records are alre:d) computcnzed. record linkage studies can usualiy be conducted efficiently. Examples of studies to be consrdered under this pro;ect rnclude: (1) The linkage of parental occupation and rnatemal dr ue exposure registries to ecalu3te sibsequent cluldhood cancer in offspring. (2) the bnriage of twin repsures and cance, regtstnes to evaluate ctuldhood cancer in twms follow- ing prenatal x-ta%. (3) tF.e 9nkaEw of End Resuhs Prngram ind SEER data tapes tc determme second breast canccts tu.Io-utL radtacton treatment for breast oncer ( and subsrquen+ re.ord abstraction). (4) the linkage of the Swedish 190 census drta and certatn octupanonal repstnes.krth the Swcdr0h Can.cr Rep,ury to generate and test hypotheses regardme cancer rr a• ettoloevv, (5) the further linkage of data in socnl c.nL0 ures to evaluate second cancers followine radratrun trcatnrcnt fc+r centcnl cancer (and adJmonal rc.oru ahstraction). and (h) the Itnl.aee of sta:e unemploymcnt msurance files or 0thr; specta: state uccupauonil rosten H-nh app kI(",Jte I:.S tumor repstnes. It is planned that ieasrbtlm studies. Fenerilh ui mmtmal expense. would he initiated to determrne ..hcthcr appropriate records can be linked anJ to 0aluatc the typc onL' qualrty of additional data that can bc abstracted frun, e-tuuni files. These would then be followeu by enhanced studics to obtain detar ed rntorrnatrun avadahlc in hrs; nal and ot her records. These may be morc costl~., however. and thc BuerJ would be asked tn appruAe an, pr„tect exceedtnf S500 0.'(t The Cancer LettL-r Vol. 9 No. 23 1 Page 3

The Doard approved the coneept of a cont•ac1 for the study of synergistic effects of atmospheric pol- lutants as environmental carcinogens, at hn estimated c^st of S50,000 for one year. The contract would be a joint project 'with the En- vironmental Protection Agency. Joellen Eev+•tas of EPA, the project Gfficer along with'•9orris Kelsey of NCI presented the justific:tion: PolycyeLc aromatic hydrocarbons occur to a larga extent in our environment, and recent estimates indtcate that their production from the combustron of fossil fuels accounts for a majority of the pollutants responsible for the low level (' -,) of cancer deaths attributable to "pollution" (Doll and Peto, 1951). Benzo(a)pyrcne(BaP) has been used as a,general indic- ator nf atmosphenc pollutron, in the form of PAH, yet re- ports in the literature estimate that it conpributes less than 10 percent of the total carcinogenic activity of automobile exhaust condensates whtch arc a maior source of PAH release into urban atmospheres (Gnmmer, 1979). CyclopentenolcrJ) pyrene (CPP) has been found to be present at levels higher than BaP m these condensates (Grimmer et al, 1977); Cavalien et al. 1983), and carc;fnogenicity tests (mouse skin painting) of CPP have shown it to be a moderately potent skin carcinogen compared to BaP tested in the same system (Cavaben et al, 1981). Cavaben (1983) has shown an rnteiestrng synerpsm of BaP and CPP from two-frve trmes that of each alone thussug- gesttng that these two; compounds may account for the major- ity of mut3gemc/carcpnogenic activities present in automobile exhaust and certain urban atmospheres. Therefore, further studies are needed to t: st the significance of these resultsand hypotheses. This project would consist of analysis of varihus ambtent air and automobile exhaust ondensates for the occurrence and levels of BaP and CPP tn order to determine, and confirm the hrgher ratio of CPP to BaP in such samples. Stnce the EPA has extensive experience in the collection of such samples, they would be asked to become tnvohed in a collaborative effort With the contractor. Newer and more reliable analytical methods will be employed in these analyses since pte%rously published techniques ~rnay result m decomposition of the CPP. Once ratios of CPP and BaP are determined in such environ- mental samples, it is anticipated that they could be tested both in vitro and in vivo for synergistic effects. Such investigations could be performed by proFrams within NCI or those of the National Toxicalogy Program. The Board gave concept approval to the recompet- ition of the following contracts for ongoing projects: lnduction, biological maricers, and therapy of tumors in primates. Pres^nr contractor, Hatleton LaboratUnes America Inc. Est:mated first year aµard, 5550,000. total project. 5..75 million, five vears. Susan Steber. DCCP deput} dnectot and project officer for the contract, presented the description: P1uch in vivo cancer research and a considerable amount of in vitro %vorl.unbirc the mouse or other rodent species as the test animal. Rodents are used almost e%clusrvely in the p:rmar% screening program designed to tderoufp materials Ntth antr tumor effect. Lkemse, tLevarc uscd e>tensreel\ to screcn compounds for carcmneemc effects. It is evident that many of the basic building block~ for the foundation of cancer research are formulated from rodent data. Unfortunately, there ts not good agreement on how accurately rodent data can be exuap• olated to man. N'iule it is clearly not feasible to ueplace rodent studres p71h studies in nonhuman primates. nevertheless there rsa neeZ to uulve nunhurnan pnmatesand otner arunral species more et,tensiveh 1o complement rodent stud±es a:id to verify the rodent data by comparative studies in other s% stcrr%. This project v%as initiated in I Qt•1 and until May 198' -as strpported by the Dn. of Cancer Treatment. On 51318: it was naresfcrrcd to 1X'CP with the relocation of the project officer from DCT to DCCP. The present colorn-consistrng of 484 anirnai,, is compnsed of four species 1sSnoca r.rulatta (rhesus). hracaca fasciculans (cynon,olgus). Cercopithecus aetluops (Itfitcan green) and Galago crassrcaudatur (hushbabics) Se%enty-mne of these monkeys are adult brc~•dcrs xhose off• spnng are used for experimental studres- A total of 28 khem• icals have been- or are being evaluated for their carcmocenrc potential in lifetime studies in monkeys. The chemrcals, tested rnclvde antibeoplastic and immunosuppressive agents (proa arbazme- methylmtrosour:a. adnamycin. melrhalan. arath,o- prrne and cyclophosp}hamrde), food additives and envu'omnen• tat contaminants iaf)atoxin Bi. cycads. stengmatoq•suno cyclamate, sacchann. butter yellow. 3-methyl-DAB, DUT, arsenic and cigarette smoke condensatel, "model" rodent carcinogens (urethane. 3-methylcholanthrene, _•acetylarr.m,)- fluorene, 2.7-f3uorenylenebisacetamrde, copper chclate of N• hydloxyacetylarnmolluorene. drbenzpyrene and dibenz(a.h) anthiracene), and nrtroso-compoun,ls (dtmethylnrtrosaruture. dietbyln:trosarnine, dipropylmtrosamine. I-mtrosuptpendme and Is9?vTTG). Pvesults acquired over the past 22 yea: s indicate that pri- mates are not as susceptible to chemical catcmocenesrs as rodents, that the mduetion period is often in the ranre of se~•eh-ten years and that the organ and; or tumor type may differ consider3bl% between rodents and pnmates for a par- ticupar carcinogen. Substances which have carcinogenic acnuty rn some species, usuaBy rodents, but which have not resulted in ttimor induction in the course of this study include 3- methylcholant ht ene, .•acetylammofluorene, 2.7•fluorenylene- bisacetaminde, copper chelate of 1-hydroxy-acetylammo• fluoiene, and dtbenzpyrene. On the other hand. sexera) chem• icais,(diethyinitrosamine, (ipropylnrnosanune, 1•mtrosoptper- tdrene. urcthane, allatoxrn B;, cvcads and stengmatocysun) have demonstr, ted carcinogenic activity in nonhuman prn mates. lheth) butrosamme produces hepawcellular catcrnoma within two years in essennall} 100 percent of exposed amm• als. Treatment with dipropylnitrosamtne, I-nitrosopipehdme and arengmatocysun also resulted in the detelopment of prirnary hepatocellular carcinomas. Animals exposed to aflatoxrn BI deveioped osteosarcomas and aumors of the hepatobrliary systcm, and treatment with cycads produced a variety of tumors of the liver, pancreas, kidn'ey, esophagus and small intestine. Tumors induced by uret)r2ne included brain and intestinal tumors and liver hemanposarcomas. Cancer chemotherapeutic agents with carcinogenic potenttal in nonhuman primates are procaihar:ne. methytmtrosourea and possibly adriamycrn. The ma1rF*.:naes induced b% procarbanne include acute nonh mphr;y n: leukemia. osteosarcomas and other solid tumors hlethvlm- troseurea admrmsted by the oral routc mduced squamousoll carcinomas of the esophagus and uropharym. The present cohnv has been in contrnucd evstcnce for _^ vearsand supports the largest .tudy. of chenucai earcrnoFenes• ts in nonhuman primates undertzhen in tlas country. In ad• drbun ro prosttLrtg data un the carcmogemcrty of a vanerr uf chermcal.- unaudmr anUtumur anJ rnenunosuprressr%c ec:nts in chnrcal use. rt hrs also made tt pc.srble to acqurre mfo nu• nrm on the spontaneous tunior mcrdcn.e in nnnhuman pn- rr3tes, and thetn lifespan in captnv:tl. 1\ormal anunal, of all dFes as v~ell as tumor heannc annnals hake been used in phar- macolrpc studres and chemotherapeuttc tmis The a.ailabtl- rtv of mcv},os receornr chront; tre3rrncnt Hnh chcrnr,:al• has made it pnssrb:c to rdenul, \ som.• consequences of Ianc tem chcnncal cxprsures other then tumrrr devrlol+mcn0 hlonkeys hernnF chemrcalh mdu.ed hcpato,rllular ~.u m omw ha%c hccn used in studres of AI-P s\nthests and ro co- 'Phe Cenc+er Letter Page 4/ June 10, 1983

relate serum AFPlevels with degree of tumoi differentiation and response to therapy. More recently, tumor bea;rmg mon- ke}-s have been used to develop new contrast media to en• hatue computekized tomography of liver and spleen, and to compare the distribution of free and hposome entrapped ara•C in tumor tissue and in adjacent normal tissue. The ac• cumulated experience with specific carcinogerts has also made it possible to initiate studies r.• the prevention or reversal of chemically induced tumon. This piograrn is designed to study the response of pnmates to known roderit carcinogens in order to obtain cempar-,tive data on susceptqbitity, latent period, target organ, dcse re sponse, and tumor type. It is anticipated that this data, when examine.d along with other animal data and human epidem• iologic data, will allow a more meaningful stepwise extrapola- tion to man. The low incidence of spontaneous tumorx, the long life span, and the phylogenetic position of nonhuman primates makes it possible to perform a number of procedures (sequential lapai oscopic exarninations, biopsies, diagnostic radiology, bone marrow aspiration, and hematology and clin• ical chemistry determinations) not readily performed m rodents. The objectives of the program are as follows: (1) Obtain comparative data on the response of nonhuman pnmates to known rodent carcinogens and to materials suspectgd to be carcinogenic in humans: (2) Evaluate the long term effects of antiner,ptastic agents which are being used clincally for long teml remission, in adjuvant therapy, r.»d in the treatment of diffuse collagen dssorders;(3) Obtain model tUhnor systems in nonhuman fnmates in order to ascertain the potential useful, ness of various anticancer agents in man; (4) Tq try to develop models for chemoprevention therapy; (5) l)evalop biological markers and diagnostic tests for detecting preneaplastic changes as well as frank neoplasia and for moriitoring nonhu• man primates andlor patients prior to, during and f~cllowing t-,rrapy;(6) Make available normal and tumor bearuig animals for pharmacologic, toxrcologic, biochemical, and rmtnuno• logscal studies; and (7) Maintain a breeding colqny ov various species so that offsp:ing may be readily available for use. The majority of the animals on this project,are housed in an isolated facility which contains only animals committed to this study, and with the exception of the breeding colony, most animals are housed in individt.al cages. Until 1982, nea nates produced by the breeding colony were separated from their mothers at 6irth and handreared in a.uusery. This made it possible to beign dosing with carcinogens during the first few days of life by adding the test compound to the Similac formula at the tir!se of feeding. However, financial considera• tions have recent)y made it necessary to ail~s ILe offspring to remain with their mothers until weaning. Test compounds are given subcutaneously, intraverously, intrapentoneally or orally. The dose level chosen is dependent on the chemical under evaluation. Antrneoplastic and immunosuppressive agents are administered at doses likely to be cncountered in a chnicsi sstuauon;other substances, such as emuonmental con• tarnsnants, are given at levels 10-40 fold hu•her than the es- uruated human etiposure level. The remamuer of the chenr scals tested are admmistered at maximallv tolerated doses w)nch, on the hasis of weight gatn, blood chemistry and hematoloFy frncrrngs, and clinical observations,appear to be dewtd of a.ute toxtctt). DusrnF continues untd a tumor is dsa;rwscd or until a predetermined erposure period has been conrpleted. A vanet' v of chnscal. bicchemical and hematoloPcal param• eters are monltorcd weekly or monthly, not onh to evaluate tne gcnesal health status of each animal. but also for the early detecuon of tumors. A lapatosrope is used to periodically examsne the abdominal cavitY, matnlh the hver: for evidence of rumor. Surgical htopsses are obtained when rnritcated and submrtted to NCl for hrstoparhutugrcal evaluation. SarFrwl procedures are perfurmed under ketaminc hydn,rt .,~r dc or Godrum pemobarbrtal anesthesia. All animals Ntnch dre or are sacrtficsed are carefully necropsrec and the trssues suhjecreJ it, htstopathologrc examination. Animals are bred, housed and dosed u7th test chenncals In the coiltractor. Surgery, btopsrer and other procedures arc pc: - formed jointly by the project ofGrer and the cunuactvr i hc project officer provides the contractor with w-rrtten prutocuh f,3r all cxpenmental studies. Test matenals are preparrJ by NId-1 peisomre! and all monkeys are necropsred at \lli. "Tt~ show that a rodent carcinogen is not neces- sarily a primate carcinogen is a fascinating pre.e of information," Board member Renato Dulbccco commented. board member Hilary Koprowski suggested that the animals would be uceful to investigators for othcr puipoyes, especially in studying effects of drirga on brain tumors. "The blood-brain barrier is pure theory," Koprowski said. "Your animals could be extremely important in studying that issue." Sieber said she would be willing to consider that suggeslion. Adalnson teferred to the lack of mammary cincers and the overall lack cf spontaneous tumors in pri- mates, which he s:,id possibly could be attributed to low arrounts of fat in their diets. DCCP is considering manipulating the diets of some, "maybe feeding them h,ambutgers," and another group hamburgers along with ci•uciferous vegetzbles, "and see wttat hsppens." Ornenn mentioned "the elaborate setup of seven or ei&h¢ prinlate centers around the country. Are any of those people knowledgeable about primates in- volved (in the NCI project)? This is too valuable a resource to keep within KCI." "We have approached other primate centers. They have not been too interested, otlter than in use for breedirlg," Adamson said. "Things may have changed," Omenn said. Adamson said that he plans to "let it be known what we have avaiiahle," "I think you should take ad>,intage of the exper- tise around this table; " Board member Edward Bresnick said. "I dqn't have any problem with b.tilding that into the RFP," Adamson said. dtesotltee to support the chemical, economic and biological information needt of DCCP and to provide chemical process, production and economic information as support to IARC. Presem contractor, SRI International. Estnrrated first )car award, 5700,000, total cost, 52.1 mdlson. for thrcc ye.+rs. Herman I:raybill, DCCPsnentrfi. coordrnatur for I;n% rrun• lnent„i C'ancet. prese:rted the project description: The objective of this project is to protrde a mech:uusm for the development of rnfurmauon and data in the areas of en• v7ronmental and occupattonal cancer. The project, which w,rs initiated etg.ht } eats .igo and was recompesed about four vcars ago with the awardruF of a rew contract befmnu,g in l7uuber 1079. consists of four r7arur tasks. The first task has been to support the effur:s of hCI's Ch nucal 5clc;rhon 51 „r1.mg Group (CS«(") to select and nonrmate chemscals for carirn0• Fcrucrt) tioassJy. N( I. and this d stsmn in partrcular. l,a,e The Cancer Letter Vol. 9 No. 23 / Page.:

been and wtll continue to be, the pnmary source fo• nomina- tion of candidate chenucals to the Nattonal Toxrcolugy Pro- gram for caresnogertnty testing (fortnerly the sole respon- sibtlny of this Instrtute). Thrs task involves conduct of class studies (cherrucals b% use and structure classes). During the past three years (FY79-81). 12 class studies were completed, two class studres are curr~entl)- in progress. From such class studies and other information sources, summary sheets are prepared wluch the CSNG uses ul the selection and mon• tnanon process. ln addtttbn to being a source for nomination, these class studies are published in the open literature. Ad- dttronally, IARC monograph reviews and random nortuna- uons (i.e., nominations iiom sources other than class studies) serve as sources of summary sheet preparation. In the past, three years. 131 summary sheets (106 front cl3ss st udies ard IARC monograph reviews and 25 from random sources) have been prepared. Also. resuhs frum two contracts on short term testing, administered by thts Division and up for concept e• vieµ at tbs meeting. are incorporated into the summary sheets. In the second t3sk• the project provides support to IARC (imem^,uonal Agency futr Resezrch on Cancer). Lyon. France. )t im•olves submission to IARC of data contained in the fihst section of each monograph. such as chemical and physical data. production and exposure data, and analytrcal methods. In the last three years such data werc furnished on 146 chemicals at 12 woskmg ~soup meetings in Lyon. Additional information for 35 chemicals and a data table for 275 rubber processing chemicals were provided. In the third task. major emphasis is on the development of data and information for the Chemscal CarcmoFenests Re- search Information System. Tlus data base has become quite significant. It contains compilauons,of data on carcinogens, mutat:ens,a dn tumor promoters and cocarcrrtogens. There is also a hmited amount of data on chemicals which were tested for carcmogerttan• and yielded negative results. The data is routinely stored in PROPHET, an Nil] supported time shar mg computer system specifically designed to meet the data analy- sis needs of scientists involved in biomedical and phamtcolog- rcal research. Afure recentl), the data base has been entered into C1S (Chemical I.nformation System). a multi•agency sys• tem, cosponsored by 1<IH, which rs a pubhcly accesstble sys• tem used on a fee for service basis by some 1,400 users in 30 countries. For chemicals tested for carctnogemctty• there ate data for 473 chenucais (36Q chemicals wrth positive results, 104 chemicals with negative results• and a total of 1,55,'2 test results.) The mutagenrcity data base contains information on 4b5 uniqoe chemcals (308 chemrcals tested in the Ames assa, v. 97 b.% E. coh \tP2 test system, 16 by Chinese hamster ovary cell HGPRT tocus (CI1O/HGPRT)• 112 by Chmese hamster \'•79 cell assay and 16 for mouse iymphoma cell L5178Y (T1C{!') assay ), for a total of 1,137 test results. Data are being accumulated on mammalian cell transfor- matton and other II systems. Thus far, there :• nformatton on 89 tumor promoters and cocarcinoeens (115 test results) These figures are as of tio~.e•nber 1QS'-;. All CCRIS data re- sulte d from a search of eptdznnologrcal and animal evsdence, from KCIrKTP technical rcporis IARC monographs, NCII contractor studies on water and air pollutants. XCi/contractnr class studies pre.iously mentioned under Task 1, and recseNs as,J surveillance of bteraturc. Another function of tlns task is the de%elopment of the Broassay Report Suntmary 1landhool.. a most useful refetence source on 215 chemicals. as of tlue date. This handbook contains summanes of the':CI/KTP technical reports from the broass3y propuam and wtll be con• tinualh• updated as ui1) the data bases referred to above, rn• cludsng the short term test program data base Finally. the fourth task relates to recearch and doclop• ments that twll yield data for so;ne of the foregomg data hases plus new data bases that can be utilzed in production vf ready reference sources (hard copyland for introductton into online searchable data resources. Special research tasks in the past and in prngress include (a) lists of organic and inorganic con- taminants in drtnkubg water evaluated for carcmogenicrt) and mutagemctty, also promot;ers and/or cocarcmogens and. where mdreated, monoeraphs on each of these chernrcals:(h) study of air pollutants, identsfication and classuicatuon as to carcmogemeit) • mudagemcity and also listing of promoters and/or cocareinogens: (c) a survey, of environmental momtor- ing data. (d) species to species camparison of inetabulism, a hsttng of ugirttfrcant metabolites,(e) a'study on metal con- taining drugs,and (f)an abridged hsnng of chenucals,that are currently recognized as inhibttors of c:uctnogenesrs. Also, this task ;,rovtdes for review, editing, and ultrrnateh , the bublrca• tton of aforementioiied class studies and special studies re• ports in the open hterattrre for use by the scrent:fic comnw• nmty at large. Tasks relating to chemical selection included (a) selection and ordering of classes for study, (b) significance of in vitro tests in chedtical selecuons:(c) development of sum- mary sheet format and content ; artd (d) chermcal selection of lists of promoters aspd cocarcinogens. The current contract project is funded through Sept. 29. 1984. It is the inteniton of DCCP to carq• forward the four tasks. It is proposed that the contract project covers thrce years• on a competitive type award,at the same level of fund- ing as proposed for the first year. For Task I it is planned to have the same level of financial support as in the current contract on tate assumption that the nomination and selection process will continue at the presem rate of 15 nc.minauons per year. In the event thst the tesnng program will start testing more ehemscals (or carctnogenrcrty (t.e., 30) then some future adjustments will have to be made. As tt stands now, st ts anticipated that in Ilte three yecr period of performance this will snvoh•e approicimateh 10 class studres (depending on the size and scope), about 45 summary sheets. and nominations for short term studre?, at the rare of 70•90. For Task 11 involving ItdRC support, the same level of effort is anticipated in the future three year performance penod. It is expected that for nine meettngs (three meetings per year) physical and chemical data. productton and expo• sure values, and analyttcas data wil have to be provided on approximately 225-270 chemrcals,(75•90 chemicals per year). For Task 111 the current mechanism set up for securing rn• formation and data for the Chermcal Carunogenesrs Research Information System will be continued. N'e anticipate evaluz• tion of approximately 450 cher•,ncals for classification as car• cmogens and about 1,000-1,500 for classification and iden- tification and identification as muiagcns. For the Broassay Report Summary Handbook we expect compilation and ad• dttton of 52 new sur,tmaries prr year for a total of 156 for the three year contract period. Ad'dttrunally• data will he added to CCRIS from special studies deceloped under Task IV, Ne do not hate a precise estumate at lhts time but front past elpenen.e, a!;sunnng three to four specral studies per yeat with a% ield of information oii about 50 chenncals (elmt• maung duplscattons). one could expect total input tnt,o CCRIS on appru\mrarcl- % 600 chettucalt Inforntanun from t¢te shor. tenn tesnng nrogram should comc frum tesung ol at least 150 ,hr:.:i.als in threc Nears. Nlth tlre proEresston of etiplatratorc suh•tasks under T,ak I\', niore daw utll be entered or, pro, muters. cocaresnuFem and mhrhnors. Task 1\' rs the toundat•rm tor rese3rch and de.clopmcnt on mechanisms and resoun;es for securing mfurmatron th3t is uscd in rdcntrfi,atrnn an,-' classuAcaunn of carcrnopens- muta• Fens. prornoters- cocaronupcns. minhrturs. and then metab• ohtes that arc rr, thc enrtuunment The mformauon and dat.r deteloped Ihcrcftum ate publrshed as special guvermx•rt rc• rnrts or rn reWit artrclr. tn thr ufK•n hrctatur: anJ Jrc ulmn• The Canaer Letter Page 6 / June 10, 1983

alely incorporated into CCRIS. While these data bases are of great use toNCl, they are also m'rdely used bv other agencres, academra, nonprofit research foundations and mdustr) . They have been utrlized, for examplc, in the preparation of position papers and presentations at scientific meeungs such as organic pollutants identified in au and dnnkrng water. We expect at least three special studies per year, or for the three year period of this p:oposed contract, a total of nine or 10 such studies In order to be able to be responsive to current issues, it may not be predent to get locked in on specific studies for the three year performance perrod, but studies may be in- dicated on carcinogens and mutagens oceuning in natural products; specification and/or identification and classification of natural chemrcal inhibitors in foods and diet (carrots, Brussels sprouts, garlic, etc.), effpcts of thermal and radiation processing on formation of carcmogens and mutagens in food; survey of carcinogens, mutager,s and promoters in excretory products (feces and urine); and survey and identification of contaminant chemical exposures that may be associated with potential carcinug.nic effects. Encompassed undet Task IV is also the pubircation of class studies and special studies repurts. With the continuout de- velopment of class studres, the division decided sume time ago that this important resource should be published. Therefore, some effort is needed to edit and prepare in final form for publication the class studies and special reports accomplished un der this task, "What would happen if you did not have this con• tract?" Ornenn asked. "You would get a Chevrmlet instead of a Buick," K.raybill answered. "Fewer ehe:nicals nominated, less information about them." "NC1 nominees have the best information of those submitted toNTP;' Adamson said. This includes biological, exposure, and production data. "How many NTP chemicals selected for testing are NCI nominees?" Omenrp asked, "The greater majority," Adamson said. "Ninety- three percent; " Kraybill said. "Why make this competitive?" Hoffmann asked. "No one else can do this." "Yes they can," Adamson said. "Anyone can come in and compete for it. We've seen some interest by otlrer organizations. We're not wedded to SRL" Kraybill pointed out that in the previous compet- ition for the contract, five organizations submitted proposals. Omenn offered the motion to approve the con- cept, commenting, "To make any further cuts I don't feel would be advisable." Biomedical computer support services. Present contractor. ORl Inc. Estrrnated first year award. $1.05 mrliron; total cost, S3.3 nullrrm o%er three years. lsbchael 5tump presented the project description: Ti:rs is a support services contract for the Brometr) Branch. Scnt.es are proctded to the Office of the Chref. the 13rometnc Reuarch & Analytical Studies Sectton, the [kmographrc Analcsrs Sectron. and the Computer Science Section. Sernces pro%rded under thrs contract include computer programming. cunnmrer systems analysrs, tc chnrcal ducumentatron. orera- tron of the lar:duN rentote terminal facdny. and ch n.•.l supp pon rclated tc, computer apph,luons. The leiel yd eflun for ttus contract is currentl. 20 persons and r,%l+ected to reirraln at thl Ics-cl tlrroughout tirr c>>ursc of .f • qf11 • the coraract. The Brometry Branch?ras relreajon support contracts for a majorit) of rts computer related sen'rce needs since 1970. The pnlmary reason for usinF a contractor in lieu of mhousc resovrCe's is thc varrabrhty of computer support rcqurrements front year to ya•ar. The concept of contratun; for these ty pes of servrces was rev:exed and approved by the IaCCP Board of Screntrfic Counselors in February, 1982. Cumractur sernices are procrded m an orfarnzcd tcam of computer project,manaFcr~t computer professronals, and sup- port personnel. ThC contract is admwrstered by tne Computer Sdence Section. The contractor's project manager and the NCI project offrcers jointly allocate contract resources in accordance with Arometr% Branch priorities and needs. End projects are comptuer prograrnsand systems.tecluucal ducii- mentauon, computer output such as listings. tablcs. and graphs, and services such as data entry (keyrhg). A partial list of 3iontetry Branch projects receiving support from this contract includes: 1) Development of a user orrented software package for the analysrs of incrdence and mori: bty, data; 2) Editing, conecpng and tabulating rr6conung data from SEER registries; 3)Dkveloprpent of a prototype data n;anage• ment system for SEER repstries; 4) Systems devclopment for data collection and analysis of a followrop study of survnors of cancer in childhood and adokscence. In vitro evaluation of chemical candidates for in vivo testing. Present cdritractors are Aficrobiolopcal Assoctades, whose contract is being recompeted for three years wrth an estimated first year award of 51 85,000 and total cost of 1s577,0D0;and Research TrianFle Insutu.e, who..e contract is being recompeted (or three years with an estimated first year award of $62.400 aind total cost of 5195,000. Thomas Cameron, DCCP assistant scientulic coordinator for environmental cancer, presented the project description: In March 1981 two contracts (Ames salmonella typtumur- ium and mouse lymphorna L5178Y Tl:•/') were compeuuvely awarded to aid the Offrce of the Scientific Coordinator for Environmental Cancer in its support of intramural and extra- mural activatrers of the drvrsibn. The primary thrust of the cun• tracts was to frll gaps in knowledge in mutag:enicrty data needed to select NCl nominations for carcinogemcrty testrng iri the National Toxicology Program. To comply with the mission of NCI andi of this d'ocuron's role in identifyrng etiol• ogical factors of cancer, we have been and will conumre to be the major source of' nomuranons to that rnulu•agency actrvn.. A format has evolved to look at large grouprngs of cheriucals (by chemical classslor use category) in order to systematically select the best carid6dates. This has routinely shown the paucity of in vitro ylata on most of the compounds. U31a ob- tained in these mutagenicity assays have provided rnforiitatiun to the selection group, enabling them to make mfom,ed choices in a trmely fashion. Other apphcatrons of these contract activities have de• veloped as individuals and org mzattons hz.se Icarned ot thcrr availabrht). One example concerned the initial tentative assoctatron of anal mtrare usace with the occurrence of ac• quired immune defuciency s' vmdrome in a certain popuiauon subset-that compolund and four clrseh rclateu compounds were tested, at the request of the Field Studies group nnd thc nTP, to sopplv additional brrolopcal information for vprmons and acuons they were for:nulatrng. lrkewrse, in a conperatrve effort with the Bureau of Foods. FDA, seven compeunds :on- tarnrng the cinnamyl radical were tested because that rnuret% had been a part of a food additive positive in a chrornc roJent broassay. Out resulfis comll confurned those presruuslt obtained in the F UA lahurator%. and wIll permit them to move forward with confrUence. l.rmrteJ pusilme bro.rs,a% findings released by the hredenck Cancer Research haoirt%e surplcmentcd h~ posrtne findings fr-:lt our :nntr.r,:s. h.~c The Cancer Letter Vol. 9 tvo. 23 / Page 7

convinced private industry to investigate thoroughly a major chemical. In the two years that these contracts have been in operation 110 compounds have been identified for study and are in var- ious stages;:.e., being procured, on test, or reported out. Over 60 compounds have been completed in both assays, and we are presently analysing those reports. fh addition to reporting the results to those groups and in dividuals who initiated the original request, we are preparing a series of manuscripts presenting the results as a consequence, of chemical structure or by chemical usage as appropriate. The initial manuscripts will be on five sulfur containing heter'ocyclics and seven cin• namaldehyde anafogs; papers on a group of metallic inorganics and some 16 dyes and dye intermediates will follow. Correla- tions will be made between the two assays as well as references found in the open literature and to reports available from other laboratories. This ?, an excellent oppo-'••nity to cor related'mdings between assay systems and between laboratories under well controlled conditiorrs,and wid add to t:ie govem- ment and private sector activities that are presently evaluating many of the assays available either commercially or as de- velopmental projects. In order to cpntinue this support to intramural and extra- mural activities of this divison, approval isrequested to initiate a competitive renewal of contracts for these assays- the Ames Salmonella typhimurium and the mouse lymphoma -for the purpose of awarding three year contracts for each. The present conlracts call for a maxirirum of 75 compounds a year to be tested in each assay and the capability to tepeat 25 of those tests in the event of equivocal results. The chemical selection activity of the NCI has been moderately reduced to conform with the anticipated chronic rodent bioassay com• ponent of the NTP; consequently, rt is no longer necessary to continue at the )rresent leveL It is esumated that a reduction by 40 percent-down to 45 initial tests and the provision fw 15 retests-woul,d be adequate in the foreseeable future. The proposed workscopes for the ienewed contracts will duplicate those presently in effect, Each compcund w-ill be tested in frve tester strains of Salmonella typhimurium both with and without S-9 activating systeins derived from both rat and hamster liver. Each test will have five dose levels deter- mined by prior range finding tests, and will incorporate des:,- nated positive " well as solvent or negative controls. In the mouse lymphoma assay five doses selected on the basis of cytotoxicity will be tested both with and without metabolic activation. Appropriate positive and solvent or negative con- trols v,=,ll also be included in each assay. Test compounds will be procured through another contract (the chemical procurement and repository activity presently under contract to DCCP) and abquot portions will then be supplied to each laboratory conducting the assays. Chemicals are acquired by the repository on an as needed basis and in sufficient quantity (usually 30 grams) to permit reposrtory to retain a like or greater amount for future reference or to resupply the laboratories if additional compound is required for retest. Each individual chemical shipmer/t sent from the procure• rnent source to the laboratories is identlfred by a code number and is accompnaied with instructions as to the cor• •ect solvent to use: i.e., watcr. DA1SO, ethanol, or acetone. Bod' laboratones have been instructed to coordinate their purchas° of solvents so that they use the identica3 supplier batch as designated by lot number. In addition, each chem• .t ical shipped is accompanied by i'sealed cnvelope:aadiAsed to the safety offrcer specified by the laboratory, containing the available tnformauon on toxicity, neutralrzation, cleanup pro• eedures, etc„ to be opened only in the eie.^.t of an accident with that particular compound. When the test is completed, if the envelope has not been opened because of an emergency, it is returned unopened to the project officer. Each laboratory shaU prepare two reports on each compound-a brief narrative and completed computer forms for input toa data bank for the use of govemment agencies. The prbposal for a study of mutagens in human food was tabled following opposition by Ontenrt, Hoffman and Conney. "We don't have a single animal model to show that these mutagens cause digestive tract or tracheal tumors," 1-loffmann said. "Before we spend $2 mil- lion on this, wait until we do." "This is not suitable for a directed effort." Omenn said. He suggested that rather b`tan issue an RFA or RFP, NCl should publish the proceedings of a recent workshop on mutagens in food and mention interest in supporting grants in that area. "We could put out a program announcement," Adamson satd. "No, no; even that," Omenn. insisted. Adamson suggested that the workshop be pub- lished, "wait 18 months, and if nothing comes in, .ve could then have a program announcement." Program announcements indicate NCI's intere;t in a subject area but do not reserve any money to fund those grants; they must compete in the regular 1103 or P01 pools. "We had a program annortncement several years ago on mutagens, and it failed miserably," David Longfellow, assistant chief of the 4hetnical & Phys- ical Carcinogenesis Branch, said. "They did not fare well in the study sections." Board Chairman Peter Magee suggested that the concept be tabled until after Boar0. members have an opportunity to read the proceedings of the workshop or a summary to be provided them. The Board agreed. "i he lung cancer-coke oven workers study ~,. as to have involved a contract with the tJniv, of Pittsl-urgh to combine and organize data in its possession on • steel workers. Board members objected to what theN said was an inadequate description of the concept. It was deferred with the sug„eestion that it he re- submitted with a more complete presentatton. The nor:cor•tpeJAire contract concepts appnrre•el 5ti• the Board w•illappearpe.tt werk in The Cuncer Letter. J The Cancer Letter -Edito, Jerry 0. Boyd P, r:1,Shp0 tcrtv e,"+t t.m,,g a vea' bY The Canrer LettP. In[ . P C) Bax _ 3;0. :-ie>ton. V.•g-n.a n,,; ooe,l shc* c' r'.e C'-c.,, :a.,.... Le•rter_ 41i .arts'eserved. None ot the conte^t o( th.s OdbI.f at1on nu~ be rrn'kdJca' Sto'trJ -1o ret'~eva's~sten', or tr,ins'~+•ft1 ~~ .+~~. 'C•r' or bs ntra'+5 ie,ectronn. n.(rI e>•vtOCM, n, fCfUr(1 r,;; o. ,:nr .~ ~vr ,. •nf+o! thf• r,..~. Vi;;igl,,r.f,',A(rpPnJ[r-e53^USJ:,xV Oe'*1)Oe!