Document 6bN752oRQekdm4j3GK3NpgDg

. Vai. 505 So. 23 CHEMICAL CARCINOGENESIS - FaRBER 1379 4 Rimixcn I. t'knnila|ir JL. Anifiail rapimm. Pkyool Rn. 1959:55.91 l-R. 1 luAtrabaiowt FF. Riflhaocul W. Kalla H. a aL Apptocaiw of vauuttnul prauara aanllwaoi n a odificiuoo if "trfhmt* fnpirauoa " > J Aaaank. 1971 44*274. 5. SfAoraad L. Dm af ikt pkyinlapiral rauaaalt far tad ikiaiapnam af kipk-lraqaaoct powa proaaw -aaiilaua* -- HFFFV. Acu Aaatufcaaol Scantf |Suppt|. 1977; *4.7-27. 4. Klaio M. Snutk Rl. Kipk rraqaaacy pamnanauaa tnoaracfcaal jat taulmo*. Cm Can Mad. 1977. S:2W7. 5. lumadl JR. Kirtooa K.H. Sbaaaaa DC. Hip* (raquaacy paauva pn an -aaultuoa dopi aad rtkkiu. Aa Rt Rapu Do. 1971; 117: luppntt ibttncL *. Roka DJ. Miytiaka K. Maftkak L Tkoapaoo WK. Froaa AR. Irvaa AC Vaaulauoa k> kipfc-lnqaaaqr oanllauaa J Appl PkyaoL 17*0. 4* 7104. T. Railar `J. Raka DJ. Rryaa AC Fraaa AR. Venqliuoa by ktpkfnauaacv aanUauoa a kuaaaa Aatnt Aulp (Cloak 1910. 50.577*4. L Carta* GC. Ray C Jr. Khia H. McCaraack FM. Hipk-fiagt--O) paaum pnaaan naulauaa a aanayamrm af a pauaat nt limarka pttural fiuaia. Aaanamolaty. 19*0. 52:1*142. 9. Siuuky AS. Rrova R. Lahr J. Raaiaap TM. Dram JM. Hi(k fraquaacy vanuUueo. a praouuap aa* approach a aabaaicil naiaiauoa. Mad laana. 19*1: 15:229-55. R. Fraaa AR. Rryaa AC. Hiph fraquaacy vaouliiino. Aa Rrv Rapa Die. 19(1: 125.244-50 11. Siauky AS. Draw JM. lapraa RH Jr. a aL EfTaaiv* pulaaaary aaklauaa nk touU-voluma aaollaueai at kipb fraquaacy. Scaacc. 19*0; JOT-*07-11. 12. Shuaky AS. Kama RD. Raaaap TH. a aL EJfccu of ftaqwncy. tidal -alultn aad lanp -olumr aa CO, cfaaunatiaa a dapa hy ktpk fraqutacy (2-50 Hik to* tidal ralaar raaulauaa. J Clia lava*. (a prauk 15. Sj*araad U. Saaaary af capanmaatal aad cbiucal faaturw af ktpkfraqaaan poaniva-prauui* raaulauaa -- HFFFV. Acta AaiankUiBl Scaad ISuppt). 1*77: *4:1*5-7*. 14. Fraau ID. Stark AR. Wankaaatar J. Imprai nnaal a pulaaaary lawnuual ampnyMaa *nk ktpk fraqacacy raaulauaa. Faduv Raa. 1711. 19:719. akuracL 15. Oeldauui DH. Siuuky AS. lapraa RH Jr. toaaunaaa F. Vaaapaa J. Draaaa J. CO, aJuataauea by ktpk fraquaacy raaulauaa (4 to 10 Hi) a aoraal utbjacu. An Rrr Raptr Dta. 1911: 125:251-9. I*. Citaur JR. Shaaaea DC. Hiph fraquaacy raaulauaa wkaaaa aay*aa- atiaa aad aWaelar raaulauaa at raducad atraay prauuna a aa aaiaal nodal af pulaaaary alii Aa Rrr Rapu Dta. 1979; 119: SupphJt*. akuracL 17. Sckmid ER. Kaapp TJ. Rchdtr K. latrapubaoaary pu traaapan aad perftinea dunap ktpk fraquaacy naillanaa. J Appl FkyaoL la prauL II. Fukuckt Y. Reuusa CS. Macklaa FT. Eapai LA. Caaracuoa. dtffu- uaa aad ardaopaatc ntatap of iaipirad pu a the luap: aa capanaaaial approach. Raptr Fkyel. 197*: 24.77-70 19. Slutsky AS. Ou autap by cardiopcaa omllaiioai- a tkaoraual quo*utaura aaalyna. J Appl FhruaL da prank 20. Fiadbcrp JJ. Aupmaatad dtlTuuea a the airways caa tuppar puk noaary pu adupi J Appl FkyaaL 1910: 49.2524. 21. Haaakaa FR. Sekam FW. Rraadual hiftuaauaaa aad mptratary atau traaapan. Soaau 17*0. 20*:*9-7l. 22. Taylor G. Dupuatoa of tolubla aorta a wfraai flowtoq ttowly tfcroupk a tuba. Proc R Sac A. 1995: 219114-205. 25. /drat. Tka diapanroa of auur a turfcutaat flow tfcroupk a pip*. FrocR Soc A. 1*54; 225:44*41. 24. Ckatwta PC. Oa tin toapnudmal diapamoa af paaur* oaaiintaaat a oicillaiary flaua a tuba. J Fluid Mack. 1975; 7l(2k5l5-27. 25. Mead J. Caetnbuuaa af eotapliaau af sirwoys a fraquracy dapaad tat behavior af traps. J Appl FbyatoL 1949. 2t:*7lkl. 2*. Routap TM. Sluukr AS. Lekr J. at aL Tka afluaaea af tidal raiuuc (V^aa CO, ampul (VCOJ dunap ktpk fraquaacy raaulauoa (HFV) a dops. An Rrr Rupu Du. 19(1; 125(4k Fan 2JQJ. abstract. MEDICAL PROGRESS t CHEMICAL CARCINOGENESIS Emmanuel Farrrr, M.D., Ph.O. THE perception of cancer as a disease primarily related to the environment has been progres geographic location to another were important in changing the whole perception of the genesis of sively strengthened since the publication of a Medicacl ancer.w Progress article on chemical carcinogenesis in 1971.' This radical change has encouraged increasing By the mid-1960s, the view of the cause and patho attention to the nature of the environmental influ genesis of cancer had already begun to change radi ences. The available epidemiologic evidence indicates cally from that of previous decades, during which no the likelihood of several (if not many) components in dear perception of the possible role of the environ this environmental outlook. Diet, carcinogenic chem ment in the genesis of most of the major forms of can icals, radiation, and viruses are among the major fac cer was evident. Although the relation of cancer to en tors that appear to be involved. Of these, chemicals as vironmental hazards in the work place and to a few carcinogens have been receiving increasing attention unusual cultural patterns around the world was es as having the greatest role in the genesis of cancer. tablished, the examples were considered exceptional. How justified is this perception of the causation of The general acceptance of cigarette smoking as a cancer? - major factor in the development of lung cancer and About one third of the cancer in North America and the increasing number of examples of major shifts in Europe is related to the use of cigarettes or other to the organ or tissue distribution of primary cancers bacco products. There is incontrovertible evidence with migration of distinctive ethnic groups from one that chemicals related to the work place or occupa tion are responsible for a segment of cancer in human Ft-- tfcr daponaom df Fatkolop tud Riortnaiwy. Oatvamty ufTuueia. 100 CoU*t* Sl. Toramo. ON MSG IL5. Cqaadq. *>kan npnot r fNM tfeouM fee iMimi. Sapponad b* tauanfc (fiats fraa tka Naaookl Caaau lattimu of Ciada. tkt MadKsI Roaank Cauaal of Coudk. asd tfcc Naiioul Camu lo- uw (L'XA-k beings (Table 1). To these must be added a growing list of naturally occurring chemicals and of drujp used in medicine. All thae known agents, together with ul traviola light as the single most common cause of can cer, can easily account for over 50 per cent of the cases T ta ra e rm ijE S f 067 42 THE NEW ENGLAND JOLTIN'A l. OF MEDICINE Dec. }. H*1 'i. Chemicals Known or Strongly Suspected to Be Car* etnogenic tor Human Beings. -- wlCurin i ..man,... V .TV ; 1-* W.tu . T.-.r v 'thv**:*'-.* Smot (.**! BUJtftr Stmtatf ht. Branc&us. prtur*. n4 ptniOMsm Marrow Irortdtifi Kwyirwont rraa -.-r. % 1 <sai* iT. *- BfOfWfeltt Brcnduu iMiwhiuar.: Skin anti lunfi Niul Mnuin ljvr r* *dpfe.'Ui: ... . - .)uric ... - .jibcurol r. w r* "*" -.** *ia<wp~*tc:idtn) .' - - ' - - *mokt ............rtrutpuvc* : vldcr }-. TiMOfOmh' tUi.. Ltvf Sfcm BiotMV V*flU L- .Hioid mil Rs.-ii patois Livar Bionchm. moutb. pharyaa. larva*. noph*|us. MaMar. ud paocraat Livar Mc*u:h .f thf ' ':d States, Canada, and several other :t vn ci ties. Kn ab'' he remaining cancers -- those in the . bre*. '::erus, hematopoietic-lymphoid sys- . . . -ost.. ! other sues, including ' listantial ortion 01 >riose in the urinary bladder and pan- " Car. - <r be closely related to the chemical ... ..umination of the air, water, and food that has .:. xcunmt in the industrialized countries? No ;-ive an. r is available. Evidence can be offered :-.ir of si: ,i a view or against it. the positive side are the following considers- the known relation, mentioned above, between :~mv different types of cancer and exposure to chem- -. in tobacco and in the work place; the wide- . .d presence of chemical mutagens and potential . it unogens in the environment in industrialized .lUries, as monitored by short-term in vitro tests in '.; okaryotes or eukaryotes; the observations that some religious groups in Utah and elsewhere, who have dif ferent patterns of tobacco and alcohol use and differ ent codes of behavior, appear to have a lower inci* dence of some forms of cancer in the respiratory, tastrointestinal, and genitourinary systems'; the in creasing evidence that cancers of many systems, re sembling cancers in human beings, can be induced by -AmicaJ carcinogens in one or more laboratory ani- -:s; and the observations that cancers of the esoph* .. us or liver have an unusually high incidence in some geographic locations in China, and that domestic ani- maii in close contact with human beings in these lo cations frequently have similar cancers in the same anatomic sites. Oo the negative side, no clear-cut clinical expericr or epidemiologic evidence has been presented to i' >ate environmental chemicals at causative v:"its for the wide variety of cancers seen clinically. V - .ding to German" and Cairns," portents with xc. oderma pigmentosum, who have a delect in their lasts in the repair of DNA danu. * by some cals as well as by ultraviolet light, ' *ve no ele* 1 risk of cancer in organs or tissues ot cr than the k> If the general environmental exposure to chemica` >ere effective in the causation of cance,, such pa* tie ' could be expected to have elevated incidences of r?.. ,r not related to ultraviolet light. In orr.e can* <uch as leukemia and cancers of the stomach and cei...a, there were decreases in age-adjusted inci* dci ' and in mortality from 1969 to 1971 and from 19 , to 1976 among white persons in the United St , while there were only small increases in most of - other tumors, as compared with cancers of the lui and with melanoma." No increase comparable to de< Unix K ne of the above considerations are by any means co;:- iusive. Most of the arguments on either side have enc-igh contingencies to leave the question in major doubt. The close monitoring of cancer occurrence over the next two decades may allow a more definitive po sition to be taken. In the meantime, a greater under standing of how chemicals are involved in cancer de velopment would seem important in helping us to arrive at a conclusive position. In addition, the large increase in the use of chemi cal carcinogens in the development of new experi mental models for the study of the possible cause, de velopment (pathogenesis), or treatment of cancers in specific organ or tissue sites in human beings further emphasizes the importance of the study of chemical carcinogenesis. Such studies should generate a much more critical understanding of the relative, roles of exogenous and endogenous factors, including diet and hormones, in cancer development and behavior. The orientation in this presentation will be mecha nistic, not descriptive, and will attempt to relate fun damental concepts and understanding derived from experimentation in animals and from other sources to the causation, prevention, and (to some degree) ther apy of cancer in human beings. For this reason, little coverage will be given to the many different types of chemical carcinogens themselves or to their distri bution." Canceb as a Cmomc Multistage Process It is now appreciated that the development of cancer in human beings in various sites takes many years and that progressive tissue and cellular changes 1 1 'is n n o is i DOW 06743 VeL Ni No 21 chemical carcinogenesis - farser ini can be teen during the long 10-called latent period. some nitrosamides (e.g., alkyl nitrosourea), bis(chlor- Often, new cell populations appear that probably rep* omethyl) ether, and nitrogen mustard, are active by resent stages or steps in the cellular evolution Jrom themselves and do not seem to require any metabolic normal cells through initiated, preneoplastic, and conversion to more reactive metabolites. premalignant cells to highly malignant neoplastic cells."*" Research in laboratory animals has concen Activation and Metabolism of ProcarcinogeiM trated heavily on the early events and has suggested The first major type of metabolic activation discov the existence of common patterns of early preneo- ered was the conversion of an aromatic amine, 2-ace- plastic changes in several organ systems and in sever tylaminofluorene, by jV-hydroxylation to an N-OH al species." Research in human beings has concen derivative.0 This type of metabolic product is seen trated largely on the later events and has confirmed with several aromatic amines, including the human the occurrence of atypical hyperplasias, dysplasia, bladder carcinogen 2-naphthylamine (0-naphthyl- and carcinoma in situ as probable precancerous steps amine). in several organs late in the process."'1* However, the More recently, much effort has been spent on the critical properties of each different cell population clarification of the activation of benzo(e)pyrene and that relate to the possible roles of these cells in cancer the many other polycyclic aromatic hydrocarbons. development and to the manner in which the two Many of them are easily generated by burning (py aspects of carcinogenesis (the experimental and the rolysis), are widely distributed in our environment, human) fit together into some biologically meaning and are thought to be partly responsible for the carci ful pattern remain as challenges." nogenicity of coal-tar products, oils, and tars. These The conceptual advances made in the late 1930s compounds undergo epoxidation to form reactive ep and 1940s concerning the first two early steps in oxides, some forms of which are considered to be ulti chemical carcinogenesis, initiation and promotion, mate carcinogens.0 In the case of benzo(e)pyrene are well known."*"*' However, their mechanistic (and probably other polycyclic aromatic hydrocar bases are only now unfolding, and these will be topics bons), the initial site of epoxidation may undergo hy for review. The basic validity of these concepts for dration to form a dihydrodiol in a reaction catalyzed cancer development in human beings has been estab by epoxide hydrolase. This inactive derivative, in lished in a few instances and as such is reassuring turn, can be convened to another epoxide at a second both for the physician and for the scientist. For exam site to form a dihydrodiol epoxide. These are consid ple, a relatively brief exposure to diethylstilbestrol ered to be the most likely ultimate carcinogens for at during pregnancy may be associated with the devel least some polycyclic aromatic hydrocarbons. This opment of vaginal neoplasia some 15 to 25 years later series of reactions for benzo(e)pyrene is illustrated in ( in the exposed person's daughters.11 Parenthetically, Figure 1. Another potentially imponant carcinogen it should be mentioned that it is not known whether for human beings that is subject to activation through diethylstilbestrol acts in this situation as a chemical epoxidation is aflatoxin B,.0 This substance under carcinogen or whether the effect is predominantly hor goes oxidation at its 2,3-position, and this derivative, monal. Again, a limited exposure for only a few the 2,3-oxide, appears to be one form of ultimate car months to a known chemical hazard, such as vinyl cinogen of this mycotoxin. Vinyl chloride is also acti chloride, may lead many years later to the appear vated through epoxidation.0 ance of angiosarcoma of the liver.0 Nonneoplastic cel lular and tissue changes are seen during the apparent latent period. IWITUTOaS ANB ImTUTIOH Intttetors Until fairly recently, one of the most puzzling and confusing aspects of chemical carcinogenesis was the diversity in the chemical structure of carcinogens. This problem has now been largely resolved by the discovery of metabolic conversion of many carcino- !;ens to highly reactive metabolites." The best-known orm of reactive moieties, generated from several dif ferent types of carcinogens, is the "electrophilic re actant," which is a positively charged molecule that reacts well with sites of electron densities in many dif ferent cellular components, including DNA, RNA, protein, glutathione, and probably also polysaccha rides.0 A minority of chemical carcinogens, such as Figure 1. Current View of the Activation of 6enzo(a)pyrene (BP) to Benzo(a)pyrene 7,-Olhydrodiol..lO Epoxide through the Mixed-Function Oxygenase (MFO) System (Cytochrome P-450 System) and Epoxide Hydrolase. z m o o o is j | Z DOU 06744 THE NEW r.Mf.LAND JOURN*l OF MEDICINE Dtt. J, mi C'.her types of metabolic conversions are alio cons:;',c.-r.ri important in carcinogenesis. Nitrosatriuas are roi./cned to highly reactive alkylating moier-;, prob- through oxidation. Aromatic or heten;t:yclic niu ipounds. such as nitrofurans and 4-uiirr.quinour.r A'-oxide. probably undergo initial reduction to h/oYoxy-amino derivatives. In the case of 4-nitro5u/ -.oILre-//-oxioe, this form is considered to be an ul timate carcinogen. To*- the majority of kniwti conversions, the system most active in the cell is the "mixed-function oxygena.;e`' system, consisting of several cytochromes P-450, rtc-m-ed iiKonjamid" J.-i'ine dinnclcotide phosj.ha:r cytochrome redi.ri.aie, and lipid " This induci ble system is 'seated .i.mdominamly m tj microso mal frarii.M of the ceil (endopiasr-uc reticulum), nJ'.huuf.h rcecr.; work increasingly points to a second cer.inarnble system in the nucleus." In addition to -here oxidative systems, reducing systems also exist for jciiie prccarcincgens, such as the aromatic or betwocydic nitre-compounds. Oiaphoraae or other redbcvc' nicotinanide-3<Jenine dinudeotide phosphate or reduced nicotinamide-adenine dinucleotide reduc tases arc widely distributed among different cells and are effective in redudng the nitro-group to the hy* riroxy-amir.o-dcrivati ve. The liver r; by far the most active and most versazih organ in the metabolism of procarcinogens and of xencbiftic agents generally. It and other organs have an ability to detoxify potential carcinogens as well as activate them, and the ultimate fate of a chemical de pends largely c:i the balance between activation and iueetiwnion -- a balance that is easily modulated in major wnys by drugs and other chemicals, age, nutri tion, and hormones, as well as genetics."'" For ex ample, >he carcinogenicity crf-several aromatic amines fr.r the liver cm be completely prevented by simultadcoc: exposure to phenobarbitai or 3-methylchoiandume -- agents that induce many liver enzymes. This phenomenon of resistance of the induced liver to some carcinogens may be of great practical impor tance to human beings. Virtually all people in the VVerrsnt world have levels of several xenobiotic such as chlorophenothane, dieldrin, aldrin, polychlorinated biphenyls, and dioxins, in their adi pose and other tissues. These agents as a group are ef fcctiv- enzyme inducers in the liver. In addition, many drugs induce various microsomal or other enzymes in the liver or other tissues. Are these inducers making tissues more or less susceptible to the acute toxic or carcinogenic effects of other environmental agents? The organ or tissue distribution of the carcinogenmetabolizing enzymes may be involved in the organ' orropism of carcinogens. Since there is an almost .. ,* ", certain requirement for activation, and since the metj < abolic patterns affecting carcinogens and other xeno;; : biotic agents are so variable from cell to cell or from t organ to organ, the absolute activities of the various enzymes and especially their relative balance may *f''' have key roles in determining which organ will be a target for a particular carcinogen. An interesting ex ample of modulation at this level is the liver-kidney axis with dimethylnitrasamine. This potent carcino gen net mally induces liver cancer when taken through the gastrointestinal tract. However, if the animal is placed on a low-protein diet, the hepatic activation and metabolism fall off. This pattern allows more of the carcinogen to be available for action on the kid ney and changes the dominant cancer pattern from the liv.tr to the kidney." Clcui iy, the pathologic consequences of exposure to any potentially toxic xenobiotic are related not only to the pathways available for its metabolism but also to the physiologic state at the time of exposure. Thus, the presence of a known mutagen or carcinogen in the environment is by no means synonymous with a mutagenic or carcinogenic response by the exposed person. Possible Molsculsr Targets for Ultimate Carctnogens The molecular targets for the electrophilic react ants are many. To date, the bulk of the effort has been concentrated on DNA, with some interest in RNA and protein. In principle, many other molecular tar gets exist at the macromolecular and "micromolecu lar" levels. Because of the ease of relating changes in DNA to a permanent change in the biologic behavior of cells, DNA has received the lion's share of atten tion. Since the first discovery of the chemical nature of an adduct of a carcinogen with nucleic acids in a tar get organ in vivo," there has been an increasing inter est in establishing the chemical nature and site of in teraction with several different carcinogens." As shown in Figure 2, virtually every potential site for in teraction with DNA bases (as well as with phos- '.n phates) reacts with one or more carcinogens. In at- CO tempts to narrow down the possibilities for relevance --4 to cancer, sites that are more likely to be involved in CS hydrogen bonding between bases (purines and py- CO rimidines) in DNA, and thus to be involved in possi- CO ble miscoding, are often considered most relevant. cn This presupposes that the major or only biochemical - lesion in DNA that is relevant to cancer initiation is a "M miscoding lesion. This judgment may not be justi* to Tied, since the evidence is circumstantial and incon clusive. Conceivably, other types of alterations in DNA besides miscoding, such as recombinations and gaps,, may be important to the early events in cancer development. In fan, Cairns has suggested that . . r mutagenesis may be of only minor importance in the initial events in chemical carcinogenesis, and that genetic transposition including relatively large re- _ -ci gions of the genome may be more relevant to this ' *' process." The application of this newer technolo- . if gy to appropriate "dean" cell populations during -Jr the development of cancer is. to be awaited with interest. ridfld1'?'.! Another important aspect is the site of interaction '.^ArifKftSsT of the ultimate carcinogen within the long DNA mol!- '`'velrh ecules. With several different approaches, such as k[ DOUI 06745 ; Vrf 105 No. 21 CHEMICAL CARdNOCENEStS -- FARBER 1313 Figure 2. Diagrammatic Representation el Sites of Interac tions of Activated Forma of Carcinogens with the Four Baaea of DMA. T denotea thymine: A. adenine: C. eytoaine: 6. guanine: MNU. M-methyKAAnitroaouraa: ENU. N-ethyt-FAnitroaourea: ENNG. .V-etnyi-W'-nitro-M-nitreaoguanidine; 7 Br MBA. 7Dromotnyi-Den20(a)anthracane: BP epoxide. benze(a)pyrene 7.B-dlhydrodioi,0.l0 epoxide; 4NQO. 4-nitroquinoline-W. oxide: DMS. dimetnyiaulfate: DMN. dimethytnitroaamina: MMS, methyl methaneeulfonate; MNNQ. FAmethyi-H `-nitroNmitroaoguanidine: 1 .2.DMH. iJJ-dimethyfhydrazine: DEN, diethytnitroaamine: N-OH-l-naphtftylamina, W-hyflroxy-1naphtnylamine: 2 AAF. 2-acetylaminoftuorene: MAM. mathytaaoxymathanol; EMS. ethyl methane sulfonate; BPL, B-pro- pioiactone; and MAB, 4-methyiamineazobenzene. studies of susceptibility to nucleases, separation of transcriptionally active from inactive DNA, or isola tion of linker and nudeosome regions in chromatin, some of the interactions of carcinogens with DNA have been found to be nonrandom. However, no single region of high affinity has been found.* ITte use of DNA cloning for specific genes in biologically welldefined preneoplastic and early neoplastic popula tions should be profitable. DNA Repair In view of the essentially irreversible nature of initi ation with chemicals and the apparent focal nature of the initiation process, major emphasis at the molecu lar level is given to DNA as a probable target in ini tiation. However, the evidence is largely circum stantial. The bulk of evidence comes from studies in pa tients with xeroderma pigmentosum, who have a high incidence of skin cancers. The etiologic agent is ultra violet light, and the van majority of patients have a defect in their ability to repair the damage inflicted on DNA by this form of radiation. Such patients can be protected from skin cancer by careful avoidance of ex posure to ultraviolet light.** Fibroblast cultures from these patients have increased sensitivity not only to ul traviolet light but also to some chemical carcinogens and mutagens.*' Other diseases (e.g., ataxia-telangi- ectasia and Fanconi's anemia) also involve deficien cies in DNA repair as well as an increased risk of neo plasia.*1 Experimentally, there is a correlation under some conditions between the formation of specific DNA ad ducts (such as 0*-methylguanine in the brain), per sistence of this biochemical lesion, and the ultimate appearance of gliomas.*1 Other studies indicate that the genesis and persistence of 0*-methylguanine may be important but is insufficient to account for cancer production with some nitrosamines or nitrosamides** or 1,2-dimethylhydraaine.*1 The major protection against cancer may reside in the efficiency with which we repair DNA that has been damaged by mutagens and carcinogens. As pointed out by Gentian" and by Cairns,11 since fibro blasts from patients with xeroderma pigmentosum show a defect in the repair of DNA damage by some chemicals as well as by ultraviolet light, such patients should have an elevated risk for cancer in organs or tissues other than the skin if chemical carcinogens are important in the genesis of many forms of cancer. Yet the available data show no apparent increase in the risk of cancers other than those of the skin in pa tients with xeroderma pigmentosum..11 Patients with Bloom's syndrome do have an elevated risk. Such observations are interpreted as evidence against a role for the many environmental chemical hazards in the' causation of human cancers generally, except in wellestablished instances such as respiratory-tract cancer'! in smokers and in persons with occupational expA/7 sures.11 An alternative hypothesis must be enterH tained: that the role of repair may be quite diflerent the dynamics of cancer induction by chemicals, IP compared with induction by ultraviolet light. The past 10 years have seen a large expansion BfV studies of DNA repair, largely in vitro. These studiriT should lead to a much clearer delineation of the typtH of repair that may occur in carcinogenesis. What dod5~ happen remains poorly understood. Processes of re pair by base excision, by "long-patch versus shortpatch" removal, by possible recombination or other forms of post-replication repair, by removal of interstrand cross-links or other more complex forms of damage, and by other mechanisms are slowly being studied in many diflerent systems in vitro and to a much lesser degree in vivo.*-*' The enzymology, al though difficult, is also slowly becoming clear. In the case of methylating carcinogens, an interesting recent finding is the discovery of an enzyme in bacteria that removes the methyl group from the O* position of gua nine in DNA by transmethylation with its transfer to a sulfur-containing moiety in protein.** This raises the question of whether some of the enzymes involved in repair of DNA damage perform physiologic functions other than repair that subserve normal cellular re quirements. Obvious failings in many of the attempts to corre late patterns of DNA repair with carcinogenicity in clude the wide gap between the chemistry and the bi- DOW 06746 THE NEW ENGLAND JOURNAL OF MEDICINE :>- and the primitive itate of the art of identifying yjantitating discrete biologic steps in the carci- - -True- process. _ :.;:rsgen Maiaoolism !n Human Tlaauea _ ratifying aspert of recent studies of the early :.:~r;cai and biochemical events in carcinogenesis is ..trail s:milarit>` in patterns cl activation and : jf adducts seen in tissues from human beings r': those from laboratory animals. Studies with itrosamines. `.cnzo(a}pyrenc, allatoxin B,, and -ircinogens**'4-` have shown that human tissues .r "'*al resemble one or more animal tissues in .r.i - . i items of activation and in the type of carcinor WA ,'.Vi.*s formed. *:rrc: ing development that may help to clarify tpec-- if this important phase of activation is v.r ; of iddioimmunoassavs for specific adducts ir l.'-A, o-u-rially with highly sensitive new aptrccti.cs to radioimmunoassay.*4-** Such detection of ;r:tc:c qu-:r.uies of carcinogen-induced adducts in D*.W 'pent rp the possibility of studying exposure c ittern; to ut.cinogens. This technique, coupled with -rcy. jzre medical examination and appropriate epi* cm.-evcjic studies, might well offer new approaches "Itimste problem of risk assessment. Although :: .00 e/.rlv to discuss such possibilities except in 'IsT.t-r-. terms, adduct formation is an index of expo* .t:.-i' t it initiation, and persistence of a chemical leDNA is bv no means synonymous with cancer <evc;cp:nent. As discussed below, initiation of the car* rt.ti.c- tic process is not an inevitable consequence of s-.t-iur. formation. cells resisted in vitro transformation with i-r-cc'-als for several years. However, the past three '-ave seen positive results in some human-cell ;V-a I.: ti-r classical system of skin carcinogenesis in ~.rd rabbits, a single or brief exposure to a car* 'in<t induces some change in the tissues, called ini* such that focal proliferations called papillo* be made to appear by application of croton `,,i! cr tther agents called promoting agents, which by j-.e-njtivjs are noncarcinogenic or only weakly carrinog'nic. More recently, this phenomenon was also icurd in several other organs, such as the fiver, brain, mammary gland, colon, and urinary bladder.**-** Su-b focal proliferations (papillomas, polyps, or hyperplastic nodules), in turn, are sites for further evolution to neoplasia. The term neoplastic refers to a cell that can proliferate without the need for an added or known stimulus for growth -- i.e., a cell that has acquired some degree of autonomy. Initiation at the skin, liver, and mammary gland, and probably at most sites, is generally permanent. This suggests that the very early carcinogen-induced altered cells are not recognised by the host in a manner that leads to their destruction, and it raises serious doubts about the va* lidity of the concept of immune surveillance at an early stage in carcinogenesis,*1 as has been proposed for host control of cancer development.** TT.rse observations are most easily interpreted as rrficccuig some permanent change in the DNA in the rare coll affected during initiation in vivo. Whether the choree is a mutation in a structural or regulatory seg ment of DMA**-4* or whether it involves more complex man-mgements of larger segments of D.VA, as in nran; position* remains unknown. Pertinenr arc the vhv.-rvirions on transformation initiated with x-rays or with polycyclic aromatic hydrocarbons, in which somr change cr -hanges other than a mutation in a rare cell appear :o be involved as an early step in ini tiation >n vitro -'li a highly selected cell type.*1-** G ie cannot rquate activation of carcinogens lea<'-.og to DNA-a-lduct formation with initiation. For example, many carcinogens, such as benzo(a)pyrene and ", 12-dimethyibenz(c)anthraccne, can be activat ed by the liver to form adducts without initiating or indr...:g liver cancer in adult animals. However, if coupi rd with one round of cell proliferation, many can nitiare`**n and induce liver cancer.'* In vitro, with dif ferent cell systems, cell proliferation early in the car cinogenic process is required for transformation with x-rays.'* some viruses," and some chemicals.'* Thus, as shewn in Figure 3, initiation is at least a two-step process: a biochemical step that is reparable, fal lowed by a round of cell proliferation that "fixes'* some change so as to make it essentially permanent. The cell proliferation can be generated by some pri mary mitogenic stimulus, such as partial hepatectomy, by a chemical mitogen,*' or ns a response to cell death." The mechanistic role of cell proliferation in initiation is not understood. A popular hypothesis in volves DNA synthesis or replication as somehow fix ing damage in a daughter strand. The probable requirement for cell proliferation for initiation has important implications for cancer de velopment in many sites. In the nonproliferating tissues, such as the pancreas, salivary gland, fiver, kid ney, urinary bladder, and brain, an important ratelimiting step for beginning the carcinogenic process may be cell proliferation. Thus, concomitant cell ne- Figure 3. Steps m the initiation of Carcinogenesis with . Chemicals. . The listings under "Initiation" refer to tome propertlee either . - used in the next phase, promotion (liver), or associated with the initialed tissue (skin or colon). 'r' s m n o o is ii DOW 06747 vl jos x a CHEMICAL CARQNOGEXESIS -- PARSER 13S5 crosis induced by viruses, toxic agents, parasites, or dietary deficiencies, followed by cell regeneration, could be a major determinant of cancer initiation in many sites. In addition, the presence of many prolif erating cells is probably one basis for the susceptibili ty of the fetus and neonate to many chemical carcino gens'' and could account for the peak in cancer incidence in the first decade of life. The human fetus, unlike the rodent fetus, acquires the capability of ac tivation of some carcinogens early in development"'" and thus may be at greater risk than some laboratory animals for cancer development with chemicals. A most important question about initiation con cerns the essential biologic nature of the initiated cells. What properties have they acquired that allows them, as a group, to be precursors for the ultimate de velopment of cancer? The available evidence is against any conclusion that the initiated cells have acquired any autonomy of growth. In most systems, the properties critical to initiation remain unknown. In two continuously proliferating tissues, the skin" and the colon," an early property of carcinogen-altered cells may be some disturbance in programming or control, such that the cells do not show the normal progression of differentiated proper ties. In the liver, the cell with acquired resistance to the inhibitory effects of carcinogens on cell prolifera tion has been shown to be one type of initiated cell."'" Although a majority of chemical carcinogens fall well within the current paradigm in which initiating effects are related to some form of DNA damage, there are known carcinogens that appear to be exceptions. A growing list of hypolipidemic agents" and several pesticides, herbicides, and other xenobiotics" have not been shown to generate mutagenicity or other DNA-damaging effects. Is this merely a reflection of deficiencies in our technology, or are there pathways to cancer that do not involve DNA damage of exoge nous origin as essential early steps in the process? PaOMOTZBS ANS PaoMOTION The term "promotion" is often used for the process . whereby neoplastic development, tumor formation, or cancer development is accelerated or encouraged in a tissue that has been exposed to an initiating dose or doses of a carcinogen. Early in the recent history of chemical carcinogen esis it was found that a noncarcinogen, croton oil, could stimulate tumor formation in the skin after a brief initial exposure to a carcinogen. This naturally encouraged a chemical "attack" on croton oil Hecker" and Van Duuren" discovered that esters of the diterpene phorbol, isolated from croton oil, have potent promoting effects on mouse skin. Many bio chemical, metabolic, and biologic effects are induced in many different normal cells by the phorbol esters and related compounds; in the vast majority of cases, the intensity of the particular effect closely parallels the efficacy of the compounds as promoters of skin papillomas in mice after exposure to a single dose of dimethylbenzanthracene or a similar carcinogen." " These effects include changes in morphology, micro tubule polymerisation, cell proliferation, enzyme induction, polyamine synthesis, phospholipid synthe sis, membrane structure and function, ATPlie, re lease of prostaglandins, inhibition and sometimes stimulation of differentiation, and many others in a wide variety of normal cells and cell lines. Many of the effects are considered pleiotropic. Recently, with the use of a less active phorbol ester, 'H-phorbol dibutyrate, membranes of fibroblast cul tures and mouse epidermal cells were found to con tain a high-affinity receptor for many phorbol esters, including one of the most active, 12-0-tetradecanoylphorbol- 13-acetate."'" The "natural" metabolites for the receptors have not been identified. Given the wide diversity and large number of effects seen in treated cells, it may be that more than one type of receptor is involved. At present it is impossible to relate the findings in vitro to chemical carcinogenesis in vivo. Given the array of phenomena induced by the phorbol esters, how does one select relevance to promotion? A major problem concerns the matching of the tar get cells in vivo and in vitro. In the intact animal, an active promoter does not induce focal proliferations (such as papillomas) in the normal skin, but does so only after initiation. However, many skin promoters , do induce general hyperplasia of the epidermis in an- ' imals in which initiation has not taken place. Studies in several laboratories have shown that a general stim ulation of cell proliferation is insufficient for the selec tive or differential stimulation of initiated skin to form papillomas." A question that requires an early answer is wheth er the differential effect of a promoting environment on initiated tissues is directed primarily to the initiat ed cells or to the surrounding cells." There is consid erable circumstantial evidence to suggest that the first major phenomenon in promotion is the selection of an appropriately altered cell to produce a focal prolifera tion, and that promoting environments create differ ential effects on the initiated cells and on the sur rounding cells.Cancer frequently arises in an atrophic tissue or organ, not a hypertrophic one. Is this the consequence of a change in the local environ ment, favoring growth of the rare initiated cell? As observed in vivo in experimental models in com mon use today, cell proliferation is an essential phe nomenon in promotion. It is therefore to be anticipat ed that many biochemical changes that are seen in the different phases of the cell cycle," such as an increase in ornithine decarboxylase activity, will be seen in promotion. Determining whether one or more of such changes in enzymes, the cel) membrane, DNA organ ization, or other factors will have a special role in pro- DOW 06748 NEW ENGLAND JOL'RNAL OF MEDICINE Dmt. X mH ... over and above thai related to the cell cycle ~mains an interesting challenge., u a growing belief that one of the major fac- /etermirjrc cancer development is the pres- r'.- -vi intensity of promoting environments.** lr. to jomr specific agents such as phenobarb; - jivlated hydroxvtoluene, and polychlorinated :!-.... .-.vis fcr the liver,** prolaain for the mammaiy piu d.** anti oilc acids for the colon," " diet has been (J i;J'u"r-.c carcinogenesis ir. several sys ems if- ?hc specific roles of individual die :.r; cm.ip-unc.tf. . nd of their balances remain to bo in tr.cst instances. :s als; ? suspicion on the part of some inves- ,`hat :::;ues or organs may create a physio .-".ic r/.*ajnc,.ing r.r selecting environment. The most ~rc -ve evidence relates to carcinogenesis in the . i:i,i:i w and the urinary tract. ,*M*1 In each of these .diversion of the normal movement of con- ;ents ruj been found to lead to a decreased incidence t?f recjL-.sia with known carcinogens. There are several examples in which synergism or ji: irr.ui mn may be operating in human beings. For ex- tmrlc. exposure to asbestos, nickel, or uranium may 'e as:oc;ated with only a relatively low risk of lung cancer. However, when coupled with cigarette smok ing. the risk becomes extremely large -- much larger bin L.-.t a'sociated with smoking alone. ri-i-scc :unt Stapa f-iO'jrssvcn :J proliferative lesions resulting from a promotnrironment, such as papillomas, nodules, or pol yp;.. J idcrgo a number of further changes before ma- behavior is expressed. i::xny organs, including the bronchial tree in the smoker one consistently sees several types of putative prcccr.cerous lesions, such as atypical hyperplasias, dyv ii.it, and carcinoma in situ.1*-1* How these le: rlaie to each other and to altered biologic behivkr of cells transformed in vitro (e.g., atypical grew ib, growth in soft agar, or tumorigenidty) is not < Jr.,- &nd remains a potentially fruitful area for study. An important property of many of these changes is reversibility. There is considerable evidence in exper imental models and in human beings that some focal proliferative lesions, such as hyperplastic nodules in me liver (and their probable human equivalent, liver "adenomas," which are seen rarely in women using oral contraceptives}, polyps in the colon, and papillo mas in the skin, can undergo regression or remodel ing with normal diirerentiation.l''"> This area is be coming of particular interest in view of the reported ellicacy of vitamin A analogues, such as or-retinoic add, in preventing or delaying cancer development initiated with chemical carcinogens1** in several sites, such as the bronchus and the urinary bladder. Ttanaf*etlon An interesting recent development is the induction of transformation by the transfer of DNA or chroma tin to susceptible cell lines. DNA from several types of cells transformed in vitro or in vivo with different car cinogens was shown to induce transformation. "*" Of gmat interest is the observation that DNA from nor.cal cells was also effective."* These new approaches .-> chemical cardnogenesis open up many areas of exr'oration, including the question of whether the invernation contributions of the DNA are positive (i.e., they code for an identifiable component that is im portant in cell transformation) or negative (i.e., they *i;org3iiize the host genome in an appropriate manner). (Mat an-j Carelnaganasia The r imposition of the diet may influence the inci dence c: cancer in some sites, such as the colon, breast, tnd endometrium."r'1** The mechanism or mechanisms through which diets exert their influ ences ai c not w'ell understood. In some instances, car cinogens occur in the food as natural substances, as contan.-nants (e.g., aflatoxins), or as products of foodpreparation methods (e.g., pyrolysis). Dietary altera tions also modulate the activation of carcinogens. In other instances, micronutrients have a role in the endogenous formation of carcinogens. The past 10 yean or so have seen a revival of the concept of the en dogenous formation of carcinogens. This hypothesis was proposed in the 1930s in relation to cholesterol or other sterols, but it was progressively abandoned as the evidence failed to materialize. The resurrec tion of this idea assumes a new form in the genesis of nitroso-compounds from nitrite and secondary or tertiary amines."* Dietary amines or drugs such as oxytetracycline of chlorpromazine can react with ni trous acid, generated in the stomach from nitrite, to form nitroso-compounds. Some of these substances are carcinogenic in laboratory animals. The forma tion of such nitroso-compounds can be effectively in hibited by dietary ascorbic acid"1 and by vitamin E. This general model is being explored in colon cancer in human beings."1 The hypothesis states that carcinogens can be generated in the feces and that the levels of the carcinogens, as measured by mutagenic action, are influenced by the dietary composition, in cluding vitamins C and E and Tiber content. Chemotherapy and Carelnaganasia Some of the most effective chemotherapeutic agents for cancer are carcinogenic. For the treatment of can cer in patients above 50 or 60 years old, the impor tance of the risk of carcinogenicity is clearly minimal, given the long latent period for cancer development. However, in children and young adults, the devel opment of second cancers yean after the effective treatment of the primary' tumor is now becoming a recognizable p^oblem.,`,,,* Over 25 drugs used in chemotherapy have been found to be carcinogenic in animals, and some have also been implicated in human beings. The magnitude of the risk associated with the many treatment regimens is not fully known. However, for FST0005W 7 DOW Yat. 305 No. 13 CHEMICAL CARCINOGENESIS -- FARBEK lir some patients the risk of second primary tumors varies from 7 to 12 per cent."1 These figures include some risk factors aside from the therapy, that are pos* sibly genetic and favor second or multiple primary tumors. However, there is an additional risk from the chemotherapy itself. This risk will increase in volume as current types of chemotherapy for cancer become more successful. However, as mechanisms by which chemicals induce cancer and kill cancer cells are clar ified, ways will be found to prevent the carcinogenic effects without interfering with the drugs' ef&caqr in treating cancer. A common problem in cancer chemotherapy is the appearance of resistant cancer cells. Since resistant cells are also produced by carcinogens during carci nogenesis, and since such resistance constitutes one form of initiation, it is conceivable that the induc tion of resistance to therapy and that of cancer are related. New Bioassays fob Caecxnocins and Promoters The basic knowledge that has been generated dur ing the past 20 years or so has spawned a large array of short-term tests (mostly in vitro) for potential car cinogens, and more recently for promoters.11* These tests generally fall into two broad groups: those that use some correlate of DN'A damage or chromosomal damage as end points and those that use cell transfor mation as the end point.1'**"1 The majority require the inclusion of an appropriate activation system. This development is an essential requirement for rapid monitoring of our environment. In addition, these tests are being used increasingly as rapid assays for some more basic aspects of chemical carcinogene sis, such as patterns of activation in tissues and the en dogenous production of carcinogens or mutagens, to name but two of many examples. Conclusions The past decade has produced new insights into the need for metabolic activation, the nature of the active molecules, the enzymology of activation, and the array of products generated, including major ulti mate carcinogens. The interactions of such deriva tives with DNA and other cell constituents and the possible toxicities and other effects on cells are be coming clearer. There is a general belief that DNA damage is involved in cancer initiation in most in stances. The basic studies have generated over 100 short-term assays for possible carcinogens, with many of the assays reflecting damage to DNA or chromo somes. The importance of the modulation of metabolic ac tivation by enzyme induction with hormones, diet, drugs, and chemicals (including many environmental contaminants such as pesticides, herbicides, and poly chlorinated biphenyls) is appreciated. How this ubiq uitous exposure may influence cancer development in human beings is not known. The repair of lesions in DNA is receiving increas ing emphasis. The majority of such studies are in rel atively simple in vitro systems and are generating in sights into what may happen. The study of what does happen remains a major challenge. It may be aided by the development of ultrasensitive enzymatic radioim munoassays for carcinogen-DNA adducts. There is an increasing realization that many post initiation phenomena, including promotion, are of major importance in cancer development. Alterations in diet, hormones, drugs, and xenobiotic agents have major influences through effects on promotion and other later steps. The reversibility of many of the precancerous steps is being studied with vitamin A and iu analogues and with other dietary components. Despite the major advances, the study of the later phases of chemical carcinogenesis lags far behind that of the early biochemical events. A nagging uncertain ty in this field in general concerns the role of chemical carcinogens of either exogenous or endogenous origin in the causation and pathogenesis of some of the major forms of cancer. There is a general agreement that cigarette smoking and ultraviolet light are two major factors in the genesis of several important types of cancers. There is also incontrovertible evidence that many chemicals to which persons are exposed in the work place or its environs cause cancer in several, organ systems. However, the relative quantitative im portance of these considerations in the majority of pa tients with cancer not related to smoking is unclear. The resolution of this problem, although no doubt dif ficult, will almost certainly have a major impact on our approaches to cancer prevention in coining decades. I am indebted to Mil* Hdlkne Robitaillc br asaiitance in the preparation of this manuscript and to my coHe*fues. On. A. Med line and D. S. R. Sanaa, lot their critical comment*. Rtmixcb I. Ry**r HJ-P. Chemical aiuopM**. N End J Med. 19TI; 2SL72I14. L Frtuami JF Jr, ad. Penoat n kith risk of ranrar a* apprisedi in earner eoolefjf aad control. New York: Academic Pratt IP7J. I. DoU R. The epidMielop of canon. Cuon. IPSO; 41:247141. 4. Pern R. Dbinrunf the tpidemiolnsy of cancer the seed fee e more heleeeed oer<iew. Neturr. IPSO: 244:2V7-)00. 3. tpeieie IS, Swtnx JB. Fallacna of Uaetyla miner tkiarin. Nature. 1PS1; 210:12700. 4. Population at lo* risk of marnr. J Natl Canon lam IPPO; 41:1051- IP5. 7. Kaplan HS. Ttuchitaai Fi, a*. Caacn in China. Nan York: Aka B La*. I07S. 5. Yaap.CS. 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Neoplastic inaaformatiea ef kumaa dip loid calls ia wire alter tbtmial cartmota traatuenL Nature 1*71; 275:130-2. 3*. Kepclorich L. Big NE. Hclaon L. Tumour promoter aloec tadocas neoplastic uaeifermatisa ef Gbroblaau from humans fanatically pendisposed to cancer. Nature. 1*7*; JI2:dt*-2l. C/5 40. Milo GE. DiPselo JA. Prtsensituauoe ef kumaa ecitt wnh airiaiic .ifnrit le ladurad cbemial caraaofcseria. lit J Caaeg. 1*10; 24:105- 12 *1. McCormick JJ. SOinsku KC. Katoriy SA. Tewg JE. Mahg VM. The mductioo ef ancberafc independent frowsk end turner formauoo of diploid kumaa fibroblasts by arctnofens. Proc Am Assoc Caaeg Ra Am Sec Clin Oncol 1*11; 21122. abstract. *2. Siui.naa O. Immueodeprewian and melifaaacy. Adv Caaeg Rat. I*7S; 22:261-422. (3. Thomaa L. Dtacuasiea. la: Lawreaa HS. ed. Cellular aad humeral as- CC pacu ef the kyptneaaui** mate*. New York: Harper k Row, 1*5*52*-12. 4*. Cairns J. Muuuon glection and tbc natural katnry ofranaw. Naiara. 1*75; 2551*7-200. 65. NeweO PC. The does) rrolutioe ef MM oB popoiatiottc anpeued : fenctic lability pcrmiu nepwrie urictiea ef variant nibling aad am dglict tumw profmaien. Saeaea. 1*76; IMJ34. 66. Burma FM. Ciarar lemauc-ftaeuc aoniideraiian*. Ad* Ciarar Rea. 1*71; 26:1-2*. 47. Keaaady AR. Fnx M, Marpby G. Unri JB. Rtriiieaibip beraaa a-ray tsposun and mabfaeai iraufatmatiaa in OH I0TI* aril*. Prat Nad Acad So USA. IM0; 77:7242-4. 66. Mendel S. Hcidclbcr|g C. / Wire malifaaa tnnafenaaiiea by aotb- yicberiatbraee of (be preftny of amfri arito derived from OH meeae prosuu. Prat Nell Aad Sri USA. 1*70; 65JI*-2S. 41. Ctyuna E, Tnda H. Sanaa DSR, Fatfeg E. laitiatioa ef rtiamital carriaeftaeais requiras aril proliferation. Nature. 1*76; 275:K52. 70. Tsuda H, Lee G. Fsrbg E. laduaion ef rgietaat kepaiecym as arw . - principle f possible sbon-urm m me teal fw arcibOftni. Caaeg . ., Res. IfKk 40:113744. 7]. Emmelot P, Scherer E. The ftnt rerivint ceB suyt ia ratHvgcarcmo- fcaeari: a puaautauve approach. Biecbim Biepkys Acu. 1*60; l 'i ' 605:347-304. .. .. . ... ,ar V ' 72. Craddock VM. Cell proliferation and qpsrimsnlri livg aacu. la: ` i DOW 06751 VoL 105 No- U CHEMICAL CAKC1NOGE.NZSU - FAME* 1317 Cameron HM. UaacU DA. Wtrvick CP. rii livm mB manor. Am- acraam: Eteevur Saanulk Puhiiihtag. 177215*201. n. Icrve C Sidu L 1* mm all naaformausa by X-trradteooo. Saturn. IMA 210.2744. 74. Took J. The molecular teolcgy ot tamer vinmm. New Yale CoU Spring Harbor Laboratory. 1171. 71 Kakuaaga T. Raduirnmcat fa all ivphcinoo a tk* fixation aad a* pnuioa of tea iraaaformod MU a mourn allt traatod ante 4-anim guuisliae-latidt. lu J Cuw. 1774; 14:71*42. 71. Yin* TV Sara DHL Foitm E. Rote of an tapmit imii a tin induction of earl* ttept a k* comalignum by duteyinmmamma Cancer Ra INI. 4IJ0M-I0I. 77. CeiumOaao A. Rajaiakihmi 2 Sniaa DSR. Rcgairunani ofaail pem bfcrauea tar ib* aituuao f liva arotn|Bii u amayad by ibm dtfTcrcai proodutm. Cnaar Ra INI; 41:207741 72 Run JM. a. Pnnaaul cxmnoginm Nntl Cnaar laa Meaogx. 177b: Jl:*2S2. 7*. Nniun D. Hrrttr H-J. Nan H. Langaaa J. atfa. Rota of pbarmam- kiaaua a pnatui tad pmtntial teucotegy. Stuttgart Georg Tbraa. 1771. t Pdkaaaa 0. Environmental iafluaaaaa aa baaia taaul aad plraanl mniwmt aaubolaa. Ear 1 Oil PhanaaaaL 1770: 1217-24. II. BertaMum t. A tpeeuteuve mvtew: probable aaiun of promoting aa ana and m ufaifiaaa a tht undarmnitiag of at aachaaaaa of tarannfmtiii Cnaar Raa. 1754: 14:471-7. n. upka M. Daacbiar E. Early peotfarauve chaagaa a aaadaal aaHa. Cnaar Ran. 1777: 54.24454. o. Farbrr E. Tba MOiaatal aaalytit of bo caaea iadnerioo, biocbia Btephya Aoa. 1740: 405:14*44. M. Reddy IK. Axaraoff DL Higntu CE. Hypottpidbaak hapadc para* aoaa proUfaraien form a novel daaa a cbaaaal camagoaa. Natan. 1710: 33:5774. . Raaaa SJ. Legator MS. Oiamiral cbcractmuatien af 445 lam ar auapanad carcuofcaa and temr eonttetioa *tte aulafaajc aarv*y a tba St/mmtilt lyfAmtnm lyaum. Cnaar Ran. 1777: 37J2IV31L M. Hacaa E. Bioehemmal narhtnum af tumor promotion. la Slagi TJ. Siak A. Boat*all RK. ada. Machaaoma of taaaor promotion aad am i an....intuit VoL 2 No* York: Rome From 1777:41)42 n. Vaa Duurm BL Tumor prannua* tad na ramnngaair agra a tbatairil careaoftaaaa. la Sairla CE. ad. Cbamirtl caranogana. Waabuigtoa DC. Ananraa Cbattucal Sooner, 1774: 173:2*51. n. Slumber* PM. la vitro audue on tba soda of action of pbarbol m- tan. potent tumor pronoun. CRC Chi Ra* TaaieoL 1710:1:15*77. INI: 1:177-34. n. Wemaiem IS. MaAoa RA. laa L-S. Ftabar PS. Italia J. Horowiu AD. Nanone V. Maabraaa and other biorbraical aflacu af tba pber- bol aim and their rtievaaee to tumor promotion, la Pullman S, Ta'o POP. Calbom H. ada. Cnronofioaatn: fundamental marhinuma and anroamanial offecu. Amsterdam: Rodal. 1NIJ4142 o. Sboyab M. Todaro CJ. Spatiflc high affinity nail nmbnaa raoptora tar bwlopcally ami** pbartel and iagaaal nun Natan. 1770: 2U-4SI-5. *i. Boui*all RK. Tba function and maebaniam of prnmnwa of caromm prawia. CRC Cm Ra* ToaaeoL 1774; 241742. Farbar E. Sequential a*ata in cbcmual camaofCDatis. la Sackar FP. ad. Caaeer a mmprabanana uatuaa Id *4. VnL I. No* York: Plenum Pram, (in pram). n. Saner*a R. Tba ceil cyda. N Eapl 1 Mad. INI; 504:451-7. 74. Saruablum L Tbaanuaal and practical aapacu of tba l*a nay math- atom of camiimennan la Ohffin AC Sba* CR. ada. Caraaofaua: idaatifmuod and moebaanma of acnoa Na* York: Raw Prma, 1777 25-54. . Pitot HC. Sira AE. Tba teagm af miriatfoa and promoting In tape- tocaroanganmii Stncbim Siopbya Ana 1710: (05:171.212 N. Walacb CU. Nagaaava H. Prolacua and aunaa mammary araati pT---*- a tana*. Cancer Raa 1777; 17:75142 77. Nanaava T. Magadta NE. WauOurgar JH. Wyndar EL. Promoting af. tact of bite aeda aa colon cuaaogaacau after mtnncul itaullaimn af A'Mnatbyl-N'.aitrmN.atiroaoguaaidiaa in rata. J Natl Caaaar inat. 1774; 51:1071-7. H. Raddy SS. Wauaiba K. Wauburgtr JH. Wyndm EL Prnmwing af- fact of bite aoda in coina caraae|cnaaia in garm-fraa and aaa*nataati> al P144 rata. Caaaar Raa. 1777; 37:3257-42. N. Ntvarraua A. 5pnn HI. EJTact of enlemnmy aa apmmaataOy prm ducad aaopiaama of tba colon of tba rat. Cannar. 1747; 22144*72 100. Gcnoiro AR. Villanueva R. Sukootbnmoa Y. Vitkinophu V, Ron* mood CP. Cbamal amnpgaaain in nnapoand muminnl aagmata. Caaaar Rm. 1772 33J544I. 101. Oyaaa R. Htrao Y. lami K. Promotion by Mint of urinary bliddm aunacgaamii Proc Am Ataoc Cinar Rm Am SocCltn Onnol 1770; 21:70. abmncL 102 Ra*tend RC. Htnntbany MO. Oyaaa R. Orayback JT. Eflbea af anaa and coaunuad expetura w caroaegaa oa programna of aarly aaoplaitta unaary bladder tamorn. Ciaor Raa 1770: 40:4524-7. 103. Farbar E. Rrrtmbte and irtavanibla temooa at prnrmim of raatnr davatapmaak Ik Maauaaao R. Sanach H. Tsmaus L ada. Motecaiir and aallular aapacu of carctaogaa imaaing tmu. Lyon: laiaraauooal Agtacy for Rcaaatch oe Ciaocr. 1770:145-51. (IARC tcwaulte pubb cauaaa aa. 27). 104. Sport Ml. Navtoa DL Oumapmiatwa of rtaitr *uk ratiaatda. Fad Free. 1777: 51:2527-34. 105. Stub C Shite S-Z. Ocldfaib MF. Daaaaabatg A, Wmnbaq RA. Faauga of pbmoiypm of rhminIW traaaformad ctila w iraMtaenon of DNA aad chromatin. Proc Natl Acad So USA. 1777; 7fci7l4-2 102 Cnopm CM. Ob1040111 2 Silverman L Tnnafaraung arhvity af DNA af rbaminlly tranatarmad aad aarmal mila. Naantm 1700: 2S4-4IS.]:. 107. Armatroig IK. Tba rale af dtet ia bumaa camnngtam* *ilb ^abal itfarena 10 cadomctntl cnaar Ik Hten HH. 77'ataoo ID. Woman JA, ada. Ongmi of human catcar. VoL A. Na* York: Ca4d Spang Harbor Ubaratary. I777JS745. I0S. Wyndm EL Raddy SS. Dim aad cancer of tea eoloa. Ik WMmS M. ad.uirtm eoncapu m autmtan. Na* York: Jobs Wiley, 1777; 25* " 71. 'v 107. Carroll KK. Lipida aad cnmniummit J Eaviroo Pathol TaaaesL 1770: 1:15*71. 110. Lijiaaky W. Signiftcaaet of (a *aa tarmatioa of N aiataa aam- poaada. Oacnlao 17(0: 37^254. 111. Minnab SS. Formaiaoa of N-aitraao compouada: abcmimiy, tinmra aad la mo occumaoL Toateol Appl PkarmaeoL 1775; 31J25-5I. Ill Snien WR. Eyiaaa CM. Ciampt A. Dioa pw. Boyd N. Stratagma tar dietary inurvauoo mudtm in coloa raatnr. Caamr. INI; 47:1121- 1 112. HarhaCC. A delayed compliauna cfcaneer tbarmpy--caaam. J Natl Cancer laat. 1777; 4207*7. lid. Heow R. Fraumam IF Jr. Drug!.1 II*N. 115. Mcad0*t AT. Krajmat NL Balaaoo JS. Tba madaoi 00m of care an- fuctea in atirmon af childhood caaam. Ik vaa Eya J. Solbvaa MP. ada. Staiua of tea curability af childhood canon. Nc* York: Raven Pra. 1770-^4*72 111 Stick HF, Sen RHC *dt. Sbon atm lama tar rbwiral oaranngaaa. Nc* York; Spnager-Vartes, INI. 117. Holteum MJ, MeCaaa J. Aagaioaaai* FA. Nicfcela WW. Sbon-tmm lam for caraegcai aad muugcaa. Mnut Rm. 1777: 4211*222 IIS. Banach K. Malawilte C Carnua A-M. at al. Validation aad comparetivaatudimoa 110 i-hntrab mte 5. irphimarmn atraiaa and V77 Cba- aoaa hamaim eaila ia tea pramam af vanaua aonbakaag ayauma. Maui Ran 1710: 721-30. 007S 0001S ; DOW 06752 time Digest April 1981 ret *h* personnel and work stress. -^--r .-raettristies and psrcslvsd social `.vr- .--v-r.ited these affects. Job dlssatla- *s`r.'un'd to be an intermediary pha*a In ij-.-.vl-.-jent n stress at work. The applied rha-tT -vicel was found feasible for ''>.piain- ,,f ... ationshlps between the concepts .?*-- j~ :.h<* basis of the acquired results. --Condensed froa text >j=fjos'.ior.allv Induced Stress. Strain end ?.:a>*lcads s Solaced to Asa. J. linerInen '~nc ?.Ttenirar.s. Scand. J. Work Environ. Seaitc . Dec. 1980. 23 refs. Trust Jifierent types of work 120 sen, aged a, were classified according to the triec-*:-.te Jet Otseription Questionnaire Into iwur representing specific work content (proa .kit.? IkTces, coordinating no tor and leswy innerIona, converting lnforaatlon into ruac*i>kt.'.. ji.i producing information). Work attic* asoussed with meaaurementa of oxygen eor.ioi-pi i-r C'02) and with the registration of tint eiiRiitns sn*nt at different stress levels, gel t;v - sjiubxc strain (RAS) was defined as the V^j ,:i . 'r. w.ir* as ths percentage of VOjitax. Sttu i x... -.e<ired with continuous recordinga of m>v'. rare during the workday. Peak lourie were tccordmg to the relative number of abc"e the heart race levela of 1:10. -T.i b.'ts/cin. The during work was viitfs^iy :.-.i::ttical in the age groups < 33, 33-30 and 3 T.se RAS tended to lnertase with age due : r!* - increase in 40,max. The strain remaint: ?itr.cally the same in all the age ' grcfC -ii r'.;- group "coordinating motor and * isan'cr. :u:.c-i. ,:s" strain tended to lncraaaa v>,:. . F.at loads over ISO beats/min were r.or r.'i. :`-r > <-. older subjects. The raaulta sutfcct .nit stresa and strain during work retain jcticrlly the same es age Increases. The 'it var, tends to increase with age vitlin group? doing mainly physical work and 1 run closures to peak loads. * --Authors' abstract reprinted by permission 3f-/&l ir.-nr.orica: The Mechanics of Man 3 -- Trie r.-.y.-iiaio;,-.- o; Work. C. Hayna. Occup. beai.n J2: 1G-24, Jan. 1981. 10 refs. f.t:.;'!-. Though better understood today than mar 17.?, is atlll too complex to ho measured by ary direct method. When considering the . dceMuds nf u.itk relation to energy expenditu-e smI fitlgue, it 1. necessary to be aware of thr tatty elements, both physiological and payeho logical, -tKiucisted with human performance. The . b.'Jutiaa to fstigue nay not always be in longer j work pauauc but in the redesign of activities to ; produce greater Job cnrlclraent and aatlafsctlon. --Condensed frost text 363/81 The Dare and Limits of Standard Exa-ciee Tests. l.B. Hrkuirt. Arch. Intern. Had. Hi; 229-232, Feb. 1981. 37 refs. Standard exercise electrocardiography to detect coronary artery iisesse involves limitations of accuracy in a 'orulation of apparently healthv pansna, to tfc* extant chat lta value for counsel ing such indi*. .duals is doubtful. Among subjects being examined for chest pain, however, the accuracy of tit.- exercise ECC in predicting corcuary obstructive disease {-< better, in addition, the presence of more severe coronary obstructive dltrass tends tc be associated with more distinctly abnormal tests at low levels of axarciso. This tendency of association betveen marked ST-segmcnt displacement ,i. low exertion levels and more severe obstructive disease adds a measure of prognostic value f< rhe standard exercise ECC in parsons with chest pain or after myocardial infarction. The addition of either isotopic cardiac imaging or coronary arterio graphy to exarcisa ECC will be appropriate for situ.*.dons in which alther the ECC la known to be nonspecific or inadequate exerclaa la achieved. --Author's abstract raprincad by permission 366/Ml Tharaoeutlcs of Hvpr.-tcnsion in the Work Environment. C.T. Mclnnee and E.B. Macdonald. J. Soc. Occup. Med. 31: 31-37, Jan. 1981. 12 rafa. Essential hypertension la a major health problem among people at work. Currant therapy la discussed and the potential role of the occupa tion! health worker explained. --Authors' auoaary reprinted by permission 367/81 Relative Importance of Ciearotte Smoking in Occupational Lung Disease. P.C. times. Brit. J. Ind. Med. 38: 1-13, Feb. 1981. 30 refs. Since 1900 respiratory disease has reaulned a constant serious causa of chronic ill health and premature death in Britain. The falling Impor tance of tuberculosis and pneumonia hat bean off-sat by the rite In lung cancer. Bronchitis morbidity and mortality have fallen only slightly since 1933. To product any real improvement in the future existing information as to cause mutt be studied. The relative contribution of occupatlonal exposure is compared with the Importance of cigarette smoking. Relevant information is scanty and has bean produced to emphasise the existence of occupational diseases rather than essaaa their importance to the consunlty as a whole. In Britain the evidence la that within the coal mining and iron and steel Industries ' conditions are now such that dust axposura contributes little to the morbidity or mortality compared with the workers' smoking habits. 13 I 8'iS O O O iS j DOW 06753