Document g2pDBNwajj031RDBaJg2xY0pG

FILE NAME: Neighborhood Exposures (NE) DATE: 1962 DOC#: NE022 DOCUMENT DESCRIPTION: Medical Journal Article - Environmental and Occupational Cancer Hazards - See Pgs. 795-797 ' : : .N...e..Hilyfe, "i i - - i r4 '--v`^ S' . ,'' '` .' ; . (` .' - -. '' - .- . .. v.: ' ,\ - ` ,r- '. The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S. Copyright law. LINICAL HARMACOLOGY HERAPEUTICS .... J* T ?**""?,'iSS> ....... ' VTV: . y aw -?. *': ,. 'y*\.,.'-., . . * Ty, , .... ... , >p - w.j.:-- , . i . . .. ...... . ,,.y.mvb-- i 03 Appearing in this issue Agents which lower serum cholesterol Prolonged digitalization in normal subjects Modified bioassay of butyrophenones in psychoneurotic patients Neomycin spray for staphylococcus carriers Correlation of cancer chemotherapy perfusions in rabbits and patients Analog computer and plasma drug kinetics Potent analgesics Clinical drug evaluation. XII. Antianginal agents XIII. Gastrointestinal drugs XIV. Sex steroids XV. Assay of hypoglycemic agents in man Thalidomide Poor drug therapy Complete table of contents, page 1 Published at St. Louis 3, Missouri by The C. V. Mosby Company Part I. Environmental and occupational cancer hazards W . C. Hueper, M.D. Bethesda, Md. National Cancer Institute Cancer, like all other diseases, is not a mysterious phenomenon of spontaneous creation but the result of the action of defi nite chemical and physical, animate and in animate, endogenous and exogenous patho genic agents. It should therefore be possi ble to eradicate cancer hazards and cancer by preventive and therapeutic measures. Although both methods will have to be ap plied to achieve a reasonable degree of cancer control, it is obvious that for hu mane and economic reasons, the use of ef fective preventive procedures is preferable to curative procedures. The prerequisite of prophylactic and pre ventive measures i disease control is the availability of adequate information on the causes of the disease and on the sources and opportunities of exposure to such causes. Although a recent editorial appear ing in the Journal of the American Medical Association33 contains the dogmatic state ment that preventive cancer control cannot be practiced by the medical profession be cause of the prevailing lack of data on the etiology of cancer, the irrefutable fact is that the medical profession at large, which has had access to a great mass of detailed and definite evidence concerning the causes of many types of human cancer (Table I), has shown in the past little inclination to apply this information practically (Samp206). Various industrial establish ments throughout the world, health depart- Received for publication June 15, 1962. 776 ments of many countries, and individual physicians everywhere, on the other hand, have applied for decades this knowledge in haphazard attempts at the preventive ap proach to cancer control (Hueper112'123<12S; Eckardt34; Scott and Williams212; Goldblatt and Goldblatt75; Bauer12; Chiurco36). The numerous human carcinogens of oc cupational nature are generally recognized because they have been responsible for the occurrence of cancer in various organs and tissues in thousands of human beings and have caused the death of many of them and shall continue to do so for some time to come. Their existence and their significance have found scientific, medicolegal, and legal acknowledgment (Hueper127). While the bulk of the diverse factual evidence on environmental causes of human cancer was originally related to occupational cancer hazards, numerous new data acquired dur ing recent decades have made it increas ingly obvious that many of the occupational carcinogens to which specific worker groups become exposed during production and processing procedures are subsequently in troduced into the general human environ ment in the form of industrial pollutants of the air, water, and soil and as constituents of many consumer goods and thus are brought in wide contact with members of the general population. Although such gen eral exposures to environmental carcino gens are as a rule less intense than those encountered under occupational condi tions, they are often lifelong and under the Volume 3 Number 6 prevailing circun avoidable, i.e., the placed in the role This potentially associated with tl carcinogenic conta environment and used in daily living tered astounding i aloofness by mam sional, and prival scientific and prac! was only in recent awakening from thi from the acute corn lie regarding actu; hazards related to velopments: (1) th the air, water, soil, dioactive matter, (: duction of carcinog taminants into the other general consu impressive and pro cidence of cancer < past 50 years and it ciation with the gr< general and occupa more or less chemi cinogenic industrial rapid growth in the pollution through t habit. These developmei factual background protective legislation years by Federal, sti islatures and health ; presence and contai drugs, and cosmeti chemicals, the releas lutants of the air froi the exhausts of autoi mercial operation of ionizing radiation. Ii registration with stat< dustrial, commercial, tablishments in whid used and produced, \ during the past dec; Symposium: Chemical carcinogenesis s, and individual n the other hand, this knowledge in ie preventive ap'Hueper112'128' iams212; Goldblatt Chiurco36). carcinogens of oclerally recognized esponsible for die arious organs and iuman beings and many of them and for some time to 1 their significance medicolegal, and Hueper127). While actual evidence on human cancer was cupational cancer data acquired dur3 made it increasof the occupational cific worker groups r production and e subsequently inal human environistrial pollutants of and as constituents ods and thus are t widi members of Although such genronmental carcino- intense than those ccupational condilong and under the prevailing circumstances frequendy un avoidable, i.e., die general public has been placed in the role of a captive population. This potentially dangerous development associated with the increasing artifactual carcinogenic contamination of the human environment and of goods produced and used in daily living for many years encoun tered astounding indifference and studied aloofness by many governmental, profes sional, and private parties engaged in scientific and practical work in cancer. It was only in recent years that a rather rude ; awakening from this lethargic state resulted - from the acute concern of the general pub lic regarding actual and potential cancer hazards related to the following three de velopments: (1) the growing pollution of the air, water, soil, and foodstuffs with ra dioactive matter, (2) the increasing intro duction of carcinogenic additives and con taminants into the daily food supply and other general consumer goods, and ( 3 ) the impressive and progressive rise in the in cidence of cancer of the lung during the past 50 years and its probable causal asso ciation with the growing pollution of the general and occupational atmosphere with more or less chemically well-defined car cinogenic industrial effluents and with the rapid growth in the degree of personal air pollution through the cigarette smoking habit. These developments have furnished the factual background for various types of > protective legislation enacted during recent years by Federal, state, and municipal leg islatures and health agencies relative to the presence and contamination of foodstuffs, drugs, and cosmetics with carcinogenic chemicals, the release of carcinogenic pol lutants of the air from industrial plants and the exhausts of automobiles, and the com mercial operation of equipment generating ionizing radiation. In fact, the obligatory registration with state authorities of all in: dustrial, commercial, and professional es tablishments in which ionizing radiation is used and produced, which was introduced during the past decade in several states, fulfills in part a proposal made in regard to all carcinogenic operations some years earlier and still to be accomplished (Hueper107). Considering the fact that at present about 1,100,000 persons with cancer are living in the United States and that about every fourth death of an adult is caused by cancer, cancer of all types and causes dis plays all the characteristics of an epidemic in slow motion. Through the increasing contamination of the human environment with chemical and physical carcinogens and with chemicals supporting and poten tiating their action, the stage is set for the future occurrence of an acute, catastrophic epidemic, which once present cannot ef fectively be controlled for several decades with the means available (Hueper and Payne138; Roth205). While the human popu lation has been spared such a general trag edy, in that so far it has remained restricted to relatively small worker groups sustaining exposures to various carcinogenic aromatic amines, arsenicals, and radioactive gases and dust, the distinct possibility of such an event has clearly been demonstrated during the last years by the discovery of a full blown epidemic of primary liver canceramong the rainbow trout population of American fish hatcheries. This cancer epi demic seems to be causally related to the introduction of carcinogenic ingredients with recently developed commercial feed into this industry (Hueper and Payne138). Prudence decrees that definite restraints be applied to keep the growing man-made carcinogenic contamination of the human environment within reasonable and effec tively controlled bounds and to protect the health of the general population, including those who come after us. Aromatic amino and nitro compounds, azo dyes, and related chemicals Among the most potent human carcino gens, causing mainly cancer of the bladder, are certain aromatic amines such as naphthylamine, benzidine, and xenylamine. They have elicited cancer of the various parts of The material on this page was copied fromthe collection of the National Library of Medicine by a third parly and may be protected by US. Copyright law. 77B Hueper mKSiism Clinical Pharmacology and Therapeutics Table I. Occupational carcinogens, their route of exposure, and their target organs General type Specific type Route of exposure Tarse t organ Chemical carcinogens Organic chemicals: Aromatic, polycylic, heterocyclic Benzol /3-Naphthylamine, benzidine 4-aminodiphenyl Auramine Coal tar, pitch, asphalt, tar oil, creosote oil, anthra cene oil, lamp black, lig nite, tar, and paraffin oil Synthetic hydrogenated coal oil, tar (Bergius) Shale oil, and paraffin oil Petroleum fuel oil, diesel oil, lubricating oil and grease, cutting oil, carbon black, asphalt, tar, coke, crude paraffin oil Cutaneous, respiratory Blood-forming organs (leu kemia, lymphosarcoma) Respiratory, cutaneous, Urogenous organs (bladder, alimentary . ureter, kidney) Lung, intestine(?) Cutaneous, respiratory Skin, lung Cutaneous Skin, oral cavity(?) Cutaneous, respiratory Skin, larynx Cutaneous, respiratory Skin, lung Aliphatic Isopropyl oil Mustard gas Respiratory Respiratory Nasal sinus, larynx, lung Lung, larynx Inorganic chemicals Arsenic Nickel Iron(?) Chromium Asbestos Cutaneous, ingestive, respiratory Respiratory Respiratory Respiratory Respiratory Skin, fiver, alimentary tract, lung, nasal sinus, larynx Nasal cavity, nasal sinus. lung Lung Lung, nasal sinus Lung, pleura, peritoneum Physical carcinogens Ionizing radiation Parasitic carcinogens Ultraviolet radiation Cutaneous X-Irradiation Cutaneous, transcutaneous Radioactivity (a, 3, and- y Cutaneous, trans radiation) cutaneous, respira tory, ingestive, parenteral Schistosoma hematobium Cutaneous Skin Skin, connective tissue, bone, blood-forming organs Skin, connective tissue, blood-forming organs, na sal sinus, lung, bone, liver Bladder the urinary tract after exposure in microgram amounts experienced over periods as short as 6 months and have been responsi ble for a cancer attack rate of practically 100 per cent of the population at risk when no precautionary measures were taken to prevent or reduce severe and prolonged ex posure (Hueper103'125, 126' l29; Williams250; Mattea170; Vigliani and Barsotti239; Temkin233). /3-Naphthylamine has been shown to be so powerful and its occupational cancer hazard so uncontrollable that the production of this carcinogen has been dis continued for some time by large scale chemical manufacturers in England, Ger many, Switzerland, and the United States. Supplementing this voluntary action taken by several chemical companies in the United States, the Pennsylvania State Health Department has recently prohibited the further production and commercial use of /3-naphthylamine. * There are over 2,000 cases of occupa tional bladder cancer from such chemicals Jan Lieben: Personal communication, 1961. Volume 3 Number 6 on record. They ha\ ducers of these chen manufacture of dyt dants, and dyers anc per129; Williams250; 500 of these cases the United States seven chemical comj ber of such occup; doubtlessly much hi In addition to azo compounds, other ai caused cancer of th producers are aura: first being a diphen second a triphem liams250; Gross79). The general publi carcinogenic amines duced from them b* used for many years and cosmetic colors While some of the d tives of the two napl removed from the c cent years for reaso have been retained, dyes are yellow AB sively employed for i butter, margarine, oi goods, medical prep; (hair oil and pom derivatives of /3-napl to contain significan cinogenic dye intern (Table IV) ( Conv similar fate was dec tt-naphthylamine der C orange No. 2, sho to mice when fed < bladder, as well as lated Food, Drug a No. 32, which has th as the carcinogenic c benzeneazo-2-naphth and Jull18). Three ch Drug and Cosmetic 17, orange No. 4, and retained on the cert and Drug Administ I . Clinical Pharmacology and Therapeutics -7;7 /.;,, ;,.. t . _ -3 I Volume 3 Number 6 :- : -- - . . .s ... iPBW. ---- ... . ,._ \ *.-7)7 I Symposium: Chemical carcinogenesis 779 The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S. Copyright law. organs rarget organ rming organs (leu, lymphosarcoma) ius organs (bladder, r, kidney) ntestine(?) "g al cavityi?) irynx mg sinus, larynx, lung larynx liver, alimentary tract, ;, nasal sinus, larynx cavity, nasal sinus. nasal sinus pleura, peritoneum connective tissue, bone, od-forming organs connective tissue, od-forming organs, nasinus, lung, bone, liver ler :ime by large scale rs in England, Gerd the United States, iluntary action taken companies in the Pennsylvania State is recently prohibited l and commercial use )00 cases of occupafrom such chemicals ommunication, 1961. on record. They have occurred among pro ducers of these chemicals, their users in the manufacture of dyes and rubber antitoxidants, and dyers and rubber workers ( Hueper129; Williams250; Baader9). More than 500 of these cases have been observed in the United States among employees of seven chemical companies. The actual num ber of such occupational cancer cases is doubtlessly much higher. In addition to azo dyes made from these compounds, other aniline dyes which have caused cancer of the bladder among their producers are auramine and fuchsin, the first being a diphenylmethane dye and the second a triphenylmethane dye (Wil liams250; Gross79). The general public has been exposed to carcinogenic amines and to the dyes pro duced from them because they have been used for many years as certified food, drug, and cosmetic colors (Tables II and III). While some of the dyes, particularly deriva tives of the two naphthylamines, have been removed from the certified list during re cent years for reasons of "toxicity," others have been retained. Among the decertified dyes are yellow AB and yellow OB, exten sively employed for many years for coloring butter, margarine, oils, fats, cheeses, baked goods, medical preparations, and cosmetics (hair oil and pomade). These certified derivatives of /?-naphthylamine were shown to contain significant amounts of this car cinogenic dye intermediate as an impurity (Table IV) (Conway and Lethco43). A similar fate was decreed for orange SS an -naphthylamine derivative known as FD & C orange No. 2, shown to be carcinogenic to mice when fed or implanted into the bladder, as well as to the chemically re lated Food, Drug and Cosmetic dye red No. 32, which has the same basic structure as the carcinogenic compound known as 1benzeneazo-2-naphthol ( Bonser, Clayson, and Jull18). Three chemically similar Food, Drug and Cosmetic Dyes, D & C red No. 17, orange No. 4, and red No. 14, have been retained on the certified list of the Food and Drug Administration; so has also a newly admitted dye used for coloring oranges, citrus red No. 2, a close chemical relative of the just-mentioned group of dyes of which some are established carcinogens. Carcinogenic properties have been dem onstrated also for five of the eleven tri phenylmethane dyes certified by the Food and Drug Administration. Apart from the fact that producers of the diphenylmethane dye, auramine, and of the triphenylmethane dye, fuchsin, in England and Germany, re spectively , developed cancer of the blad der, five of the presently certified triphenyl methane dyes, namely, light green SF, brilliant blue, fast green, Guinea green, and wool violet, have been shown by various investigators here and abroad to elicit sar comas following repeated subcutaneous injection into rats (Hueper115' 123). While this evidence has been judged to be ade quate for prohibiting the use of such dyes in foodstuffs in several European countries (Gross79; Boyland23), the Food and Drug Administration has considered-these find ings as inadequate evidence for attesting to their oral carcinogenicity and, therefore, has permitted their continued use in Ameri can foodstuffs and drinks, although the Delaney Clause does not justify a distinc tion between oral and subcutaneous car- Table II. Some practical uses of certified colors Foods Drugs r>.:- Cosmetics Gelatin desserts, oleomargarine, fats, oils, butter, cheese, bakery prod ucts, sausage casings, spaghetti, puddings, frozen desserts, ice cream, maraschino cherries, soft drinks, candies and confections, canned vegetables, pie fillings, oranges, sweet potatoes, etc. Watery and oily solutions, vitamin preparations, tablets, ointments, capsules, etc. Toothpastes, soap, suntan oils, skin creams and lotions, hair oil, po mades, shampoos, bath salts, lip sticks, rouges, face powders, nail lacquer, mouthwashes, hair-waving fluids, hair rinses, etc. 780 Hueper Clinical Pharmacology and Therapeutics Volume 3 Number 6 Table III. Recognized or suspected carcinogenic food dyes Evidence Dye in man Human carcinogens Auramine O (other countries) Magenta, fuchsin (other countries) Yellow AB (United States)(?) Occupational Occupational Occupational ( 2-amino-l-naphthol release) Yellow OB Occupational (United States)(?) Target organ Bladder Bladder Bladder Bladder Animal Rat Dog Dog Route Oral Oral Oral Target organ Bladder (papil) Bladder Bladder Potential human carcinogens 2-Hydroxynaphthalene compounds Sudan I Experiment (other countries) Orange SS (other countries) Oil yellow HA (other countries) Sudan IV (other countries) Sudan^brown RR (not used) Liver Mouse Subcutaneous Connective tissue, intestine Liver Mouse Subcutaneous Mouse Oral Liver Rat, Oral mouse Liver, stomach, Rat Oral hemato- poietic tissue 2-Aminonaphthalene compounds -- Thiazin brown R . Subcutaneous Rat Subcutaneous tissue Evans blue Liver Rat Intra (not used) peritoneal Trypan blue Liver, subcuta Rat Subcutaneous (not used) neous tissue, lymphoid tissue Black 5410 Subcutaneous Rat Subcutaneous (other countries) tissue Azobenzol compounds Butter yellow (other countries) Liver, bladder Rat, dog Oral Triphenylmethane compounds Light green SF (United States) Experiment Brilliant blue FCF (United States) Subcutaneous Rat connective tissue Subcutaneous Rat connective tissue Subcutaneous tissue Subcutaneous tissue Table III. Cont'd Investigator Case; Williams Yoshida and associates Hueper and associates Conway and Lethco ________D y e ________ Fast green FCF (United States) Azurblue VX (other countries Guinea green B (United States) Rhodamine B (other countries) Rhodamine 6G (other countries) Kirby and Peacock Bonser Kirby and Peacock Fluorescein sodium (not used) Eosin (water soluble) (other countries) Froin H echt.88 Willheim and Ivy: Schmidt; Hackmann cinogenicity. Thro scientifically unsou Hackmann concept of "carcint ble to circumvent law, as represented to these carcinogen Hecht It is likely that a the legal aspects of Marshall Food and Drug A Gillman; Marshall. Simpson; Brown and Thorson be obtained in Am have to decide wht curring in 5 worker contact with fuchsi Hecht the production of ir flowers was the rest Mention may be i Kinosita; Nelson and Woodard derivatives of the c; pounds are carcino reduced in the bod amino compounds. 1 Schiller; Gross; Harris; Nelson and Hagan; of practical general fluents of plants mai cals are released ir: Hecht Nelson and Hasan; Gross water. Some years a ate, chloronitrobenz the water of the Orleans after it hac 4 Clinical Pharmacology and Therapeutics Volume 3 Number 6 Symposium: Chemical carcinogenesis 781 Table III. Cont'd t Investigator --- --------------- Target Dye in man Target organ Animal Route organ Investigator Fast green FCF Subcutaneous Rat Subcutaneous Nelson and Hagan (United States) connective tissue Case; Williams tissue Yoshida and associates Hueper and associates Azurblue VX i (other countries) Guinea green B (United States) Hematopoietic tissue Subcutaneous connective tissue Mouse Rat Rat Oral, cutaneous Subcutaneous Oral Miller and Pybus Nelson and Hagan Willheim and Ivy Rhodamine B Subcutaneous Rat Subcutaneous Umeda Conway and Lethco (other countries) Rhodamine 6G . .. . 4 (other countries) connective tissue Subcutaneous Rat connective Subcutaneous Umeda tissue Kirby and Peacock Fluorescein sodium (not used) Subcutaneous connective tissue Rat ` Subcutaneous Umeda ------------- _ ^ Bonser Eosin (water soluble) Subcutaneous Rat connective Subcutaneous Umeda (other countries) tissue Kirby and Peacock From Hecht.88 Willheim and 1\>. Schmidt; Hackniann Hackmann Hecht Marshall Gillman; Marshall; Simpson; Brown and Thorson Hecht Kinosita; Nelson and M oodaril Schiller; Gros-; Harris; Nelson and Hagan; Hecht Nelson and Hagan; Gross cinogenicity. Through this arbitrary and scientifically unsound interpretation of the concept of "carcinogens," it has been possi ble to circumvent the application of the law, as represented in the Delaney Clause, to these carcinogenic FD & C dyes. It is likely that a clarification of some of the legal aspects of these contentions of the Food and Drug Administration may soon be obtained in American courts. These will have to decide whether bladder cancer oc curring in 5 workers who had occupational contact with fuchsin and auramine during the production of inks and colored artificial flowers was the result of such exposure. Mention may be made here that the nitro derivatives of the carcinogenic amino com pounds are carcinogenic because they are reduced in the body to the corresponding amino compounds. This observation may be of practical general importance, when ef fluents of plants manufacturing such chemi cals are released into sources of drinking water. Some years ago, one such intermedi ate, chloronitrobenzol, was recovered from the water of the Mississippi near New Orleans after it had been introduced into the river some 1,000 miles upstream by a chemical plant which converted this chemi cal into chloronitroanilin, a chemical sus pected of being a bladder carcinogen ( Hueper125). Other potential sources of cancer to the general population from aromatic amino compounds may be the use of certain brighteners incorporated into detergents, since some of these laundry dyes added to detergents belong to the group of aminostilbenes, of which some members are car cinogenic. Several years ago, a European manufacturer had to remove such an agent from its product when it was found to cause cancer in animals. Cancer of the bladder and liver in rats has also been pro duced by feeding a phenetidin derivative and synthetic sweetener, phenetylurea, sold in some countries under the name of dulcin ( Griepentrog77; Fitzhugh and Nelson62). It may briefly be mentioned that o-tolidine, a benzidine derivative, employed in the folliculinization test, has been shown to be weakly carcinogenic to rats and that one of the recently developed oral antidiabetic chemicals, a sulfonamide derivative, when 782 Hueper mm- rtttfttl'iY" '''v-i^ -'iifii''-r --j-i*-- Clinical Pharmacology and Therapeutics Table IV. Free aromatic amine content of food dyes Aromatic amine content (p.p.m.) 2-Naphthylamine . Total by aromatic chromatographic Dye Batch amines method FD & C yellow A 116 84 No. 3, B 196 157 yellow AB C 193 165 D 203 175 "V E 278 274 F 1,090 908 FD & C yellow G 98 76 No. 4, H 95 77 yellow OB I 131 108 J 135 135 S.D. 7.2 10.8 From Conway and Lethco.43 fed to rats caused cancer of the bladder (Spitz, Maguigan, and Dobriner222). An identical effect was obtained in mice when pellets containing 8-hydroxyquinoline and pyridium were implanted into the bladder. 8-Hydroxyquinoline is used as a spermatocide in many contraceptives and as a bac tericidal agent in hair lotions, rectal sup positories, and ointments ( Hoch-Ligeti98). When fed to rats or intravaginally or intravesically introduced into rats and mice, this chemical elicited local and systemic cancer (Hoch-Ligeti98; Boyland and Wat son24). Pyridium (2, 6-diamino-3-phenylazopyridine) is a red dye employed as a bladder sedative in the treatment of acute and chronic cystitis (Allen colleagues2; Boyland and Watson24). While the epidemiologic studies on aro matic aminocancer of the bladder among dye and rubber workers following occupa tional exposure have definitely established the etiologic importance of these chemi cals, the evidence is rather vague as far as the causation of bladder cancer in the general population is concerned. It is im possible with presently available epidem iologic methods to reliably identify specific but generally distributed chemicals in the causation of any type of human cancer. Circumstantial evidence, however, seems to support the existence of such correlations. Bladder cancer rates were elevated up to twice the normal rates of the area in one county and in one city in which there was large scale production and use of carcino genic aromatic amines for years. Moreover, there has been a moderate increase of deaths in the United States from bladder cancer during the last 10 to 15 years. In assessing the nature of the causal fac tors underlying these epidemiologic obser vations, proper consideration must be given to the fact that the production of cancer of the bladder and other organs by other amino compounds, such as diphenyl meth ane and triphenylmethane dyes, sulfona mide derivatives, o-tolidine, chloronitroanilines, and phenetidin derivatives, ex tends the potential scope of economic and occupational carcinogens to a large variety of chemicals and thereby extends the pos sible associated cancer hazard to many ad ditional members of the public. Miscellaenous organic chemicals Several additional organic chemicals which are widely used in the human econ omy and which when administered to ex perimental animals have produced cancer in various organs deserve consideration as potential human carcinogens. Aminotriazole, of cranberry fame, a weed killer and defoliant, when fed to rats elicits tumors of the thyroid, as reported by Flemming.09 This herbicide can be purchased in the open market by the general public. Ure thane or ethyl carbamate, used especially in the past as a sedative and employed more recently as dope in fish hatcheries, causes tumors of the lung in mice and rats and even reaches their offspring by the transplacental route (Larsen156; Klein118). It has been incriminated by Balo,11because of its former frequent medical use, as one of the causes of the increase in lung can cer. American and Canadian fisheries dis continued its use some time ago because of a possible cancer hazard to women and Volume 3 Number 6 eries and having extensa solutions of urethane phenylisopropylcarbau, to be an effective ear gators in the Netherla Genderen, and Yink:" it was used as an ant potatoes. /?-Propiolaeti mercially in the plastic used as a virucide in poliovaccine in one Eui active carcinogen to t mice. It has been pn try for application as . tericidal space disinfc< well as a soil disinfi (Roe and Salaman2"1; The latest addition environmental carcino served for many years of soft drinks, especia shown to cause canc< fed to rats kept on a this reason potentially ous than the various a yellow type which ha1 genic effect on the rat an action only when tl flavin-deficient diet (I leagues96' 97). The advisability of r carcinogenic propertie mately 300 flavoring a in the preparation and is strongly suggested fc tomas develop in rats I sicum) (Hoch-Ligeti9 loids ( Schoental-1'*). chemicals originally c carcinogens have been cinogenic initiators u mental conditions, it h that lemon oil has bet be a cocarcinogen. Special mention m; eral newly introduce! known as nitrosamim trially used compoun when fed of eliciting Clinical and Therapeutics Symposium: Chemical carcinogenesis 783 of human cancer, however, seems to f such correlations, ere elevated up to of the area in one n which there was md use of carcinoor years. Moreover, lerate increase of tates from bladder 0 to 15 years, e of the causal facndemiologic obserition must be given iuction of cancer of organs by other as diphenyl meth ane dyes, sulfonaiidine, chloronitroin derivatives, ex>e of economic and s to a large variety >y extends the poslazard to many ad- e public. offspring of women working in fish hatch eries and having extensive skin contact with solutions of urethane. The weed killer phenylisopropylcarbamate has been shown to be an effective carcinogen by investi gators in the Netherlands (van Esch, van Genderen, and Vink237; Hueper110), where it was used as an antisprouting agent on potatoes. /J-Propiolactone, employed com mercially in the plastic industry and being ; used as a virucide in the preparation of poliovaccine in one European country, is an i .a active carcinogen to the skin of rats and mice. It has been proposed in this coun i try for application as a virucidal and bac tericidal space disinfectant in hospitals as well as a soil disinfectant in agriculture (Roe and Salaman201; Searle213). The latest addition to this dismal list of environmental carcinogens is safrol, which served for many years as a flavoring agent of soft drinks, especially root beer. It was shown to cause cancer of the liver when fed to rats kept on a normal diet. It is for this reason potentially much more danger ous than the various azo dyes of the butter c chemicals organic chemicals yellow type which have a similar carcino !- 4 genic effect on the rat liver but exert such n the human econ- an action only when the rat is given a ribo idministered to ex- flavin-deficient diet (Homburger and col e produced cancer leagues96' 97). ve consideration as The advisability of investigating for their logens. Aminotria- carcinogenic properties all of the approxi , a weed killer and mately 300 flavoring agents presently used rats elicits tumors in the preparation and processing of foods ted by Flemming."' is strongly suggested by the fact that hepa purchased in the tomas develop in rats fed red pepper ( cap neral public. Ura sicum) ( Hoch-Ligeti99) and senecio alka te, used especially loids ( Schoental208). Since practically all ive and employed chemicals originally considered to be co- in fish hatcheries, carcinogens have been shown to act as car lg in mice and rats cinogenic initiators under proper experi r offspring by the mental conditions, it is appropriate to note .arsen156; Klein"'). that lemon oil has been found by Roe199 to I by Balo,11because be a cocarcinogen. nedical use, as one Special mention may be made by sev crease in lung can- eral newly introduced organic chemicals ladian fisheries dis- known as nitrosamines. These are indus time ago because of trially used compounds and are capable ird to women and when fed of eliciting not only cancer of the liver but also cancer of the lung and bladder in rats and hamsters (Druckrey and co-workers52; Dontenwill and Mohr49; Thomas235; Argus and Hoch-Ligeti7). This observation demonstrates that cancer of the lung may result not only from inhalation of carcinogens but also from their ingestion. Observations on men occupationally ex posed to benzidine who developed not only cancer of the bladder but also cancer of the intestine and lung had suggested such possibilities for some years (Link158; Uebelin and Pletscher236). The carcinogenic effects of nitrosamine on the lungs of experimental animals may have additional wide implications because of the suggested carcinogenicity of isonicotinic acid hydrazide in mice (Schwan211; Viallies and Casavona328). While the de velopment of cancer of the lung from tuberculous scars and cavities has been ob served and reported for many decades (Hueper100), the greatly increased fre quency of such occurrences during recent years poses the problem of whether or not the administration of tuberculostatic, and tuberculocidal chemical agents, especially isonicotinic acid hydrazide, may have played in the last decade a specific causal role in this respect. A new bread emulsifier, named polyoxy eth y len e^) stearate, when fed to rats pro duced bladder stones and cancer of the bladder ( Fitzhugh and associates63; Hueper and Payne139). By invoking the by now obsolete concept that chronic irritation of nonspecific type is a recognized cause of cancer (Fitzhugh and associates63; Food Protection Committee65), it has been argued that the chemical was merely causing the production of bladder stones and that these stones in turn, through the mechanism of chronic mechanical irritation, were the real and primary cause of cancer of the bladder. The scientific merits of this interpretation become evident from the fact that some years ago the Food and Drug Administra tion banned the use of diethylene glycol as a humectant of tobacco because, like polyoxyethylene (8) stearate, it caused blad- 78'4 Hueper Clinical Pharmacology and Therapeutics der stones and bladder tumors in rats when fed (Fitzhugh and Nelson63; Hueper and Payne139). It is noteworthy that diethylene glycol is one of the constituents or impuri ties contained in this new bread emulsifier. Among the various additional organic chemical carcinogens which have been in troduced during recent years into human economy and which so far have displayed carcinogenic properties in experimental ani mals only, special mention may be made of several hepatotoxic chlorinated hydro carbons used as solvents, such as carbon tetrachloride and chloroform ( Edwards and Dalton56), or as pesticides, such as DDT and Aramite (Fitzhugh and Nelson64; Sternberg and colleagues224). All of them when fed have produced cancer of the liver in rats, mice, and dogs. Aramite proved to be the most powerful carcinogen of this group. The Food and Drug Admin istration has set a zero tolerance limit on Aramite in foodstuffs which are handled in interstate commerce. Since this carcino genic pesticide can be bought in the open market and because its use is subject to little, if any, control by intrastate agencies, protection of the general consumer against any cancer hazard related to this carcino genic pesticide has remained defective. Natural and synthetic estrogens when administered in adequate doses to experi mental animals of several species have caused cancer in many organs, e.g., uterus, breast, kidney, and blood-forming tissues. They thus fulfill the conditions generally associated with the definition of carcino gens. It has remained controversial or un certain whether they exert a similar car cinogenic effect upon the uterus and breast of man in general or of certain hormonally predisposed members of the human race, such as women with breast cancer and can cer of the corpus uteri. These hormonal agents are administered under more or less controlled conditions for medical reasons to both men and women. They are used with out any controls in cosmetics and are im planted in pellet form or given as feed additives to cattle and fowl and thus may subsequently reach the general consumer in food (Hueper115'122'123). Potential cancer hazards from the introduction of estro genic chemicals into consumer goods pre sent a public health problem deserving serious study for occupational reasons (pro ducers of estrogens and estrogenized cos metic and pharmaceutic preparations and animal feed) as well as for patients and consumers of estrogens. The voluntary arrangements made sev eral years ago by the Federal government with the industrial producers of estrogens and their commercial users in the produc tion of food animals lacked the force of law and thus could be violated at will. The Food and Drug Administration, therefore, has recently prohibited the implantation of estrogen pellets into food animals. In view of the present overabundance of the Amer ican food supply and because of the grow ing tax burden imposed on the general citi zen for storing excess foodstuffs and for enforcing regulations pertaining to it, a continuation of the past practice of admin istering stilbestrol to food animals not only appears to be economically unsound but, more importantly, also creates for the con sumer a needless potential cancer hazard. This critical attitude toward estrogens in foods and general consumer goods, such as cosmetics, should be adopted, although nat ural estrogens are physiologically impor tant products and despite the fact that the physiologic nature of estrogens has been cited by commercially interested parties as an argument in advocating the continued uncontrolled use of these chemicals in cos metics and in the production of food ani mals. The intrinsic fallacy of this argument becomes apparent if one considers that ex posure to ultraviolet radiation in physio logic doses is beneficial and essential to the maintenance of life. This fact, however, does not provide any rational basis for con sidering indiscriminate, unnecessary, un controlled, and excessive exposures to this actinic energy as a harmless procedure, be cause ultraviolet rays have distinct carcino genic effects on the skin of Caucasians. i,.,. m.. w ......... - >`rV <y.- ' . The produ' bladder, lung various cyclic aliphatic hyd agents, herbic sprouting age traceptives, ai tal animals p the growing economy with (H u e p e r123). Polycyclic e and carboi distillation There exis from observa various occup tries that pro to combustioi coal, oil shale as coal tar, t soot, lignite ; petroleum co oils, tars, asp] sponsible for the scrotal sa cancer of the 1 tified in 1775 cancer recogn cancer obsen lignite tar dis first occupati products of i mann241). Son skin cancer ca mentioned ha' ord from dii England (Hei Teutschlander Hueper111' 126; bank and St shank and Sqi vitch73; Huep< The great i ring in Ameri fineries, coke coal tar distil tories, and tai been made a . , ____ .... ..*<.'Unri.fi wir, Clinical Pharmacology and Therapeutic* v_ Volume 3 Number 6 Symposium: Chemical carcinogenesis 785 the general consumer .2,123) Potential cancer introduction of estro>consumer goods preih problem deserving upational reasons (proand estrogenized cosutic preparations and 11 as for patients and ns. angements made seve Federal government producers of estrogens d users in the produclacked the force of law violated at will. The ninistration, therefore, ed the implantation of food animals. In view mndance of the Amer1because of the grow led on the general citi es foodstuffs and for s pertaining to it, a >ast practice of adminfood animals not only imically unsound but, so creates for the contential cancer hazard, tie toward estrogens in nsumer goods, such as adopted, although natphysiologically imporspite the fact that the >f estrogens has been ly interested parties as ocating the continued hese chemicals in cosroduction of food aniillacy of this argument one considers that e.xt radiation in physioial and essential to the . This fact, however, rational basis for coll ate, unnecessary, unssive exposures to this armless procedure, bes have distinct carcino- skin of Caucasians. The production of cancer of the liver, bladder, lung, skin, and other organs with various cyclic, polycyclic, heterocyclic, and aliphatic hydrocarbons used as flavoring agents, herbicides, solvents, sedatives, anti sprouting agents, emulsifiers of food, con traceptives, and disinfectants in experimen tal animals provides further evidence on the growing contamination of the general economy with potential human carcinogens (Hueper123). Polycyclic aromatic hydrocarbons and carbonaceous combustion and distillation products There exists abundant valid evidence ; from observations made on members of various occupational groups in many coun tries that prolonged exposure of the skin to combustion and distillation products of coal, oil shale, lignite, and petroleum, such as coal tar, tar oils, pitch, carbon blacks, soot, lignite and shale oils and paraffins, petroleum cooling, lubricating, and fuel oils, tars, asphalts, and waxes, has been re sponsible for cancer of the skin, including the scrotal sac and the vulva. The scrotal cancer of the English chimney sweeps iden tified in 1775 was the first occupational cancer recognized (Pott198), while the skin cancer observed in 1876 among German lignite tar distillery workers represents the first occupational cancer attributable to products of modem industrialism (Volkmann241). Some 3,000 cases of occupational skin cancer caused by the various products mentioned have so far been placed on rec ord from different countries, especially England (Henry91'92; Passey192; Schiirch309; Teutschlnder234; Butlin30; Berenblum14; Hueper111'12e; Hueper and Payne137; Brockbank and Stopford28; Eckardt54; Cruickshank and Squire42; Gilman and Vesselinovitch73; Hueper and Cahnmann133). The great majority of such cases occur ring in American industries such as oil re fineries, coke oven operations, gas plants, coal tar distilleries, creosoted lumber fac tories, and tar paper operations have not been made a matter of published record and, therefore, are one of the reasons for the distorted statistics on occupational can cer incidence in this country (Heller94; Hueper112' 126' 127). Occupational and medi cal observations as well as experimental findings indicate that tars obtained by the distillation of wood or vegetable matter are carcinogenic to the skin of man (Shiro kov213; Sulman and Sulman227; Neve184; Hueper and Payne136; Kuratsune and Hue per153' is*. Hueper123). Such tars contain 3, 4-benzpyrene (Table V), although in much smaller amounts than coal soot and coal tar. Recent evidence obtained in mice and rats extends the incriminating evidence to the synthetic oils and tars produced by the indirect and direct hydrogenation of coal by the Fischer-Tropsch and Bergius proc esses. The Bergius oils were shown to cause occupational cancer and keratoacanthoma of the skin and oral mucosa in man (Hueperin, n4. Sexton214). Cutaneous contact by members of the general population with such carcinogenic materials in consumer goods probably accounts for only a small fraction of the skin cancer observed. Where hydrocarbon products might be involved in the causation of skin cancer in Table V. 3,4-Benzpyrene concentrations in pyrolysis products Source Soot, domestic (Gouldon and T ip le r 76) Soot, coal (Kuratsune152) Soot, wood (Kuratsune152) Charred matter from biscuit ( Kuratsune152) Coffee soot ( Kuratsune and Hueper153) Condensed smoke from cigarettes (Cooper and Lindsay39) Condensed smoke from cigars (Cardon and colleagues33) From Kuratsune and Hueper.153 3,4-Benzpyrene (y per 100 Gm.) 30,000 1,200-5,600 170-3,600 1.1-7.2 20-44 0.91 per 100 Gm. of ciga rette 11-70 per 100 Gm. of cigar -.--.mi!. mm 786 Hueper ' ~ v..V Clinical Pharmacology and Therapeutics the general population, one might suspect undue contact with such household goods as floor wax, shoe polish, lubricating oil used in workshops and for servicing auto mobiles and motorized equipment, pesti cide sprays containing methylated naphtha lenes, coal tar and carbon black paints, and soot from fireplaces ( Hueper123' 127). Carcinogenic hazards to parts of the ali mentary tract may result from the frequent ingestion of insufficiently refined mineral oils - of various derivation taken for laxa tive purposes. Boyd and Doll21 found that individuals habitually taking mineral oil laxatives had a statistically higher attack rate of intestinal cancer than persons using other laxatives. A similar connotation have the scattered observations on the occur rence of cancer of the lung in individuals using mineral oil nasal sprays or drops and on the development of carcinomas and sar comas in tissues injected for cosmetic or prosthetic purposes with waxes or paraffins obtained from the distillation of lignite or petroleum (Hueper123). Since mineral oils and waxes free from demonstrable amounts of known carcino genic polycyclic aromatic hydrocarbons have elicited cancer in experimental ani mals when injected parenterally,4 failure to isolate and identify known specific car cinogenic chemicals from waxes and paraf fins does not at present provide valid evi dence ensuring the safety of such products when used in consumer goods. Attempts have recently been made to present cancer produced in the subcutaneous tissue or bladder of mice and rats around implants of "pure" paraffin as foreign body reactions of nonspecific nature or to equate them with the sarcomas elicited by plastic films and /to disregard the distinct probability that: they are specific effects of carcinogens of unknown type contained in paraffin. Such arbitrary interpretations not only un duly favor industrial interests at the ex pense of the health of the general con sumer but also ignore the fact that crude P. Shubik: Personal communication, 1962. waxes are potent carcinogens to the hu man skin (Hendricks and colleagues0"). The paraffins and microcrystalline waxes which caused cancer in these tests were used for impregnating food containers, for coating confections, fruits, and vegetables, such as citrus fruit, apples, and cucumbers, and for removing feathers from fowl. A possible carcinogenic hazard to the human consumer from the ingestion of carcinogenically active paraffins and waxes is suggested by the observations of Falk, Kotin, and Miller,151 who reported that 3, 4-benzpyrene and 1, 2, 5, 6-dibenzanthra cene added to dairy wax are eluted within 55 hours from the coating of test tubes pre pared with such waxes into the milk and cream placed in the lumina. Brief mention may be made here of the fact that various detergents, or certain constituents of house hold detergents, made from petroleum chemicals have exerted a definite cocarcinogenic effect upon the action of car cinogens applied to the skin of mice or< proposed for use as food additives. These include Tween 60, intended for use as an emulsifier, and dodecane and dodecyl ben zol, present in the raw material from which household detergents are manufactured (Shubik217; Hueper130; Eckardt54). Whether these agents have similar promoting effects on the carcinogenic action of coal tar, petroleum oils, and similar carcinogenic products when in contact with human tis sues is still undetermined but has become a matter of serious concern. It is suspected that an accidental contact with such chem icals might account for some of the "acute traumatic" cancer in skin previously sensi tized by exposure to submarginal doses of a carcinogen. Recent experimental observations indi cated that effluents from oil refineries re lease carcinogenic wastes into public waters which, at some distance from the source of water pollution, may serve as supplies of drinking water to large metropolitan areas (Hueper and Ruchhoft132; Borneff and Fischer19). It is undetermined whether a prolonged consumption of such water con- " y--* ^ U' ..... --------- ; Volume 3 Number 6 Table VI. Lung a Author Kawahata443 Kawai and colleague.- Doll45 EDCO stitutes a cancer public. Increasing evidei various countries i and prolonged coi stuffs as meats and of preservation m cancer of the alin the stomach. Che: smoked foods haw pyrene originally ] not only demonstra of such smoked m but is found also ii penetration of carci ing material of fo proper is thus simil; cinogens noted wh carbons contained i containers are take i.e., the milk and cr pyrene is retained waters contaminate; fuel oil (Hueper12, per153; Hueper and In some of the o mental demonstrati; ity of tarry materia exposure of choleste yeast, and rice brai was employed by Kt experiments on c! American and Japai extended these obse: tion of carcinogens b procedures to other Clinical Flarmacolnen and Therapeutics Volume 3 Number 6 w a&i*. i-li'lWMlliifi riil^ '' liifri jm.--arts Symposium: Chemical carcinogenesis 787 cinogens to the hus and colleagues0"), icrocrystalline waxes in these tests were ; food containers, for ruits, and vegetables, >ples, and cucumbers, rhers from fowl, genic hazard to the 1 the ingestion of car>araffins and waxes is bservations of Falk, who reported that 3, 2, 5, 6-dibenzanthravax are eluted within ting of test tubes prees into the milk and lumina. Brief mention the fact that various constituents of houseide from petroleum ted a definite cocarn the action of carthe skin of mice or food additives. These itended for use as an ane and dodecyl benv material from which s are manufactured ; Eckardt54). Whether lilar promoting effects : action of coal tar, similar carcinogenic ntact with human tisilined but has become oncern. It is suspected ntact with such chemfor some of the "acute skin previously sensisubmarginal doses of tal observations indifrom oil refineries reistes into public waters nee from the source of v serve as supplies of rge metropolitan areas lihoft132; Borneff and determined whether a ion of such water con- i, ^ ---- " "* Table VI. Lung cancer death ratios of coke oven and gas retort workers Author Kawahata143 Countn/ Japan Kawai and colleagues1*4 Japan Doll45 England No. of cases 21 10 97 EDCO United States 12 23 Mor tality rate 500.0 284.0 202.0 784.0 148.7 10-25 Year and occupation 1933-1937: gas retort workers, Yahata Steel Works 1946-1960: gas retort workers, Yahata Steel Works Gas stokers, coke oven chargers gas production men 1946-1960: coke oven workers gas plant workers other employees stitutes a cancer hazard to the general public. Increasing evidence is accumulating from various countries indicating that frequent and prolonged consumption of such food stuffs as meats and fish smoked for purposes of preservation may increase liability to cancer of the alimentary tract, especially the stomach. Chemical analyses of such smoked foods have shown that 3,4-benz pyrene originally present in the smoke is not only demonstrable on the outer surface of such smoked meats, sausages, and fish but is found also in the meat proper. This penetration of carcinogens from the cover ing material of foodstuffs into the food proper is thus similar to the transfer of car cinogens noted when carcinogenic hydro carbons contained in the coating of waxed containers are taken up by the contents, i.e., the milk and cream, or when 3,4-benz pyrene is retained by oysters living in waters contaminated with carcinogenic ship fuel oil ( Hueper123; Kuratsune and Hue per153; Hueper and Cahmann133). In some of the oldest successful experi mental demonstrations of the carcinogenic ity of tarry material, tar produced by the exposure of cholesterol, bone, human tissue, yeast, and rice brain to high temperatures was employed by Kennaway.146 Subsequent experiments on charred foodstuffs by American and Japanese investigators have extended these observations on the produc tion of carcinogens by such food processing procedures to other foods ( Kuratsune152)i Table VII. Rates of lung cancer frequency in selected occupations in England with exposure to fumes, gases, and dust from coal tar, petroleum oils, and combustion products of motor fuel Occupation Workers in gas plants Workers of gas retorts Producers of gas Crane operators in gas plants Superintendents of gas plants Printers Chimney sweeps Asphalt workers Street cleaners Drivers of automobiles From Kennaway and Kennaway.347 Lung cancer rate 129 284 202 138 136 119 119 164 169 149 There can be no doubt that the consump tion of meat or fish broiled over an open fire and exposed thereby not only to con tamination with carcinogenic soot but also to the development of carcinogens in the charred surface layers carries a cancer haz ard corresponding to that related to the in gestion of smoked foodstuffs and is also associated with the addition of carbon black, a type of commercial soot, to food stuffs (Nau and colleagues181). Until several years ago, carbon black was used in the manufacture of imitation caviar in Ger many. Medical and epidemiologic evidence ac quired during the last 30 years in Canada, England, and Japan incriminates occupa- 9 - -... --------------------------------------------------- ............................................................................................:. 788 Hueper Clinical Pharmacology and Therapeutics Volume 3 Number 6 Table VIII. Relation of density of that "there is no evidence to suggest any they release, population in urban areas in England to relation between inhalation of oil mist and ditions of tr lung cancer rates from 1946 to 1949 lung cancer" is not supported by facts excessive stre; available but not reported. It should also Mor be mentioned for the record that no pub tality lished data are available on the frequency oe I Urban area rate of cancer of the lung or skin among the Groups of conurbations with more than 200.000 inhabited houses: many workers employed for decades in London, East Ham, West Ham, Croydon 156 American steel plants, coke oven opera Birmingham, Smethwick, Walsall, tions, tar distilleries, and gas works and West Bromwich 134 Liverpool, Bootle, Birkenhead, Wallasey 164 Manchester, Salford, Stockport 159 Leeds, Bradford, Halifax 132 Sheffield, with 124,000 inhabited houses 135 exposed to coal tar, although the United States possesses by far the largest indus trial establishments of this kind in the world. Newcastle and Gateshead, with 87,000 The presence of excessive lung cancer inhabited houses 114 Groups of cities each with 50,000 to 85.000 inhabited houses 113 Groups of three cities each with 40,000 to 50.000 inhabited houses 107 rates has recently been reported for inhabi tants of several fishing villages on the Baltic coast, where smoking of fish is car ried on as a home industry (Voitelovich Groups of twelve cities each with 30,000 and associates240). to 40,000 inhabited houses 104 Groups of thirteen cities each with 20,000 to 30,000 inhabited houses 100 Groups of twenty-nine cities each with less than 20,000 inhabited houses 89 These observations on the excessive li ability to cancer of the lung of workers ex posed to distillation and combustion prod ucts of coal and petroleum provide an im From Stocks.223 portant clue to tiologie factors operative considerable drocarbons in X ) . I n additic tions on pope exposed to cai tained in fun chronologic, t data on urban incriminate thi tant, but not t the rise and lung. The acti\ occupational p evident from t Table X. 3,4-B, particulate pha English cities Medii of City 0 in the remarkable rise of lung cancer London tional inhalation of coal tar fumes in the development of cancer of the lung in coke oven and gas retort workers and in individ uals employed under similar exposure (Tables VI and VII). The existence of simi lar causal relations has been demonstrated among urban populations in all advanced countries during the past 60 years and par ticularly in metropolitan and highly indus trialized regions (Hueper112' 117>119>124'134). Chemical analyses on the exhaust of gaso line and diesel engines have shown that Sheffield Leicester Burnley Bilston Cannock Hull Bristol From Waller.'- for workers exposed to the inhalation of fogs, mists, and sprays from crude paraffin oil, cooling oils, and lubricating oils en countered by workers engaged in paraffin pressing operations of oil refineries, in tex tile spinning, and in mtallurgie plants (Hueper134' 137). It is noteworthy that a recently published report on the occurrence of scrotal cancer among paraffin pressers of one American oil company does not include the complete data of coexisting lung cancer and that similar observations on the exces sive frequency of lung cancer among oper ating employees of another American oil company have been withheld from publica tion for as many (10) years. The recent statement of Hendricks and colleagues39 Table IX. Lung cancer death rates in three districts of Connecticut District Occupational character Naugatuck Rubber, metal, Valley area machinery, chemicals Standard lung cancer rates Fe Males males Both 85.02 14.87 48.01 Northeast area Textile, paper, agriculture 69.24 21.69 45.01 Rural Agriculture 30.60 15.00 Area by oc- Industry cupation Agriculture From Griswold.78 85.02 17.35 50.54 38.65 14.87 26.53 cancer mortaliri large industrial' Morrison179) (T number of reco carcinogens (Ta Since cigarett tains minute am carcinogenic pol bons but often a pesticide residue chemicals, such ized type of air cigarette smokin gravates the care respiratory muco halation of Clinical Pharmacology and Thcrapeutict nee to suggest any ition of oil mist and supported by facts >rted. It should also record that no pub>le on the frequency or skin among the red for decades in , coke oven operaand gas works and lthough the United r the largest indusf this kind in the cessive lung cancer reported for inhabiag villages on the olcing of fish is cardustry (Voitelovich on the excessive li lting of workers exd combustion prodoum provide an imic factors operative se of lung cancer >ns in all advanced st 60 years and parn and highly indus- , g r 112, 117, 119. 121. 131 \ he exhaust of gasos have shown that death rates in three Standard lung cancer rates 1 Fe- Males males Both 1, 85.02 14.87 48.01 69.24 21.69 45.01 30.60 15.00 S5.02 17.35 50.54 38.65 14.87 26.53 Number 6 Symposium: Chemical carcinogenesis 789 they release, particularly under urban con ditions of traffic and when exposed to excessive stress and defective maintenance, considerable amounts of carcinogenic hy drocarbons in the air (Tables VIII, IX, and X). In addition to the significant observa tions on population groups occupationally exposed to carcinogenic hydrocarbons con tained in fumes, soot, mists, and gases, chronologic, epidemiologic, and chemical data on urban air pollution and lung cancer incriminate this development as an impor tant, but not the only, factor operating in the rise and causation of cancer of the lung. The activity of a variety of factors in occupational pulmonary carcinogenesis is evident from the wide fluctuations in lung Table X. 3,4-Benzpyrene content in the particulate phase of air pollutants of English cities Median annual concentration of 3,4-benzpyrene in air City (lig per 100 cu. M.) London 4.6 Sheffield 4.2 Leicester 2.9 Burnley 2.7 Bilston 2.7 Cannock 1.9 Hull 1.8 Bristol 1.3 From Waller.244 Smog days 17.3 cancer mortality rates among members of large industrial worker groups (Mancuso167; Morrison179) (Tables XI and XII) and the number of recognized respiratory human carcinogens (Table XIII). Since cigarette smoke condensate con tains minute amounts, not only of various carcinogenic polycyclic aromatic hydrocar bons but often also of volatilized arsenical pesticide residue as well as cocarcinogenic chemicals, such as phenols, the personal ized type of air pollution in the form of cigarette smoking contributes to and ag gravates the carcinogenic exposure of the respiratory mucosa associated with the in halation of carcinogens of organic and inorganic nature present in the general and occupational atmosphere ( Doll45'46; Wynder253; Hammond and Horn86). Recent sta tistical studies carried on in the United States, France, and Denmark have, more over, linked cigarette smoking to an excessive liability to cancer of the bladder ( Clemmesen37' 3S; Denoix44). While such correlations may be demonstrable on an in dividual basis, they fail to become evident when lung and bladder cancer rates of American cities are compared, i.e., there is no parallelism between the levels of lung and bladder cancer rates for individual cities. These observations may be of some significance because such a parallelism ex ists when state death rates for lung cancer are compared with those for heart disease, which also has been connected with ciga rette smoking (Table XIV). Whether such statistical associations are mainly attribut able to the influence of cigarette smoking, however, is doubtful, because ^numerous additional exogenous and endogenous agents exhibit relations to arteriosclerosis and neoplasia (Table XV) (Hueper108). Of the various recognized and suspected respiratory carcinogens, those produced by the incomplete combustion of carbonaceous matter and by the distillation of coal and mineral oil appear at present to possess the greatest importance because of their wide distribution in the human environment. Mustard gas The occasional delayed appearance of cancer of the lung and larynx in soldiers poisoned by gas in World War I was re ported during the first two decades after that conflict ( Hueper106); more recent epi demiologic analyses on the frequency of lung cancer among English and American veterans yielded suggestive statistical evi dence supporting the existence of a causal relation between gas poisoning sustained in 1917 and 1918 and lung cancer develop ment decades later in individuals who sus tained such chemical trauma to the respira tory tract (Case and Lea34; Beebe13). The occurrence of cancer of the lung and larynx 790 Hueper ":'-:; Clinical Pharmacology and Therapeutica Volume 3 dumber 6 Table XI. Lung cancer death rate per 1,000 deaths of all causes for seven industrial groups in Ohio in 1947 among 5,309 cancer deaths in men Industry Iron and steel Transportation Agriculture Rubber and plastics Stone, clay, and glass Nonferrous metal Mining and quarrying All industrial groups From Mancuso.167 Respiratory cancer 2.18 2.91 0.82 2.34 0.66 3.22 1.53 1.76 among Japanese producers of mustard gas recorded during the last decade has pro vided more definite confirmation in man (Yamada and colleagues254). This is, more over, supported by experimental observa tions on the production of cancer by sulfur and nitrogen mustards in mice. These find ings provide one of several illustrations of the carcinogenic action of carcinostatic chemicals used in human and experimental cancer therapy (estrogens, urethane, arse nic, alkylating agents, benzol, 4-nitroquinoline-N-oxide, x-radiation, radioactive chemi cals). Isopropyl oil Cancer of the paranasal sinuses, larynx, and lung first noted by Nale and Hueper112'186 in 1946 among producers of isopropyl alcohol in One American factory was found subsequently in several other similar plants in the United States (Eckardt54). The occupational origin was thereby es tablished beyond any reasonable doubt. The evidence on hand strongly suggests that some constituent present in the viscous crude liquor from which isopropyl alcohol (isopropyl oil) is distilled, and not the alcohol as such, is responsible for the can cer. This suspicion is supported by the re sults of studies on experimental animals conducted by Weil, Smyth, and Nale249 with the cooperation and guidance of Hueper. Benzol Benzol, a product of the distillation of coal tar as well as a petrochemical, is widely used in chemical manufacture and is a frequent constituent or impurity of or ganic solvents and degreasing agents. While its toxic, aplasiogenic effect upon the blood-forming tissues represents its main health hazard, observations of the last three decades have established benzol as a leukemogenic agent capable of causing both myeloid and lymphoid leukemia ir. in dividuals who usually are exposed to it for occupational reasons (Browning27; Hue per112' 126; Kahler and Merker142). It may be noted that these hematic reactions to benzol are not, as claimed, leukemoid re sponses representing agnogenic myeloid hyperplasia (Hueper112). An anemic phase Table XII. Standard mortality rates of malignant neoplasms of the respiratory system in occupational classes in Scotland Occupational code No. 160-164 231-249 131, 132 589 134-138 681 912 600-609 Occupation SMR Above 130 Platers, riveters, shipwrights 183 Electrical apparatus makers, electricians 170 Moulders 162 Masons and stonecutters 162 Foundry workers, etc. 161 Dock laborers 157 Crane drivers 150 Painters, decorators 132 019, 021, 029 010, 011, 018, 020 110-119 013-015 620-629 Farm workers Farmers, etc. Foremen and overlookers in metal manufacture Market or other gardeners Managers of industrial undertakings (other than office departments) From Morrison.179 Below 70 25 27 54 56 69 may precede the su of leukocytotic, eosii reactions which are manifestations ultii character of definite The maturation arre sponse of the bon' conditions has man' ties to the myeloid ionizing radiation ; chemoallergic agrai ited by an apprecial drugs usually of arc These have been ii practice during the of the evidence nc such agranulocytoti. per126) should be i leukemogenic manii Table XIII. Respira Material Metals and minerals Arsenic Chromium Nickel .. Asbestos Beryllium (?) Iron oxide(?) Radioactive chemica Organic chemicals Coal tar Petroleum oils Incomplete combust products of carbo: matter (soots, gas and diesel engine hausts, tobacco fi etc. ) Crude isopropyl ale Mustard gas Oxidation and polyi: tion products of a compounds of vol gasoline(?) J.r\ . .. : ^ ... - - Clinical Pharmacology and Therapeutic* jt of the distillation of as a petrochemical, is mical manufacture and tuent or impurity of orid degreasing agents, .siogenic effect upon the tes represents its main servations of the last established benzol as a nt capable of causing vmphoid leukemia in inilly are exposed to it for >ns (Browning27; Hueind Merker142). It may se hematic reactions to claimed, leukemoid reng agnogenic myeloid er112). An anemic phase d mortality rates of ns of the respiratory mal classes in Scotland Occupation SMR Above 130 . riveters, wrights 183 cal apparatus ers, electricians 170 ers 162 s and stonecutters 162 ry workers, etc. 161 laborers 157 drivers 150 rs, decorators 132 workers rs, etc. Below 70 25 27 en and over- ers in metal ufacture 54 t or other leners 56 j;ers of industrial ertakings (other i office artments) 69 Volume 3 Number 6 1 '1 may precede the subsequent development of leukocytotic, eosinophilic, and basophilic reactions which are followed by leukemoid manifestations ultimately assuming the character of definite leukemia (Hueper101). The maturation arrest characterizing the re sponse of the bone marrow under such conditions has many morphologic similari ties to the myeloid reactions produced by ionizing radiation and accompanying the chemoallergic agranulocytotic effects elic ited by an appreciable number of synthetic drugs usually of aromatic chemical nature. These have been introduced into medical practice during the past 50 years. Because of the evidence noted, patients surviving such agranulocytotic drug reactions (Hue per120) should be invesigated for delayed leukemogenic manifestations. Table XIII. Respiratory carcinogens Material Organ affected Metals and minerals Arsenic r~'jf Chromium f--4 Nickel TOW* :: < Asbestos Beryllium(?) Iron oxide(?) Radioactive chemicals Lung, larynx, paranasal sinuses Lung, nasal cavity, paranasal sinuses Lung, nasal cavity, paranasal sinuses Lung, pleura, peritoneum Lung Lung Lung, paranasal sinuses Organic chemicals Coal tar Lung, larynx(?) Petroleum oils Lung, larynx(?) Incomplete combustion products of carbonaceous matter (soots, gasoline and diesel engine ex hausts, tobacco fumes, etc.) Lung, larynx(?) Crude isopropyl alcohol Lung, larynx, paranasal sinuses Mustard gas Lung, larynx Oxidation and polymeriza tion products of aliphatic | ; compounds of volatilized gasoline(?) Lung(?) Symposium: Chemical carcinogenesis 791 Table XIV. Crude death rates per 100,000 for arteriosclerotic heart disease and cancer of the lung in selected states State Connecticut Massachusetts New York Illinois New Hampshire Alabama New Mexico Wyoming South Carolina North Dakota Deaths from Deaths from heart disease lung cancer (1950) (1948) 288.6 11.1 298.2 10.2 322.5 11.9 236.2 8.2 316.0 10.1 130.4 5.1 85.4 3.0 135.6 3.9 118.8 3.7 168.2 4.1 Arsenic ~ . During recent years, various American investigators have challenged the validity of the widely held conclusion that arsenicals are human carcinogens (Eckardt54; Frost67; Johnstone and Miller141). It should be emphasized, the lack of proper occupa tional and environmental observations on arsenic cancer from American sources not withstanding, that the global epidemiologic and medical evidence available and pub lished on carcinogenic manifestations in various organs elicited by arsenicals follow ing medicinal, occupational, and dietary exposure is ample and adequate for estab lishing the conclusion firmly (Hueper112'127; Neubauer183; Sommers and McManus220; Roth204,205; Tello232; Rockstroh203; Henry92; Hill and Faning95). The endemic occurrence of arsenic can cer of the skin among population groups consuming drinking water polluted from industrial and natural sources with arsenic and showing cutaneous stigmas of chronic arsenic poisoning has been recorded in Ger many, Argentina, and Taiwan. The dermat ologic literature of many countries contains an appreciable number of case reports on the occurrence of often multicentric carci nomas of the skin in patients given arseni cal preparations for various reasons (Neu bauer183). The site distribution differs characteristically from that found in cancer 792 Hueper Clinical Pharmacology and Therapeutics Table XV. Exogenous and endogenous agents possessing tumorigenic and arteriosclerotogenic associations Agent Arteriosclerotic manifestations Carcinogenic manifestations Exogenous agents Arsenic Asbestos Endarteritis (Raynaud-like vasospastic disease) Periarteritis nodosa Fibrosing pulmonary arteriosclerosis with asbestosis Carcinoma of skin, liver, and lung Carcinoma of lung, pleural, and peritoneum Beryllium Fibrosing pulmonary arteriosclerosis with berylliosis Carcinoma of lung (rat), and bone (rabbit); sarcoid granuloma of lung and skin Schistosomiasis Ergot alkaloid Parasitic pulmonary venosclerosis Carcinoma of bladder and fibrosing arteriosclerosis Fibrosing peripheral arteriosclerosis and "thromboangiitis obliterans" Neurofibroma of ear (rat) Nicotine Ultraviolet radiation; vitamin D Fibrosing endarteritis, thromboangiitis Adrenal adenoma (rat) obliterans, coronary sclerosis(?) Calcifying arteriolsclerosis (rat) Carcinoma and sarcoma of skin and orbit (rat and mouse); carcinoma of skin Ionizing radiation Fibrosing endarteritis Cancer of skin, bone, lung, hematopoietic tissue, liver, etc. Endogenous agents Epinephrine Fibrosing arteriosclerosis Natural and synthetic estrogens Hyperestrinism Hypoestrinism (oophorectomy) Thyroid hormone Hypothyroidism Antiatheromatogenic effect Atheromatosis Atheromatosis Parathyroid hormone Hyperparathyroidism Calcifying arteriosclerosis Hepatic functional defi ciency (cirrhosis nutri tional impairment, choline deficiency) Atheromatosis Macromoleculoses Lipoproteins Hyperlipoproteinemia Hypercholesterolemia Lipoidoses Hyperproteinemia and heteroproteinemia Waldenstrom's disease Atheromatosis Reticuloendotheliosis; amyloidosis arterial Pheochromocytoma, ( epinephrine production, hypertension ) Cancer of uterus, breast, etc., (mice, rats, and man) Adenoma and carcinoma of thyroid adenoma of hypophysis Parathyroid adenoma, carcinoma Adenoma and carcinoma of liver; gynecomastia Carcinogenic action of cholesterol(P); carcinogen-carrying action of cholesterol ( ?) Myeloma Sarcomas of lymphoid and reticuloendothelial origin Exogenous Carbohydratic Macromoleculosis Polyvinyl alcohol Polyvinyl pyrrolidon CarboxymethylcelluL Dextran and iron de of the skin elicited b} cutaneous carcinogen conforms to the topogi cancerous cutaneous 1c the arsenic cancer syrn observation of isolate cancer in other organs after occupational, m mental contact with ai in copper ore miners and arsenical insecti< users (Hueper12s>12e; R and Lombard219; Osbu ing95) during past dec of a severe epidemic ot cer affecting the skin liver, and other orga vineyard workers sufh arsenic poisoning whic! occupational use of arsi the drinking of wine coi Table XVI. Topographi cancer of the skin Face, nose, and neck Hands and arms Feet and legs Haired parts of skin Nonexposed skin From Hueper.112 ~;"`r . ' - v - 1 . . .. . ' Clinical Pharmacology and Therapeutics 4 Volume 3 Number 6 ' SrA . . - ; if . .... Symposium: Chemical carcinogenesis 793 manifestations i, liver, and lung g, pleural, and g (rat), and bone id granuloma of Table XV. Cont'd Agent Glycogenosis Arteriosclerotic manifestations Atheromatosis Exogenous Carbohydratic Macromoleculosis Polyvinyl alcohol Polyvinyl pyrrolidone Carboxymethylcellulose Dextran and iron dextran Atheromatogenic Atheromatogenic Atheromatogenic Atheromatogenic effect effect effect effect From Hueper.108 Carcinogenic manifestations Glioma, adenoma of skin, rhabdomyomatosis of heart Carcinogenic effect (rat) Carcinogenic effect (rat) Carcinogenic effect (rat) Carcinogenic effect (rat, mouse, ham ster) idder ear (rat) ; (rat) trcoma of skin and mouse); carcinoma >ne, lung, issue, liver, etc. ia, (epinephrine pertension) breast, etc., d man) rcinoma of thyroid; ,-pophysis orna, carcinoma cinoma of liver; >n of cholesterol(?); ving action of ihoid and liai origin of the skin elicited by other environmental cutaneous carcinogens (Table XVI) but conforms to the topographic pattern of noncancerous cutaneous lesions associated with the arsenic cancer syndrome. Following the observation of isolated cases or groups of *1 cancer in other organs, especially the lung, after occupational, medicinal, or environ mental contact with arsenicals, particularly in copper ore miners and smelter workers and arsenical insecticide producers and users (Hueper125'126; Rockstroh203; Snegireff and Lombard219; Osbum190; Hill and Faning95) during past decades, the occurrence of a severe epidemic of hetero-organic can cer affecting the skin, respiratory tract, liver, and other organs among German vineyard workers suffering from chronic arsenic poisoning which resulted from the occupational use of arsenical pesticides and the drinking of wine contaminated with the i residue has brought the cancer hazard from arsenic into sharp focus (Rockstroh203; Roth204-205) (Table XVII). Rockstroh203 reported the occurrence of 45 cases of lung cancer among members of a plant population averaging 111 workers during the years 1932 to 1953. Roth205 found in eighty-two autopsies of vineyard workers with symptoms of chronic arsenic poisoning performed during the period of 1950 to 1959, 61 individuals with one or several cancers, often involving not only the skin but also internal organs (74.4 per cent). In 44 of these cases, the cancer was situ ated in the respiratory tract (nasal sinus, larynx, tracheobronchial tree, lungs) (53.65 per cent). In 4 of these instances of lung cancer, bilateral cancer of the lung was present, and in 1 a carcinoma of the larynx and in 1 a carcinoma of the tongue were present, in addition to cancer of the skin. Table XVI. Topographic distribution of solar, arsenic, and roentgen-induced cancer of the skin ! I 1 Region hnvironmental solar cancer (%) Roffo Tello Arsenic cancer (%) Dietary (Tello) Medicinal and occupational (Neubauer) Occupational roentgen- induced cancer (%) (Hueper) Face, nose, and neck Hands and arms Feet and legs Haired parts of skin , Nonexposed skin 95.00 3.07 0.52 1.02 0.39 1 77.73 1.43 0.01 21.33 8.57 6.27 i 443 jio./o 80.73 12.21 46.61 41.18 4.76 84.52 0.00 10.72 From Hueper.113 794 Htieper Clinical Pharmacology and Therapeutics Volume 3 Number 6 Table XVII. Occupational arsenic-induced cancer of the lung, larynx, and paranasal sinuses Lung 7 Larynx Incidence by site Nares and Coexisting nasal sinuses keratoses Skin Exposure cancer period (yr.) Occupation Copper smelter worker Author and year of publication Snegireff and Lombard, 1951 19 1 Gold ore miner Osburn, 1957 1 5 Pesticide producer Derobert and Hadengue, 1952 Q ' 9 4 17 Vineyard worker Braun, 1958 1 36 Cobalt smelter worker Krug, 1959 19 1 2 19 9 Vineyard worker Roth, 1956, 1958 2 Arsenic smelter worker Schmorl, 1928 1 1 Farmer Montgomery and Waisman, 1941 1 43 Arsenic worker Currie, 1947 2 37 Pesticide worker Bridge and colleagues, 1939 17 8 - 20 Copper ore miner Akazaki, 1960 6 3-8 Vineyard worker Hess, 1956 45 45 8-45 Nickel-cobalt ore Rockstroh, 1959 smelter worker 5 - 1... _------...------- Pesticide producer Hill and Faning, 1948 2 Sheep dip producer Henry, 1934 4 37-43 Sheep dip producer Merewether, 1944, 1 1 1 Vineyard worker versus Pein, 1943 1 1 Vineyard worker Liebogott, 1950 8 Vineyard worker Koelsch, 1958 1 Furrier Frommel, 1927 2 1 1 - -- Pesticide sprayer Hueper, 1961 There were, moreover, 5 cases of esopha geal cancer, 8 hemangiosarcomas of the liver, 1 cholangiocarcinoma, and 1 renal carcinoma present in Roth's series. The latent period of these cases was up to 50 years. Roth205 concluded from these cata strophic late effects of chronic arsenic poi soning that arsenic is a highly dangerous carcinogen which produces cancer in vari ous organs and tissues. He emphasized also that the combined occurrence of multiple cancer of the skin and of internal organs should be considered suspect of arsenical causation. It is significant that 7 of the in stances of arsenic cancer observed by Roth204 were found in female vintners. Oc cupational arsenic cancer thus exhibits an exposure-dependent sex liability similar to I that noted in cai English asbestos scrotal and vulvar spinners. Although the wi in many natural precludes eliminati man population w evidence strongly any needless expos avoided and she proper laws where Asbestos Asbestos is a ci variable fibrous sil of silicon, magnesi and iron oxides. 1 may range from ( chrysotile to some 3 Cape crocidolite in cently demonstrat pyrene. Since the fii 1935 on the coexis; carcinoma of the 1 English textile wo; ne74), it has becon that the inhalation pecially when it resi of asbestosis ( Mum sive liability to the of a carcinoma of t frequently may be being derived from matoid and metapl bronchial epithelial 1. in such lungs. The first and still dicating excessive lie develop cancer of tl from postmortem o this material is select the evidence obtaine by the consistency shown by studies fr< and occupational gr During recent years, tions have been confi tistical studies on the experience of English Clinical Pharmacology and Therapeutics Volume 3 Number 6 Symposium Chemical carcinogenesis 795 Author and year of publication irker Snegireff and Lombard, 1951 Osburn, 1957 r Derobert and Hadengue, 1952 Braun, 1958 irlcer Krug, 1959 Roth, 1956, 1958 !irker Sclimorl, 1928 Montgomery and Waisman, 1941 Currie, 1947 Bridge and colleagues, 1939 Akazaki, 1960 Hess, 1956 Rockstroh, 1959 r Hill and Faning, 1948 er Henry, 1934 er Merewether, 1944, versus Pein, 1943 Liebogott, 1950 Koelsch, 1958 Frommel, 1927 Hueper, 1961 ies. He emphasized also occurrence of multiple and of internal organs ed suspect of arsenical tificant that 7 of the inj cancer observed by ! in female vintners. Occancer thus exhibits an t sex liability similar to that noted in cancer of the lung among English asbestos workers and in cases of scrotal and vulvar cancer of English mule spinners. Although the wide distribution of arsenic in many natural and industrial products precludes elimination of contact of the hu man population with arsenic, the available evidence strongly supports the view that any needless exposure to arsenic should be avoided and should be proscribed by proper laws where indicated. Asbestos Asbestos is a complex and chemically variable fibrous silicon polymer consisting of silicon, magnesium, aluminum, sodium, and iron oxides. The iron oxide content may range from 0.1 to 11 per cent for chrysotile to some 39 to 44 per cent for blue Cape crocidolite in which Harrington84 re cently demonstrated traces of 3,4-benz pyrene. Since the first discovery reported in 1935 on the coexistence of asbestosis and carcinoma of the lung in American and English textile workers (Lynch164; Gloyne74), it has become increasingly evident that the inhalation of asbestos fibers, es pecially when it results in the development of asbestosis (Murray180), creates an exces sive liability to the subsequent appearance of a carcinoma of the lung, which not in frequently may be of multicentric origin, being derived from the multifocal adeno matoid and metaplastic bronchiolar and bronchial epithelial lesions commonly found in such lungs. The first and still most frequent data in dicating excessive liability of asbestotics to develop cancer of the lung were obtained from postmortem observations. Although this material is selective, the significance of the evidence obtained from it is attested to by the consistency of its character, as shown by studies from different countries and occupational groups (Table XVIII). During recent years, the autopsy observa tions have been confirmed by Doll48 in sta tistical studies on the lung cancer mortality experience of English asbestos workers and by Mancuso* on American employees of an asbestos brake lining plant (Table XIX). The scientific value of these observations was recently challenged by Bohlig, Jacob, and Mller17 and by Braun and Truan26 in investigations on the morbidity from lung cancer among asbestos workers in Saxony and in the Province of Quebec, respectively. While Bohlig, Jacob, and Mller17 main tained that the lung cancer morbidity rate of all German asbestos workers is not higher than that of a comparable general population (between 5 and 6 per 10,000), it is doubtful whether this calculation re flects the actual conditions. The epidemi ology of occupational cancer of various types has clearly shown that the anatomic reactions to such hazards, as a rule, become manifest only in long-term workers who have sustained prolonged and often severe exposure or in individuals for whom, after cessation of exposure, a latent period elapsed which extended over 10 to 25 years. Unless proper methodologic precautions in the collection and evaluation of epidemi ologic data are taken, data of the type used by Bohlig, Jacob, and Mller contain a dilution factor which a priori may negate and defeat the purpose and validity of such studies (Hueper127). More serious objec tions must be raised against the scientific merits of the claims made in this matter by Braun and Truan,26 who studied asbestos miners and millers in the Province of Que bec. According to the data published, this study was based on a survey of about 6,000 individuals employed by the asbestos in dustry in Quebec. There is an analysis of the degree of dust exposure and the num ber of individuals in each of three gradu ated groups, but no data are offered on the duration of exposure to asbestos dust. Al though there is a statement on the number of smokers and nonsmokers, the report is devoid of information on the number of as bestotics in the population group analyzed. No information is available regarding the number of long-term workers and their T. F. Mancuso: Personal communication. =CDr 3Ql H--nT I QL I O C/ ! SCCOD CD 5 Cc/D> o 4-og CQD-* ? I CQD. Oo'' CD CT iC3D Q3 . I *< CT CD 11o2 COD CQD. 'CCT C GO Io I C$D relative liability to lung cancer. No mention is made in the report on autopsies which have been performed on those who died during the period surveyed. This is particu larly important, since Braun and Truan26 professed that only 9 "proved" cases of lung cancer were discovered to have occurred in the population analyzed. This is a rather surprising observation since during a some what longer period than that covering the survey, a histopathologic study by the pa thologists of the Saranac Laboratory, under the sponsorship of industrial management, on lungs from dead asbestos workers from Quebec revealed 34 cases of asbestosis can cer of the lung. The conclusions reached by Braun and Truan26 concerning an absence of an exces sive liability to lung cancer among Quebec asbestos workers are incorrect even if proper epidemiologic procedures are ap plied to their data as reported. While the statement of Braun and Truan26 that the annual rate of deaths from lung cancer in the asbestos group for the years 1950 to 1955 is only slightly higher than the rate for the inhabitants of the Province of Que bec would be correct under these condi tions, this statement represents statistical acrobatics which tend to obscure incrimi nating evidence on hand by use of a highly biased population group as a "normal" stan dard. It is a well-known fact that urban populations in all industrialized countries have a decidely higher lung cancer death rate than that in rural regions ( Hueper117' 124). Since the asbestos mines are situated in rural areas of Quebec and are not located within the fume zones of Que bec and Montreal, where a high lung can cer rate prevails (Montreal rate 32.3), the lung cancer death rate of the asbestos miners, which stands at 33.8 per 100,000 has to be compared with the rates present in rural counties of the Province of Quebec. According to the data provided on this Table XVIII. Frequency of cancer of the lung in autopsies of asbestotics Author~ ' ; Merewether174 W y e rs253 Doll48 Gloyne74 O'Donnell and Mann188 Lynch164 Becker22 W edler248 Boehme16 Sex Male Female Both Male Female Both No. of autopsies of asbestotics 222 143 365 115 105 (asbestos workers) 121 40 40 Incidence of lung cancer 48 17 65 17 18 17 20 5 92 15 17 12 14 2 31 14 Total 99" Tn Controls Becker: men over 20; average age at death 61 years (silicotics) Merewether: 6,884 postmortem examinations on silicotics; 91 instances of lung cancer; average age at death 59.4 years Percentage of lung cancer 22.0 12.0 17.8 14.8 17.0 13.2 50.0 8.2 14.0-15.0 16.0 71.0 14.0 36.0 18.4 4.0 3.6 1.32 Table XIX. Obse, mid-1960, among ( at some time in 19 _____________ Site Lung, bronchus, an Peritoneum158 *T. F. Mancuso: Perso point by Braun am sion is patently in< leading and result:tence of a marked) rate for members o The causal relat and cancer of the 1 the fact that asbesh often the lower lob (53:7) in contrast lung cancer which ii the upper lobes. As logically significant . and frequent multic< bestosis cancer are t portant metaplastic ous and cancerous cl and bronchiolar epit and accompany the i in asbestotic lungs (1 coexistence of asbes has been reported fr 1 Canada, England, Fr Switzerland, and 1 miners, millers, crus grinders, cleaners, } mixers, packers, boil fillers, weavers, spinnt ers. Recent observation Britain, the United and South Africa stro bestosis is also causa thelioma of the plei 1 (Cartier32; Mancuso*; Muller17; Leicher157; \ T. F. Mancuso: Personal c< 'inical Pharmacology and Therapeutics lung cancer in years 1950 to than the rate Province of Queder these condiresents statistical obscure incrimiuse of a highly a "normal" stanfact that urban lalized countries ng cancer death regions ( Huelestos mines are Quebec and are ae zones of Quea high lung can al rate 32.3), the of the asbestos 33.8 per 100,000 the rates present ovince of Quebec, provided on this f Percentage of lung cancer 22.0 12.0 17.8 14.8. 17.0 13.2 50.0 8.2 14.0-15.0 16.0 71.0 14.0 36.0 18.4 4.0 3.6 1.32 3 ; -4 : 1 Volume 3 Number 6 Symposium: Chemical carcinogenesis 797 1M Table XIX. Observed and expected deaths due to lung cancer, 1940 through i mid-1960, among a cohort of white male and female employees of company C at some time in 1938 or 1939 (ages 25 to 64 years at death)9 - Total Men Women Observed Expected Observed Expected Observed Expected Site deaths deaths deaths deaths deaths deaths Lung, bronchus, and trachea162' 163 18 5.29 14 5.11 4 0.18 Peritoneum158 3 0.10 2 0.08 1 0.01 T. F. Mancuso: Personal communication. 1 point by Braun and Truan,26 their conclusion is patently incorrect and grossly mis leading and results in obscuring the exis^s tence of a markedly elevated lung cancer fr's rate for members of this worker group. The causal relation between asbestosis ; and cancer of the lung is demonstrated by the fact that asbestosis cancer affects more often the lower lobes than the upper lobes 5 (53:7) in contrast to the general type of lung cancer which involves more frequently the upper lobes. Associated with this etiologically significant topographic peculiarity and frequent multicentric occurrence of as bestosis cancer are the various equally im portant metaplastic adenocystic precancerous and cancerous changes of the bronchial and bronchiolar epithelium which precede and accompany the development of cancer in asbestotic lungs (Hueper118' 124>125). The coexistence of asbestosis and lung cancer , has been reported from the United States, Canada, England, France, Germany, Italy, Switzerland, and Finland in asbestos miners, millers, crushers, loaders, sorters, ^ i grinders, cleaners, pipe laggers, cement mixers, packers, boiler coverers, mattress fillers, weavers, spinners, and cement work ers. Recent observations in Germany, Great Britain, the United States, Canada, Italy, j and South Africa strongly suggest that as bestosis is also causally related to mesol thelioma of the pleura and peritoneum \ (Cartier32; Mancuso*; Bohlig, Jacob, and ; Mller17; Leicher157; Wedler248; Koenig148; \' ^ T. F. Mancuso: Personal communication. 4 IS 1 Doll48; Keal145; Wagner, Sleggs, and Marchand243; Sleggs, Marchand, and Wag ner213). It is noteworthy that the frequent occurrence of mesothelioma, which is or dinarily a rather rare cancer, in South Africa has been restricted to the residents of the blue Cape asbestos districts and to workers and miners having occupational contact with this particular type of South African asbestos. Many of the nonoccupational victims of this neoplastic disease as children had played on asbestos dumps, had visited the mills and mines, and had lived near such establishments or along the roads on which the asbestos was trans ported and where the ground was contami nated with asbestos dust (Wagner, Sleggs, and Marchand243). The evidence on hand indicates that both carcinoma of the lung and mesothelioma of the pleura and peritoneum may develop subsequent to and as the result of inhala tion of asbestos dust and that such cancer ous sequelae may appear after an exposure to asbestos mined in different parts of the world and differing in chemical composi tion. Asbestosis of the lung does not have to be well developed, according to more re cently obtained evidence, in order to be a prerequisite for the development of cancer ous sequelae. In fact, pleural and peritoneal mesothelioma has been observed in patients showing only a minimal amount of usually locally restricted asbestosis. Beryllium, cobalt, and selenium Various experiments with beryllium com pounds have demonstrated that these - Clinical Pharmacology and Therapeutics Volume 3 Number 6 ......... Ilin..1Hi Symposium: Chemical carcinogenesis 799 ireas within the i chromate lung Rushin20). These chromates are ran carcinogens > environmental >nmental cancer i type. Whether mospheric con omite ore is not hrome holes" of and perforated lucers as a rule >us malignancy, eloping on the dermatitis was many for being at present unn of chromates contaminated 10m chromium itchen utensils e especially to the occurrence uency rates of kers of the England mg cancer rate per 100,000 General ornate populatrkers tion 70.8 16.7 ich and intesmong workers aniline dyes Buess29). It is e occasionally oma and cartainless steel screws, and ments is the result of a specific carcinogenic action of the chromium contained often in such ma terials; observations on cancer incidence among stainless steel producers and proces sors which might provide a clue in such matters are not available. The experimental work of Hueper and Payne118' 135'140>193'194 on rats and mice has definitely established the carcinogenic Table XXI. Time of appearance and frequency of nasal septum perforations in white and. Negro chromate producers in the United States Time of employment Percentage of perforated Num- nasal septa ber of All workers workers W hite Negro 0-6 mo. 41 2.4 0 11.1 6 mo.-3 yr. 117 39.3 31.5 64.3 3-10 yr. 370 55.4 44.3 74.8 10 yr. and over 369 69.6 64.0 93.1 Total 897 56.7 49.3 76.6 i From Gafafer and coauthors.70 properties of chromium when present in a biologically available form. The epidemi ologic as well as experimental evidence at testing to the carcinogenic properties of chromates (Alwens4; Gafafer and col leagues70; Fisher01; Bidstrup and Case15) refutes the allegation that the high inci dence of lung cancer in chromate workers is attributable to cigarette smoking (Oet tel187). In contrast to asbestosis cancer of the lung, which preferably is situated in the lower lobes, that evoked by chromates is located more frequently in the upper lobes and thus follows the general pattern of dis tribution of cancer of the lung. Lung cancer attack rates ranged in dif ferent American plants from 13 to 80 times normal. Negro workers exhibited a higher lung cancer attack rate than white workers because they were usually employed in jobs with greater intensity of exposure to chro mate dust and fumes. It is for this reason also that Negro chromate producers de velop nasal septum perforations earlier and at a higher rate than white workers (Table XXI). After cessation of exposure to this occupational carcinogen, former chromate producers retain their excessive liability to cancer of the lung (Hueper117). The avail able incidence rate of lung cancer among members of this worker group, therefore, is too low. Since the labor turnover in this occupation is rather high and many work ers leave employment before they develop lung cancer (Gafafer and colleagues70; Baetjer10; Bidstrup and Case15), an appre ciable number of such cancer cases are not recorded. It is noteworthy that so far, no epidemiologic studies on lung cancer rates have been made in any country on chrome platers, chrome pigment spray painters, metal cutters and smelter workers handling stainless steel and metal parts coated with anticorrosive chrome paint, and welders, although the occurrence of isolated cases of lung cancer in individuals after a period of employment in these occupations has been observed. It may be worthwhile, moreover, to explore lung cancer rates in residents of and individuals working in buildings in which chromates are used as antirusting agents of the water in steam-heating and air-conditioning plants and are released into the air. Because of the lack of any reliable data on large population groups having respiratory and ingestive contact with chro mates, the actual extent of cancer hazards from chromium is at present undetermined. Iron Recent epidemiologic investigations on the frequency of lung cancer among mem bers of occupations with pulmonary siderosis (boiler scalers, hematite miners, foundry workers) reported from England and France suggest that the presence of siderosis confers on the lungs an increased liabil ity to development of cancer ( McLaughlin and Harding171; Faulds and Stewart58; Harding and Massie83; Faulds57; Monlibert and Hayange177; Braun and coauthors35) (Table XXII). Isolated cases of lung can- a"d3 * P'0" * 1* US' ,, conecta o,tiem * * m n < % ,JL ii CD 1 3W CD O3 J|J-Woo> Ito 1 ^ 0u>3 J1*oo0 1Q_ I o 3 ill 41 :;- a 800 Hueper ---- - irrrMMHWri Clinical Pharmacology and Therapeutics Volume 3 Number 6 cer coexisting with siderosis previously re corded had been suspected as being caused by related conditions (Hueper126). Warren and Drake246had incriminated the iron con tained in the liver with hemosiderosis as the carcinogen active in the production of liver cancer often found associated with this condition. Whether or not the develop ment of sarcoma of the subcutaneous con nective tissue and of the reticuloendothelial tissues of mice, rats, and hamsters repeat edly injected with an iron-dextran complex is attributable to the iron content ( Haddow and Horning82; Haddow31; Richmond202) is uncertain since rats injected intrapleurally with finely powdered, pure iron obtained by the degradation of iron carbonyl did not exhibit any cancerous responses (Hueper and Payne140; Gilman71), while rats injected subcutaneously with several dextrans de veloped reticulum cell sarcoma (Hueper120). Since many industrial workers are ex posed to the inhalation of iron oxide, particularly when oxygen is used in the manufacture of steel, the problem of occu pational lung cancer resulting from such exposure urgently deserves study. Similar attention should be extended to the car cinogenic effect of the medicinally and parenterally administered iron-dextran com plex, since this carcinogenic agent is being used in the management of a noncancerous disease, anemia, and since it is now a wellestablished medical principle to avoid carcinogenic procedures such as irradiation in the therapeutic management of benign diseases for which effective noncarcinogenic therapeutic procedures and agents are available. Nickel After the initial report of Stephens223 on the excessive occurrence of cancer of the nasal cavity, paranasal sinuses, and lung among workers in the nickel matte refin eries at Clydach, Wales, publications on the same subject by Amor,5 Morgan,173 Doll,47 and Williams251 from England and by Loken162 of Norway, as well as observations subsequently made among Canadian nickel smelter workers, have confirmed the origi nal findings (Table XXIII). The continued development of these types of cancer and their occurrence in different countries de spite the cessation many years ago of the use of a sulfuric acid free from significant amounts of arsenic makes it most unlikely that arsenic inhaled with sulfuric acid fumes during the refinery process repre sents the real cause of this respiratory can cer as still maintained by Morgan.173 This old assumption was unlikely a priori since the workers developing this occupational cancer did not exhibit symptoms of chronic arsenicosis and the cutaneous cancer which so strikingly acompanied much of the res piratory cancer found in workers with bona fide contact with arsenicals. The production during recent years by several investigators of sarcomas and carci nomas in mice, rats, and guinea pigs after a parenteral introduction of metallic nickel powder or nickel salts or after the in halation of powdered nickel and nickel carbonyl has provided adequate experi mental evidence incriminating nickel as the carcinogenic agent ( Hueper109' 113>118' 14; Sundermann and associates231; Sundermann and Sundermann230; Hatem85; Gilman71; Gilman and Rucken colleagues176). It is i now, occupational n been placed on rec States although this principal industrial cc its alloys, and its conq Carbon and silicon and plastics The repeated dem formation in mice, rath site of subcutaneous, retroperitoneal impla, soluble carbon and silt occurrence in the retici after a parenteral inje water-soluble polymer cutaneous and intra-a in powdered form not portant practical prob possible existence of ca ated with the medical tary uses of such chemi has been followed by Table XXIII. Comparis observed and expected among nickel workers Period 1938-1947 1948-1956 Organ Nose 1938-1947 Lung 1948-1956 From Doll. Inciderti cane Exvected s 0.066 0.082 2.600 5.900 Table XXII. Siderosis of lung and cancer of lung in English hematite miners and iron foundnj workers Author McLaughlin and Harding171 Faulds and Stewart58 Harding and Massie83 Faulds and Stewart58 Occupation Iron foundry workers Hematite miners Boiler scalers Controls No. of autopsies 149 180 12 2,220 ( over 30 years ) Incidence of lung cancer 16 17 3 45 Percentage 10.8 9.4 20.0 2.0 \ regarding the type and causative mechanism ope duction of these polymer heimer and co-workers1" Schmahl30' 51; Nothdurft1" Horning1; Haddow and pern6'120'121; Lusky and h The adoption of the vie- sa report of Stephens223 on rrence of cancer of the nasal sinuses, and lung the nickel matte refinales, publications on the mor,5 Morgan,178 Doll,47 rom England and by ', as well as observations among Canadian nickel ive confirmed the origiXXIII). The continued >se types of cancer and different countries demany years ago of the id free from significant makes it most unlikely ed with sulfuric acid refinery process repreof this respiratory canled by Morgan.178 This unlikely a priori since ping this occupational >it symptoms of chronic utaneous cancer which mied much of the resd in workers with bona enicals. luring recent years by of sarcomas and carci- and guinea pigs after etion of metallic nickel salts or after the ined nickel and nickel led adequate experiiminating nickel as the (H ueper109' 113- 118' 140; iciates231; Sundermann Hatem85; Gilman71; Gilman and Ruckenbauer72; Mitchell and colleagues176). It is remarkable that up to now, occupational nickel cancer has not been placed on record from the United States although this country is one of the principal industrial consumers of this metal, its alloys, and its compounds. Carbon and silicon polymers and plastics The repeated demonstration of cancer formation in mice, rats, and hamsters at the site of subcutaneous, intraperitoneal, and retroperitoneal implantation of water-insoluble carbon and silicon plastics and their occurrence in the reticuloendothelial tissues after a parenteral injection of solutions of water-soluble polymers or after their sub cutaneous and intra-abdominal deposition in powdered form not only has created im portant practical problems relating to the possible existence of cancer hazards associ ated with the medical, cosmetic, and die tary uses of such chemicals in man but also has been followed by a lively controversy Table XXIII. Comparison between observed and expected incidence of cancer among nickel workers Incidence of Ratio oj No. of cancer expected to Ex- Ob- observed cases fl Period Organ vected served of cancer 1938-1947 Nose 0.066 16 1948-1956 0.082 13 1:242 1:159 1938-1947 Lung 2.600 36 1948-1956 5.900 39 From Doll.47 1:13.8 1:6.7 He incidence of lung, cancer 16 17 3 45 Percentage 10.8 9.4 20.0 2.0 regarding the type and specificity of the causative mechanism operating in the pro duction of these polymer cancers ( Oppen heimer and co-workers189; Druckrey and Schmhl50' S1; Nothdurft185; Alexander and Horning1; Haddow and Homing82; Hueperiie, 120. 12 Lusky and Nelson163). The adoption of the view by the majority of investigators in this field that a nonspe cific physical mechanism eliciting nonspe cific biologic effects in the tissue surround ing plastic implants, especially films, is involved in utimately causing cancerous tissue changes (Nothdurft185; Oppenheimer and associates189; Alexander and Homing1) has serious implications concerning the validity of the long-held and well-sup ported concept regarding the specificity of chemical carcinogens. Through the exten sion of this concept to the cancerous re sponses elicited by other parenterally introduced and chemically "inert" sub stances, e.g., food dyes and dairy waxes, this concept may also exert a dangerous influ ence on restrictive public health practices previously considered sound by providing scientifically dubious justification for the continued use of carcinogenic chemicals in products of general human consumption, especially foodstuffs. This situation has been complicated and worsened as far as the application of the results of bioassays on carcinogenic chemicals to man is con cerned by the allegation that sarcoma evoked by plastics implanted into the sub cutaneous tissue of rats merely reflects an "abnormal" carcinogenic reactivity of the connective tissue of rats to practically any type of physical or chemical trauma and, therefore, is of no real significance in rela tion to possible cancer hazards from such macromolecular or particulate chemicals in man (Oettel187; Food Protection Commit tee66; Hueper120). A critical appraisal of the various obser vations cited and arguments advanced in support of such far-reaching claims not only demonstrates their scientific defects concerning carcinogenesis from implanted or injected carbon and silicon polymers but also refutes the contention that cancer in duced in subcutaneous tissue of rats and mice by the repeated introduction of chemi cally inert matter is without corollary and without significance as to the carcinogenic potency of these materials in man when they are administered by the same or other routes (Hueper130). In fact, recent experi- II I i <5 IlO3 CO ! "QO> <CgD $ QC/) 1CQDl O 3 :x CD 8 CD O 5' 3 1IoeZ w 1 a 1ST I1 I CL 3 03 I'C CT CD 1CD a I I .1 W MUWM . iWPSWUiuui Clinical Pharmacology and Therapeutics "vi A -------- Volume 3 Number 6 The material on this pagewascopied fromthe collection of (he National Library of Medicine by athird party and maybe protected by US. Copyright law. mental observations made with polyure thane foams implanted into the subcutane ous tissue and the peritoneal cavity of rats have shown that the carcinogenic action of these polymers is evidently of chemical origin, that under proper experimental con ditions they are capable of evoking not only sarcoma but also carcinoma, and that they are carcinogenically active in the form of sheets, foams, and powders. It should be evident from these and other findings that it is definitely premature to abandon the chemical theory of polymer carcinogenesis and substitute for it the rather nebulous concept of a physical surface mechanism. Whether or not such macromolecular chemicals will also prove to be carcinogenic to man will be seen when an adequate latent period after their parenteral implan tation or injection into man for surgical and cosmetic reasons has elapsed in a sufficient number of individuals. Attention should also be extended to the possible occurrence of late cancerous complications, possibly resulting from occupational and nonoccupational inhalation of plastic dusts and fumes and of solutions of polymers, espe cially those used in hair sprays. Ultraviolet radiation Comprehensive epidemiologic observa tions made on the skin cancer rate among peoples living in regions with a dry, sunny, warm climate (southwestern and southern United States, Argentina, Australia, South Africa) where exposure to the ultraviolet rays of sunlight is prolonged and intense throughout the year attest to the fact that these nonionizing rays elicit carcinoma ( epidermoid carcinoma, basal cell carci noma) of the exposed parts of the skin, in cluding lips, and that fair-complexioned Caucasians are most susceptible to their carcinogenic action ( Peller195; Molesworth175; Phillips197) (Table XXIV). Accord ing to more recent observations, it appears that such exposures may also incite the de velopment of melanoma (Texas, Australia, South Africa) (Lancaster155; McGovern and Mackie173). Members of the oriental Table XXIV. Incidence of skin cancer per 100,000 population in six urban areas Author McDowell172 City Northern area Detroit Chicago Pittsburgh Southern area New Orleans Dallas-Ft. Worth Atlanta Birmingham Peller193 Cities by region and race North South West All white Negro Percent age rate for white males for Rate all cancer 24 12.3 25 12.5 37 16.0 129 26.0 140 157 38.5 43.3 Incidence of skin cancer per 100,000 population Male 1Female 23 18 116 70 41 34 38 28 5 4 race are definitely less affected by solar cancer of the exposed skin (Allison and Wong3), and American and African Ne groes are more or less totally resistant un less they are albinos; the latter exhibit a frequency and topographic distribution of skin cancer identical with that seen in faircomplexioned white people (Shapiro215). Individuals with hereditary hypersensitivity to solar rays develop xeroderma pigment osum and skin cancer during childhood which cause death early in life in 100 per cent. It seems that the amount of pigment present, the relative thickness of the epi dermis, especially its cornified layer, and the quantity and possibly also the quality of sebum produced act as natural protec tive factors which determine the observed variations of susceptibility to solar cancer of the skin among members of different races. It has remained uncertain whether the car cinogenic action of ultraviolet radiation is entirely a phy elicited by rays 2,900 to 3,341 chemical phei mentally a ma cinogenesis. Sti that the effect e to ultraviolet r largely irrevers duction of ultr coma of the sk mice and rats pecially in tho have a sparse eyelids). The v\ skin of hairless however, appe; carcinogenic a ( Hueper104' 106) Ionizing radit radioactive c Among the m gens, ionizing only universal producing canc far. Although mined whether the result of a p stituents or rep feet upon celli the general biol cer evoked in m radiation, i.e., 1< mulative effect precancerous al valent reactions generation, nec carcinomatoid ; cancer), are id with cancer eli< gens. The repoi involving the s tissues after a s exposure to ioi favor the chemii cinogenesis sinct panying the resp> seen in chemical with a depot < . ..................... .................... J,~ 1 '`WT'Nw! r.. ' iX . . *--'fir;;- ; % Clinical Pharmacology and Therapeutics Volume 3 Number 6 Symposium: Chemical carcinogenesis 803 mce of skin cancer per in six urban areas entirely a physical phenomenon which is elicited by rays between the wave length of 2,900 to 3,341 or whether it is a photo Percentage rate for white males for Rate all cancer chemical phenomenon and thus funda mentally a manifestation of chemical car cinogenesis. Studies by Blum31 have shown that the effect exerted by repeated exposure n area 24 12.3 to ultraviolet radiation is cumulative and largely irreversible. The experimental pro 25 12.5 gh 37 16.0 i area leans 129 26.0 -'t. Worth 140 157 38.5 duction of ultraviolet carcinoma and sar coma of the skin of albino and pigmented mice and rats is readily accomplished, es t --i pecially in those parts of the skin which have a sparse hairy coat (feet, ears, and ham 43.3 eyelids ). The wrinkled, thick, and cornified Incidence of skin of hairless rats of the rhinoceros type, by region d race skin cancer per 100,000 population Male 1Female however, appears to be refractory to the carcinogenic action of ultraviolet rays (Hueper104' 106). t 23 18 116 70 Ionizing radiation (irradiation, pa*m radioactive chemicals) 41 34 Among the numerous exogenous carcino te 38 28 gens, ionizing radiation seems to be the 5 4 only universal carcinogen, i.e., capable of producing cancer in all species, known so far. Although it has remained undeter less affected by solar mined whether the carcinogenic action is >osed skin (Allison and the result of a physical effect upon cell con erican and African Nc- stituents or represents a radiochemical ef less totally resistant un- fect upon cellular chemical components, 10s; the latter exhibit a the general biologic characteristics of can lographic distribution of cer evoked in man and animals by ionizing al with that seen in fair- radiation, i.e., length of latent period, cu ite people ( Shapiro21'). mulative effects of repeated exposures, ereditary hypersensitivity precancerous alterations in tissues, ambi lop xeroderma pigment- valent reactions in tissues (atrophy, de ancer during childhood generation, necrosis-hyperplasia, atypical i early in life in 100 per carcinomatoid and leukemoid reactions, cancer), are identical to those observed the amount of pigment with cancer elicited by chemical carcino ve thickness of the epi- gens. The reported appearance of cancer its comified layer, and involving the skin or the blood-forming possibly also the quality tissues after a single and relatively brief d act as natural protec- exposure to ionizing radiation seems to i determine the observed favor the chemical theory of radiation car ptibility to solar cancer of cinogenesis since the circumstances accom embers of different races, panying the response resemble closely those ncertain whether the car- seen in chemical carcinogenesis associated )f ultraviolet radiation is 3with a depot effect from a carcinogen. While a-ray and 3-ray emitters have pro duced cancer in animals, the carcinogenic action of these rays on man, while likely, is not definitely established. Cancer of the skin on the basis of chronic radiodermatitis has been observed after occupational, medicinal, and cosmetic ex posure to x-rays and y-rays. Cancerous sequelae have appeared in the skin with chronic radiodermatitis in 10 to 33 per cent of cases (Hueper126). Sulzberger and asso ciates226 have noted that chronic radioder matitis of the human skin did not develop as long as the total dose of ionizing rays remained below 1,400 r. In fact, skin re ceiving ionizing radiation within this range exhibited a lower incidence of cutaneous cancer, according to their observations, than untreated sldn of control cases. Since a plausible explanation for this paradoxic behavior of irradiated and nonirradiated skin is lacking, a competent and compre hensive re-examination of the problem of the minimal effective carcinogenic dose of ionizing radiation to the skin is indicated. Cancer of the bone has been seen after transcutaneous irradiation of the tissues overlying the bones for benign conditions in the overlying soft tissues and has been noted in painters of luminous dials after an ingestion of radioactive chemicals (Martland169; Aub and associates8). Numerous experimental results confirm these human observations. It was possible to produce osteogenic sarcoma by x-irradiation of the bones, by implantation of radioactive chemicals into bones, and by feeding those radioactive chemicals which are "bone seekers" ( Schuerch and Uehlinger210; Hue per and associates131). Cancer of the lung in radioactive cobalt ore miners in Schneeberg, recognized in 1879, represents the first occupational can cer of the lung placed on record (Hue per126; Lorenz160; Peller191). The occurrence of similar cancer among pitchblende miners in Joachimsthal noted in 1926 furnished im portant evidence supporting a radioactive cause of this cancer (Loewy161). Recent epidemiologic studies, initiated in 1948 by ' C5U >>1 O0 .1I O I cd => ->QJ T033 O03 I 02.1 03 F L C I E co 03 <0D.1I .c>ozNrI CcD o T0D3 03 I -Q 7gc5 ro 2 CD JOD OO <13 Eo.i__ F go I `Ooo .Ii 0co3 f $ 00c33oIIl a/3lI x: C 15 "0i--3 I 03 I E 03 I W-V ^ 804 Hueper .... - irfiffl Clinical Pharmacology and Therapeutics Table XXV. Latent periods of occupational cancer Organ and agent Skin Arsenic Medicinal Occupational Tar Creosote oil Mineral oil Crude paraffin oil Solar radiation X-radiation Average Range of latent latent period (yr.) period (yr.) 18 25 20-24 25 50-54 15-18 20-30 7 3-40 4-46 1-50 15-40 4-75 3-35 15-40 1-12 Lung Asbestos Chromates Nickel Tar fumes Ionizing radiation 18 . 15 22 16 25-35 15-21 5-47 6-30 9-23 7-50 Bladder Aromatic amines 11-15 2-40 Hueper among the uranium ore miners in the Colorado Plateau and subsequently as sumed and continued by other investiga tors, have yielded data indicating that a similar lung cancer hazard apparently exists for members of this worker group (Archer and colleagues6). Since experimental stud ies on the production of pulmonary cancer in rats instilled with radioactive material intratracheally have demonstrated that inhaled radioactive dust and gases can produce carcinoma of the lung, there is scarcely longer any doubt concerning the radioactive origin of lung cancer in man (Lisco and Finkel159; Cember and Wat son35). It is apparent that the cancer hazard to the lung for such workers in mines and mills is high, since about 70 per cent of all deaths among the miners of Schneeberg were due to lung cancer, while this per centage stood at 45 per cent for the miners in Joachimsthal. Whether intravenously administered thorium dioxide solution may have caused cancer of the lung in some cases is at pres ent somewhat doubtful. On the other hand, it is established that thorium dioxide di rectly injected for diagnostic purposes into the maxillary sinus has given rise in 3 cases to carcinoma of the mucosal lining (Hue per128). There are on record 4 cases of squamous cell carcinoma of this sinus among luminous dial painters who inhaled radon and thoron (Aub and associates8). Human and animal evidence obtained mainly during the last decade has estab lished the fact that a causal relation exists between leukemia in man and animals and radiation sustained by exposure to radium and Thorotrast and by contact with oc cupational and therapeutic x-rays and ra dioactive chemicals generated during the explosion of the atom bombs on Hiroshima and Nagasaki (Heyssell and colleagues23; Cronkite, Moloney, and Bond41; Warren245; Hueper102,112; Peller and Pick196; Watanabe247; Court Brown and Doll40; Furth and Furth68). It is still uncertain whether or not exposure to ionizing radiation of the fetus in utero may result in subsequent de velopment of a leukemic reaction during infancy. The appearance of a leukemic re action in exposed individuals has been pre ceded in some instances by a primary aplastic phase followed by a secondary hyperplastic phase characterized by leu kocytosis, monocytosis, erythrocytosis, and finally leukemoid reaction. The minimal latent period of leukemia resulting from the atom bomb was 3 years, while the aver age latent period of occupational radia tion leukemia, especially that found among physicians and radiologists, was 7 to 19 years. Such variations in the length of the latent or induction period of radia tion leukemia are well within the range of fluctuations observed with other environ mental cancer (Table XXV) and are de pendent in part on the relative potency of the particular carcinogen, in part on the intensity and duration of exposure to it, and in part on variations in individual suscep tibility. There has been an increase in the fre quency of leukemia in several countries and regions during recent decades. While this e ; - ................... Volume 3 Number 6 phenomenon has be< observers to effects out, there is at prese: in support of such there is no reliable ii mal leukemogenic c tion. Moreover, the chemicals possessing pecially agranulocy dustry, medicine, ai make it likely that s might possess leuke thus have contribut in leukemia. Exposure to iono incriminated in the other organs and ti nostic use of Thon sponsible for the o and sarcoma of the sinus, lung, and br< rium dioxide was which it was retai dates225; Feme an formation is avail, and site distribute workers and resid Brazil and India i containing thorium While the diagr iodine has given r cancer of the thyro established whethi followed upon an iodine generated clear material or r of nuclear power secondarily into dally milk. It is lil radioactive phospl therapeutic mana has caused or coi ment of leukemia quently as a late loid disorder. Summary The growth of . genic spectrum < suspected, and j Clinical Pharmacology and Therapeutics : 3J Volume 3 Number 6 - ..... ..................... . Symposium: Chemical carcinogenesis ,^ u ^ - 805 rium dioxide ditic purposes into en rise in 3 cases >sal lining (Huecord 4 cases of a of this sinus ters who inhaled id associates8), idence obtained ecade has estabsal relation exists and animals and oosure to radium contact with ocic x-rays and rarated during the lbs on Hiroshima and colleagues23; ond11; Warren245; 1 Pick186; Watald Doll40; Furth ncertain whether g radiation of the n subsequent de reaction during of a leukemic relals has been pres by a primary by a secondary' icterized by leuythrocytosis, and m. The minimal a resulting from rs, while the avercupational radia lly that found Ldiologists, was 7 ons in the length i period of radiaithin the range of h other environXV) and are de'lative potency of l, in part on the xposure to it, and individual suscep- orease in the freeral countries and cades. While this phenomenon has been attributed by some observers to effects frorn radioactive fall out, there is at present inadequate evidence in support of such a contention because there is no reliable information on the mini mal leukemogenic dose of ionizing radia tion. Moreover, the introduction of many chemicals possessing a myelotoxic and es pecially agranulocytogenic action into in dustry, medicine, and the human economy make it likely that some of these chemicals might possess leukemogenic properties and thus have contributed to the observed rise in leukemia. Exposure to ionizing radiation has been incriminated in the production of cancer of other organs and tissues. The former diag nostic use of Thorotrast thus has been re sponsible for the occurrence of carcinoma and sarcoma of the liver, kidney, maxillary sinus, lung, and breast, into which the tho rium dioxide was either injected or in which it was retained (Suckow and asso ciates225; Feine and Leonhardt59). No in formation is available on the occurrence and site distribution of cancer among the workers and residents of those areas in Brazil and India in which monazite sand containing thorium is found and mined. While the diagnostic fuse of radioactive iodine has given rise to the occurrence of cancer of the thyroid, it has not as yet been established whether an identical effect has followed upon an exposure to radioactive iodine generated by the explosion of nu clear material or released during accidents of nuclear power plants and incorporated secondarily into human foodstuffs, espe cially milk. It is likewise uncertain whether radioactive phosphorus administered in the therapeutic management of polycythemia has caused or contributed to the develop ment of leukemia observed not too infre quently as a late complication of this mye loid disorder. Summary The growth of an environmental carcino genic spectrum composed of recognized, suspected, and potential human carcino gens of chemical, physical, and parasitic nature should provide an impressive warn ing to all concerned with the maintenance and protection of the health and well-being of mankind to exert all possible effort to develop methods and facilities by which sources of production, channels of dissemi nation, routes of exposure, prospective and actual target organs and tissues, and num ber and types of individuals exposed to natural and man-made carcinogens can be more readily and reliably identified. Since most environmental carcinogens have been introduced into the human ecology with the advent of the industrial era and because man has therefore had insuffi cient time to develop any defensive adapta tion reactions to the numerous synthetic' components of the environmental carcino genic spectrum, it is essential that, where possible, human contact with environmental carcinogens be totally eliminated or, when ever such a stringent measure appears im practical or impossible, reduced to a mini mum with respect to degree, frequency, duration, and number of persons exposed. Needless and reckless introduction of car cinogens into consumer goods, water, air, and soil is bound to lead to an epidemic of environmental cancer the course of which, once set in motion, will resist the prophy lactic or protective anticarcinogenic mea sures now available. While the presently available methods of identifying carcinogenic agents are admit tedly slow and not totally adequate, experi mental observations and their implications in man demand that first and dominant consideration be given to the protection of the community against actual or potential cancer hazards. In such a decision, the health and life of the general public should receive the benefit of doubt without any reservation. The determination of carcinogenic prop erties in weak carcinogens and of the type and degree of cancer hazards to man cre ated by them, especially as far as chemical carcinogens are concerned, may present considerable difficulty because their action Thematerial on thispage wascopied fromthecollection of the National Libraryof Medicine_b^^^Hrdjgartj^andjTga^_be_rotectedb^U;S^CopyrighHaw^ may be direct or indirect and may be pri mary or secondary, as well. For these rea sons, the control of cancer hazards from chemical carcinogens may prove to be much less readily attainable than that of radioactive carcinogens. Toxic properties of chemicals are unre lated to their carcinogenic ones. Chronic toxicity tests, therefore, do not yield any reliable information or any possible car cinogenic qualities of the chemicals tested. References , 1. Alexander, P., and Homing, E. S.: Observa tions on the Oppenheimer method of inducing tumours by subcutaneous implantation of plastic films, in Ciba Foundation Symposium on Carcinogenesis, Boston, 1959, Little, Brown & Company, pp. 17-25. 2. Allen, M. J., Boyland, E., Dukes, C. E., Horn ing, E. S., and Watson, J. G.: Cancer of the urinary bladder induced in mice with metab olites of aromatic amines and tryptophane, Brit. J. Cancer 11:212-228, 1957. 3. Allison, S. D., and Wong, K. L.: Skin cancer. Some ethnic differences, A.M.A. Arch. Dermat. 76:737-739, 1957. 4. Alwens, W .: Lungenkrebs durch Arbeit in Chromat herstellenden Betrieben, Proceedings of the 8th International Congress on Acci dent Medicine and Occupational Diseases, vol. II, Leipzig, i939, Georg Thieme, p. 973. 5. Amor, A. J.: Growths of the respiratory tract.' Proceedings of the 8th International Congress on Accident Medicine and Occupational Dis eases, vol. II, Leipzig, 1939, Georg Thieme, p. 941. 6. Archer, V. E., Magnuson, H. J., Holaday, D. A., and Lawrence, P. A.: Hazards to health in uranium mining and milling, J. Occup. Med. 4:55-60, 1962. 7. Argus, M. F., and Hoch-Ligeti, C.: Compara tive study of the carcinogenic activity of nitrosamines, J. Nat. Cancer Inst. 27:695-709, 1961. 8. Aub, J. C., Evans, R. D., Hempelmann, L. H., and Martland, H. S.: Late effects of inter nally-deposited radioactive materials in man, Medicine 31:221-329, 1952. 9. Baader, E. W .: Aminoberufskrebse bei F r bern, Arch. Gewerbepath. u. Gewerbehyg. 18:410-415, 1961. 10. Baetjer, A. M.: Relation of chromium to health, in Udy, M. J., editor: Chromium, vol. I, New York, 1956, Reinhold Publishing Corporation, pp. 76-104. 11. Balo, J.: Lungenkarzinom und Lungena denom, Budapest, 1957, Verlag der Un garischen Akademie der Wissenschaften. 12. Bauer, K. H.: Das Krebsproblem, Berlin, 1949, Springer Verlag. 13. Beebe, G. W .: Lung cancer in World War I veterans: Possible relation to mustard-gas in jury and 1918 influenza epidemic, J. Nat. Cancer Inst. 25:1231-1252, 1960. 14. Berenblum, I.: Liquor picis carbonis; a car cinogenic agent, Brit. M. J. 2:601, 1948. 15. Bidstrup, P. L., and Case, R. A. M.: Car cinoma of the lung in workmen in the bichromates-producing industry in Great Britain, Brit. J. Indust. Med. 13:260-264, 1956. 16. Bhme, A.: Asbestose und Lungencarcinom, Arch. Gewerbepath. u. Gewerbehyg. 17:384395, 457-462, 1959. 17. Bohlig, H., Jacob, G., and Mller, H.: Die Asbestose der Lungen, Stuttgart, 1960, Georg Thieme, Verlag. 18. Bonser, G. M., Clayson, D. B., and Juli, J. W.: Induction of tumours with l-(2-tolylazo)-2naphthol (oil orange TX), Nature, London 174:879, 1954. 19. Borneff, J., and Fischer, R.: Cancerogene Substanzen im Wasser und Boden. VIII. Un tersuchungen an Filter-Aktivkohle nach Ver wendung im Wasserwerk, Arch. Hyg. 146: 1-16,1962. 20. Bourne, H., and Rushin, W. R., Atmospheric polution in the vicinity of a chromate plant, Indust. med. 19:568-569, 1950. 21. Boyd, J. T., and Doll, R., Gastro-intestinal cancer and the use of liquid paraffin, Brit. J. Cancer 8:231-237, 1954. 22. Becker, B. J. P.: Malignant disease in indus try, Leech 22:11-14, 1951. 23. Boyland, E.: Discussion remark to Hackmann, C.: Problems of testing preparations for car cinogenic properties in the chemical industry, Ciba Foundation Symposium, Boston, 1960, Little, Brown & Company, pp. 308-322. 24. Boyland, E., and Watson, G.: 3-Hydroxyanthranilic acid, a carcinogen produced by en dogenous metabolism, Nature, London 177: 837-838, 1956. 25. Braun, P., Guillerm, J., Pierson, B., Lacoste, J., and Sadoul, P.: A propos du cancer bronchique chez Ies mineurs de fer, Rev., ed. du Nancy 85:702-708, 1960. 26. Braun, O., and Truan, P .: An epidemiological study of lung cancer in asbestos miners, A.M.A. Arch. Indust. Health 17:634-653, 1958. 27. Browning, E.: Occupational leukaemia, in Raven, R. W .: Cancer, vol. Ill, London, 1958, Butterworth & Co., Ltd., pp. 287-310. 28. Brockbank, E., and Stopford, J. S. B.: Scrotal cancer in cotton mule spinners, Brit. M. J2:993-995, 1927. 29. Buess, H.: Beobn eine wenig bekan bedingten Chrom acta 17:104-136, ] 30. Butlin, H. T..- Cai ney sweeps and 66-68, 1892. 31. Blum, H. F..- On induction by ulti Cancer Inst. 11:41 32. Cartier, P .: Some bestosis in mine a dust. Health 11:2( 33. Cardon, S. Z., Alv. Hitchcock, R.: 3,4 of cigarette papei Brit. J. Cancer 10 34. Case, R. A. M., ai poisoning, chronic cer. An investigati poisoning by must, might be a factor plasia, Brit. J. Pre 1955. 35. 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