Environmental Carcinogenesis and Cancers*

W. C. HuEPER

(National Cancer Institute, Bethesda, Md.)

I. THE NATURE AND SCOPE OF ENVIRON- dustrial effluents and in automobile exhaust as MENTAL CANCER HAZARDS well as associated with cigarette smoking. Almost ~00 years have passed since the first 3. The demonstration of a considerable and ris- environmental carcinogen, coal soot, was recog- ing number of carcinogenic chemicals used as in- nized as the cause of cancer of the human skin. tentional and nonintentional food additives and The environmental carcinogenic spectrum com- produced in the food because of certain processing posed of accepted, suspected, and potentially car- procedures as well as employed as ingredients, or cinogenic agents present in the natural and artifi- present as impurities in drugs, cosmetics, economic cial human environment has grown considerably poisons, and other consumer goods. during the intervening years. Despite the impres- It is significant that, in response to these devel- sive increase therefrom, resulting in the number, opments, federal, state and municipal legislatures diversity, and spread of environmental cancer and public health authorities have enacted laws or hazards among the general and especially the in- issued regulations during the last decade providing dustrially employed and urban populations and increased protection of the general public against despite the ready availability of an abundant cancer hazards resulting from an environmental amount of reliable facts and observations on the dissemination of carcinogens in foods, drugs, and causation of human cancers by environmental cosmetics and in effluents of industrial plants and agents, governmental, private, and professional automobiles. For the first time during the modern parties directly concerned with the protection and industrial era, protective legal measures which, up maintenance of human health have displayed until to that time, had been applied to occupational recently an astounding indifference and aloofness cancer hazards only were extended to those of gen- toward this important aspect of the general cancer eral environmental nature. Formal recognition was problem. A partial awakening from this general given thereby to the long neglected fact that many state of lethargy has, however, occurred during the of the known environmental carcinogens initially last decade because of the impact produced by the encountered in certain occupational activities are strong reaction of the general public to widely dis- subsequently being introduced into the general seminated information relative to the increasing human environment as pollutants of the air, water, and probably dangerous contamination of the hu- and soil and as constituents and impurities of man environment and of many products of daily many consumer goods, and are creating through consumption with carcinogenic agents. this mechanism a serious public health problem. This rising concern with mainly industry-relat- While mankind has had contact, during the ed environmental cancer hazard was aroused by greater part of its existence on earth, with a num- three recent developments: ber of natural as well as man-made environmental 1. The growing contamination of air, water, carcinogens such as sunlight, ionizing radiations, and soil as well as of foodstuffs with radioactive arsenicals, infections with Schistosoma hematobi- matter from activities in the nuclear energy field. um, soot, and possibly tobacco products, the hu- ~. The increasing pollution of the inhaled air man race has had a chance through the thousands with various chemical carcinogens contained in in- of years of exposure to develop against these car- * Based upon a paper presented at a Symposium on the cinogens some defense mechanisms in the form of Current Status of Cancer Research at a meeting of the Ameri- detoxication and chemoimmunity reactions and can Association for Cancer Research in Atlantic City on other protective biologic responses, such as in- April 8, 1961. creased pigmentation. Mankind, on the other Received for publication March 17, 1961. hand, has not had any opportunities for develop- 84~

ing any reactions of biologic adaptation to the en- tion products, such as tubercles and gummas, and vironmental carcinogens of the modern industrial then to use such information for devising chemical era, because of their introduction during a period means against some of the biologic mechanisms or of only a few decades. The protection of modern some special constituents found in such circum- mankind against the growing number of these scribed anatomic reaction products, or for develop- man-made chemical and physical carcinogens ing diagnostic tests for infectious granulomas, ir- must rely, therefore, entirely on methods and respective of their specific etiology. measures artificially devised. Because of the past failure to obtain, by the ap- The extent to which the contamination of the plication of this biologic concept of cancer, any re- human environment with new artificial, man-made liable specific diagnostic test for cancer and any physical and chemical carcinogens has progressed effective chemotherapeutic agent against cancer- during the past century is strikingly illustrated by ous tissue, one is left wondering whether it is not the long list of known, suspected, and potential appropriate and timely to put to work in this re- human carcinogens, the various routes of contact search the many facts and observations on envi- with them, the numerous opportunities of expo- ronmental carcinogenesis and cancers, and to re- sure to them, the different sites of cancers pro- turn to those scientific principles which brought duced by them, and the progressive march of occu- success to the control of infectious diseases. The pational cancers through the individual countries advisability to explore more fully the potentialities subsequent to the development of an industrial TABLE 1 economy (Table 1) (4, 17, ~, 56, 68-70, 7~, 73). The presently known spectrum of recognized, sus- TIMETABLE OF THE DISCOVERY OF AROMATIC AMINE pected, and potential human carcinogens exhibits CANCERS OF TIIE BLADDER IN DIFFERENT a remarkable degree of diversity and complexity COUNTRIES of its component members. It is comprised of several parasitic and viral organisms, of a growing Country Discoverer Year number of carbon and silicon macromolecular Germany Rehn 1895 polymerized chemicals, of various specific organic Switzerland Schedler 1905 aromatic and aliphatic chemicals, of several metals Great Britain ROSS 1918 Russia Rosenbaum & Gottlieb 1926 and minerals, and of various nonionizing and ion- Austria Schtiller 1932 izing radiations which exert an actinochemical United States Ferguson el al. 1934 Italy di Maio 1936 action on the chemical constituents of tissues being .Japan Nagayo & Kinosita 1940 exposed to these radiations. France Billiard-Duchesne 1946 It has often been argued in the past that, because of the multitude and diversity of carcinogenic agents, cancers do not represent an anatomic of the etiology-specific concept of cancer for its reaction product of tissues to a specific carcino- diagnosis, prophylaxis, and treatment is suggested genic agent which retains in its biologic respon- by the many similarities existing between the siveness and properties a direct relation to the spectra of environmental carcinogens and of specific causal agent. The prevailing concept con- pathogenic microorganisms. siders cancers as biologic manifestations which de- Both major systems of disease-producing agents velop in response to carcinogenic stimuli and include a wide range of different component mem- which assume, once produced, complete biologic bers varying markedly in their degree of potency independence from the causal agent, thereby be- or virulence among each other--i.e., from produc- coming disease entities per se. Almost the entire ing a 100 per cent attack rate in the population to modern diagnostic and chemotherapeutic research the risk of affecting only a fraction of it or the ex- in cancer control is based on this concept. This ceptional individual. There exist, moreover, definite approach is rather surprising and unique in the and epidemiologically important differences in annals of medicine and contrasts sharply with the their pathogenicity or their carcinogenicity, re- efforts made in the past for controlling infectious spectively, for different species, strains, races, and diseases. These efforts were directed toward influ- individuals of the same race or strain. encing the causative agents and their toxic prod- This observation on the significance of the host ucts by biologic and chemical means. It has not reaction for the occurrence of a carcinogenic re- occurred to investigators engaged in such tasks to sponse has led to the contention that the host rela- attempt the development of curative agents tionship might be more important in this respect against these diseases by first obtaining detailed than the carcinogen proper and that, therefore, a biochemical information on their anatomic reae- control of cancer hazards might be achieved by

modifying in the right direction the constitution- determining the activity of pathogenic microor- ally conditioned reaction of the host organism to ganisms, such as, for instance, tubercle bacilli, in the carcinogen. It may be pointed out in this con- the host organism. nection that despite distinct congenitally or From these considerations it may, therefore, ap- acquired constitutional differences among equally pear wise to pattern the future attack on environ- exposed individuals, the realization of a cancerous mental cancer hazards on the principles and meth- reaction or of a tissue response to an infectious ods of investigation and the concepts of biologic agent, like the tubercle bacillus, is fundamentally mechanisms employed in past studies of the causa- determined by the action of the pathogen. With- tion and the control of infectious diseases. out the primary action of the pathogen the host reaction is immaterial. Past experiences with con- II. FUNDAMENTAL ASPECTS OF ENVI- stitutionally conditioned or genetic diseases have, RONMENTAL CARCINOGENESIS moreover, shown that their control is most diffi- It is one of the fortuitous and fortunate by- cult. There is also no sound scientific reason in products of the recent emergence and growing ap- support of the recently revived, speculative allega- preciation of environmental cancer hazards as tion that, in contrast to pathogenic microorgan- major public health problems that many of their isms, environmental chemical carcinogens are not scientifically and practically important but often primary carcinogens but act in the process of car- ill defined and badly understood facets werc placed cinogenesis merely as agents triggering the specific into sharper focus. The immediate need for con- action of genes or even viruses. The entire symp- siderably increased and comprehensive investiga- tomatic pattern of manifestations associated with tions on many fundamental and applied aspects environmental and experimental chemical and of the cnvironmental cancer problem became physical carcinogenesis militates against the rather painfully apparent during the recent hear- validity of such a concept. ings of several Congressional Committees (11-16) Additional similarities between environmental which led to the inclusion of the Delaney cancer carcinogens and pathogenic microorganisms are clausc into thc laws enactcd in relation to health related to the fact that both are capable under hazards from food additives and food and cos- certain conditions of eliciting chemo-specific aller- tactic colors. The various points of dispute which gic reactions, indicating thereby symptomatical- arosc at thcse occasions illuminated thc large gaps ly the occurrence of an interaction of the two in factual knowledge on environmental cancers in types of pathogens with proteins of the host or- man and on carcinogenesis by environmental ganism. The degree of response, as well as the site agcnts in experimental animals and demonstratcd of reaction in the host for both pathogens, depends the appreciable uncertainty which cxists regarding to some extent on the particular route of contact, somc of the most important scientific concepts on on the intensity and duration of exposure, and on these subjects. the modifying influences which other exogenous factors, such as diet or ehemotoxie manifestations, DEFINITION OF A CARCI:NOGEN might exert on the realization and type of tissue During these discussions, as at other occasions, changes resulting. Finally, it may be noted that difficulties were encountered in arriving at a gen- man is in contact throughout his entire lifetime not erally acceptable definition of a carcinogen. Al- only with a variety of microorganisms (some with though a definition of this basic aspect of environ- known pathogenicity to man) without developing mental carcinogenesis which fulfills all scientific re- from all exposures and in all instances an infectious quirements does not exist at the present time, it is disease, but also to diverse chemical and physical nevertheless possible to devise a definition which carcinogens acting on him from various sources is satisfactory for most scientific conditions and and at different times and failing to elicit during which is practical and applicable for medicolegal his lifetime, in most instances, a cancerous re- purposes. sponse of some tissue. It seems that the total effec- Carcinogens may be defined as chemical and tive carcinogenic burden of an individual thus is, physical agents which are capable, under proper in part, determined by the various factors men- conditions of exposure, of producing in animals, tioned; to another part it seems to depend upon including man, cancers which would not occur the degree of synergistic, antagonistic, or indiffer- without the intervention of thesc agents. Carcino- ent interaction of the various carcinogens and gens thus do not merely produce a significant in- upon their interplay with noneareinogenie endoge- crease in cancer incidence when administered at non s and exogenous factors acting in the host or- any dosage level, by any route of administration, ganism. Similar interrelationships are operating in and to any spccies or strain, but elicit cancers lo-

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1961 American Association for Cancer Research. HuEeErt--Environmental Carcinogenesis 845 cated ordinarily at sites associated with induced poration of these carcinogenic chemicals into hu- carcinogenesis. This rather inclusive definition of man foodstuffs. a carcinogen which is applicable also to so-called The same considerations apparently have re- conditional (Steiner) (75), (Nau) (57), functional cently been applied by the Food and Drug Adminis- (Hueper) (33, 38), hormone-dependent (Morris) tration and by the Council on Drugs (9) of the (53), and indirect carcinogens avoids the difficulties American Medical Association in justifying the connected with the use of definitions containing continued parenteral medicinal use of an iron- more or less arbitrary restrictions. dextran complex (Imferon), although several It is obvious that several physiologically active British investigators, including Haddow (~6), had hormones and nutrients such as estrogens, iron, shown that repeated intramuscular injection of cobalt, and, possibly, selenium must be considered large doses of this preparation into rats and mice according to this definition as carcinogens. Their produced sarcomas at the site of deposition, and carcinogenic properties may become manifest if despite the fact that Imferon had been withdrawn these substances are produced in or introduced in- from the British market. In fact, the initial but to the organism in abnormal amounts or under later revoked withdrawal of Imferon from the abnormal circumstances, such as those prevailing American market was not based on an application at times under occupational, medicinal, or dietary of the Delaney cancer clause to the Food Additive exposures, or created under experimental condi- Amendment. Only time will tell whether or not an tions. Since the physiologic nature of these chemi- arbitrary, unwise, and perhaps expedient interpre- cals has been advanced as an argument against tation of experimental evidence and the refusal to their role as carcinogens and has been used for sup- learn from previous experiences may not result in porting the demand that they be exempted from the repetition of a rather disastrous situation simi- any legal restrictions as food additives and con- lar to that which developed during the past decade taminants, it may be pointed out that chemicals of as a sequela of the ill considered use of thorium animate and inanimate origin occurring in and dioxide in past decades. produced by nature are in no way superior to or It is noteworthy that, according to observations different from those made by man in carcinogenic made by investigators of the Food and Drug Ad- respects (ultraviolet and ionizing radiations, ar- ministration (Nelson et al.) (58), which for many senicals, chromium, nickel, asbestos, ergot alkaloid, years had employed this screening technic, only senecio alkaloids, chili, crude petroleum, viruses). some, but not all, of the various subcutaneously The claim has recently been advanced by sever- administered food dyes elicited sarcomas at the al investigators (Eckardt [19], Bonser 1) that sar- site of deposition. Evidence obtained on several comas produced in rats at the site of the subcuta- thousand rats which received different chemicals neous introduction of test materials of any kind by the subcutaneous, intramuscular, intrapleural, represent by themselves not adequate proof for the intraperitoneal, and intravenous routes have carcinogenicity of the substances eliciting such clearly demonstrated, moreover, that the mere cancers. Such allegations have become, during re- presence of a mechanically irritating material in cent years, of more than purely scientific impor- the connective tissue of rats does not provide a tance, because they have been employed to dis- carcinogenic stimulus unless the chemical intro- credit the carcinogenic significance of several duced possesses carcinogenic properties (Hueper chemicals (dyes, plastics, paraffin, etc.) which and Payne [40]; Hueper [3~, 35, 86]). It has been elicited cancers in rats and which are present in found, furthermore, that many of the chemicals consumer goods. The legal objections against their showing carcinogenic properties when given to use as food additives were thereby removed in rats by the subcutaneous route also produce sar- some instances. The Food and Drug Administra- comas in mice under identical experimental con- tion, U.S. Department of Health, Education and ditions (Payne [63, 64]; Hueper and Payne [39]). Welfare, for instance, adopted this concept some In fact, a sarcomatogenic action of plastics implanted into the subcutaneous tissue is not re- time ago in its interpretation of the legal signifi- stricted to rats and mice but has also been noted cance of the sarcomas produced in the subcutane- in hamsters. ous tissue of rats given injections repeatedly of It can scarcely be maintained that the objec- various food dyes (light green, SF, brilliant blue, tions raised against the carcinogenic significance fast green) and with carboxymethylcellulose, and of tissue responses produced by chemicals in the has for this reason permitted the continued incor- connective tissue of rats should be limited to con- 1 Personal communication, Dr. G. Bonser, University of nective tissue located in the subcutaneous area. Leeds, Leeds, Eng. They cannot plausibly be applied to other mesen-

chymatous or epithelial tissues of the rat, such as duction in which and by which the carcinogenic epidermis, muscle tissue, mucosal epithelium of property of the test material became manifest. the bladder and liver, for which, in part, similar Because of the highly defective information differences in species-specific susceptibility to car- available on the target organ of the carcinogenic cinogens have been noted. Despite the need for action of chemicals tested in animals by various additional information on these aspects of envi- routes, the adoption of such a classification of car- ronmental and experimental carcinogenesis, it cinogens and, particularly, its practical applica- would be most unwise to deny that the formation tion for the determination of potential cancer haz- of subcutaneous sarcomas in rats following a sub- ards in man is unwarranted at this time. Under the cutaneous deposition or repeated introduction of prevailing conditions decisions based on the above some test material is not an indication of the car- principles would reflect mainly lack of pertinent cinogenic property of the chemical tested (Hueper factual information and would not be derived from and Payne [39, 40]; Hueper [3~, 35, 36]). concrete positive or negative evidence obtained The adoption of such a thesis as a matter of from properly designed experiments. scientific policy and experimental practice would There exist only some fragmentary data con- indeed lead to an abandonment of the subcutane- cerning such relationships which are useful in these ous route of administration of test materials in all respects. species. Since such a procedure has practically Observations in man and animals indicate that been suggested in a recent treatise (Publ. 749) (e3) agents causing cancer of the skin, such as arseni- on technics suitable for the experimental evaluation cals, mustard gas, and radioactive chemicals, may of carcinogenic hazards from the use of food addi- when inhaled produce cancer of the lung. Arseni- tives prepared by the Food Protection Committee, cals and radioactive chemicals and possibly also it is appropriate to emphasize that such advice is mineral oils, when ingested, may elicit cancers of scientifically unsound and practically operating in the digestive tract, such as the liver and the in- favor of the inclusion of carcinogens into the gen- testine or of other nondigestive organs, such as the eral food supply as advocated by some represent- bones, respectively. Whereas benzidine, 4-amino- atives of the food processing industries as well as diphenyl, and several of its derivatives which are by some of their scientific sympathizers and con- bladder carcinogens to man and dogs, when sub- sultants. cutaneously injected into rats, have given rise to Closely related to the controversy of carcino- the development of carcinomas of the intestine, genic pi'operties, in general, of environmental evidence is lacking whether or not a similar effect chemicals is the dispute whether or not the dem- can be produced in rats or in other species when onstration of carcinogenic responses in animals or such chemicals are fed, although it is suspected man from chemicals applied to the skin or injected that benzidine may elicit, under occupational con- into the subcutaneous tissue represents a valid or ditions of exposure in man, not only bladder car- probable indication that the test material may cinomas but also carcinomas of other organs, such exert, a similar effect upon the other tissues of con- as the intestine and lung. Since, under such circum- tact in the host organism, especially when it is stances, benzidine penetrates the skin, is inhaled, either inhaled, such as cigarette smoke, or ingest- and is ingested, it is not possible to state whether ed, such as food additives. In fact, the demand has such multifocal effects are attributable to the in- been made to distinguish between universal car- troduction of benzidine through one or several of cinogens, such as ionizing radiations and possibly those routes. ~-acetylaminofluorene, capable of producing can- General experimental experience indicates that cers in all types of tissues upon proper exposure, the respiratory and digestive systems of rodents and carcinogens whose specific action is limited to are apparently less susceptible to the action of vari- certain tissues and organs and whose local action ous human and experimental carcinogens than depends in part on the route of introduction of the those of man. Because of the distinct limitations carcinogen, in part upon special tissue affinities. to be placed upon the value of results obtained by The majority of the known carcinogenic chemi- the introduction of test materials through these cals, therefore, would evidently belong to the lat- routes in experimental animals, it appears to be ter class, although most of them have not been most unwise, if not dangerous, to attach any deci- adequately tested in this respect. The designation sive importance as to their significance to human of a chemical as a carcinogen, according to this cancer hazards on a negative outcome of tests in concept, would have to be specified and comple- which the alimentary and respiratory routes were mented by the additional information on the par- employed. At the present state of our knowledge ticular species, strain, tissue, and route of intro- on these phases of experimental carcinogenesis the

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1961 American Association for Cancer Research. HuEPER--Environmental Carcinogenesis 847 apparent inability of a chemical given by mouth chromates, shale oil, hydrogenated coal oils, coffee to produce cancers in experimental animals does soot, 8,4-benzpyrene), when subcutaneously or not justify the conclusion that such a chemical intramuscularly introduced in rats and mice, will does not exert such an effect in man and thus is not produce cancers only at the site of administration a dietary carcinogen. but often do not form metastases, although they As long as these and other methodological un- show extensive infiltrative and destructive growth certainties concerning the identification of carcino- and often a high degree of anaplasia (Hueper and gens prevail, it is advisable, as a matter of wise co-workers [3~, 35, 36, 39, 40, 65]). precaution, to exclude as far as possible all envi- These observations have distinct scientific and ronmental carcinogens from contact with man so medicolegal importance since Brunner (7) recently as to avoid any subsequent epidemic-like occur- demanded that the designation of "sarcoma" rence of cancers attributable to an indiscriminate should be withheld from the malignant mesenchym- decision made 10-80 years ago. atous neoplasms which develop around subcutaneous implants of various plastics because of CRITERIA OF CANCER their low tendency to form metastases. Since the It is doubtless correct that the majority of can- majority of cancers of the bladder produced in cers occurring spontaneously or induced in man man and dogs by contact with carcinogenic aro- and animals fulfill the various criteria of cancer matic amines do not form metastases in regional developed on an empirical basis and generally ac' lymph nodes or remote organs, the absence or low cepted as characteristics of malignant neoplasms. tendency of such manifestations of discontinued It has been known, on the other hand, that excep- cancerous growth cannot be considered as a scien- tions to these rules are not infrequent. The histo- tifically sound reason for assigning to such neo- logic differential diagnosis between a squamous- plasms a special position and for placing them cell carcinoma of the skin and a keratoacanthoma, among the noncancerous growths. The carcino- both recently observed in workers having contact genic nature of the chemicals causing these cancers with hydrogenated coal oils (Sexton) (74), is often would be denied by such a decision. difficult or impossible. This distinction can be During recent years repeated attempts have made at times only on the basis of the subsequent been made to relate specific histologic types of benign or malignant course which a particular tu- cancers to a specific etiologic agent (Hueper) (34). mor assumes. Clinical experiences in coal tar work- It was, for instance, contended that all or most ers and aromatic amine workers also have shown squamous-cell carcinomas of the lung were due to that polypous growths of the skin and of the exposures to cigarette smoke and that adenocarci- bladder mucosa, respectively, presenting the gross nomas were of a different etiology. It may be appearance of cancerous reactions, may regress pointed out here that abundant observations with spontaneously (false positives) (Hueper [~]; Gold- various specific occupational respiratory carcino- blatt [~5]). Ulcerative lesions in the skin of mon- gens attest to the fact that tile same agent may keys produced by the prolonged application of elicit different histologie types of lung cancer. coal tar and exhibiting, upon histologie examina- Experiences gained with various environmental tion of biopsy material, the characteristics of epi- carcinogens tested on animals have also demon- dermoid cancers likewise may ultimately heal, de- strated the absence of correlations between these spite the continued application of the carcinogenic two aspects. Recent reports based on a detailed, if material. These observations evidently indicate not minute, histologie and histoehemieal analysis that the histologie demonstration of malignancy of hmg cancers observed in this country, such as is not always proof of the biologic malignancy of a Los Angeles, and abroad, such as Japan and Italy neoplastic lesion. (Kreyberg) (46), have, moreover, shown that the Another striking and rather frequent exception increase in lung cancers affected in these areas from the criteria characterizing cancers is repre- mainly the adenocarcinomatous variety. sented by basal-cell carcinomas of the skin, which Because of these irreconcilable discrepancies it may develop following an occupational or envi- may, therefore, be wise to investigate the possi- ronmental exposure to sunlight, coal tar, and ar- bility that variations in the general and local his- senicals. Basal-cell cancers of the skin do not pro- tologic type of cancers may depend upon the duce metastases and thereby lack one of the most speed with which a cancer develops from the tissue important properties of malignant growths. It of origin and with which it grows later in various may be pointed out in this connection that an ap- parts. It seems to be reasonable to assume that a preciable number of environmentally important cancer which develops rapidly from a tissue ex- carcinogens (asphalt, coal tar, uranium, nickel, posed to a carcinogen and not, or little, damaged

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1961 American Association for Cancer Research. 848 Cancer Research Vol. ~1, August 1961 by this agent would duplicate the original tissue complexes have so far been offered in an attempt from which it is derived--i.e., for instance, glandu- to account for the development of polymer cancers lar tissue in the bronchial mucosa. If, on the other (Hueper) (37), if one disregards the recently ad- hand, a cancer originates from a tissue which has vanced speculative assumption that some mys- undergone for some time chronic, reparatory, and terious and nonspecific forces emanating from the metaplastic alterations, it is likely that the cancer surfaces of implanted plastic films are responsible would reflect in its structure the metaplastic tissue for the neoplastic phenomena observed (Noth- from which it is derived. Such conditions may pre- durft [59]; Oppenheimer et al. [6~]). vail whenever a bronchiogenic carcinoma develops Apart from the purely scientific benefits ensuing from metaplastic areas of the bronchial mucosa af- from a better understanding of the causative fected by chronic inflammatory processes of chem- mechanism or mechanisms of carcinogenic agents, ical, bacterial, or viral nature. Similar correlations the availability of such information would be of apparently prevail in determining the predomi- distinct advantage for distinguishing between car- nant histologic type of cancers of the bladder at- cinogenic and noncarcinogenic environmental tributable to exposures to aromatic amines and to chemicals and woul(t facilitate the development of Schistosoma hematobium infections. The aromatic more efficient, more reliable, and faster screening amino cancers originating from a bladder mucosa procedures. At the present time none of the vari- which usually does not display any chronic inflam- ous theories is of any real value for this purpose. matory reactions are, as a rule, of the transitional- It is also probable that an adequate knowledge cell type. Cancers of the bladder appearing in in(ti- of the causative mechanism of environmental car- viduals suffering from chronic Schistosomiasis of cinogcns would help in the development of etiolo- this viscus associated with severe inflammatory gy-specific diagnostic procedures and of rational and leukoplakic reactions, on the other hand, are and effective prophylatic and therapeutic meas- predominantly of the squamous-cell type. ures. Since some of these carcinogens are recog- The histologic type of a particular cancer, nized human allergens, such as the various metals, therefore, seems to be the combined result of the and others arc known to form complexes with cel- relative potency of the carcinogenic action and the lular proteins (various azodyes, quinones formed reactive status of the host organism. from carcinogenic aromatic amines, carcinogenic polycyclic aromatic hydrocarbons) (Hueper [~9, CAUSATIVE ~[ECHANISMS 30]; Mayer [48]; Miller and Miller [49]; IIeidel- The various theories developed through the berger et al. [~7]; and others) and thereby may be- years concerning the causative mechanisms by come antigens, a comprehensive experimental ex- which chemicals of various types interact with ploration of a chemo-specific allergenic mechanism constituents of the cell in the canccrization process of cnviromnental carcinogenesis seems to be have been, in part, of a generalized and, by neces- worth while. Experimentation with noncarcino- sity, rather diffuse type, such as the chronic irri- genie chemicals structurally similar to carcino- tation theory, the somatic mutation theory, the genic chemicals for testing the usefulness of struc- allergic theory, the Warburg's theory of anoxic tural blockade as a prophylactic measure and for fermentation, the hypotheses concerning the role determining the importance of specific spatial con- of free radicals, peroxides, and sulfhydryl groups, figuration and qualitative and quantitative struc- and the postulate of the activation of abnormal tural factors for the interaction of exogenous and carcinogenic genes or specific viruses by carcino- endogenous agents in the cancerization process genic chemicals. Other theories are of more re- offer an additional promising approach for advanc- stricted nature applying to some specific type of ing the control of environmental cancer hazards carcinogenic chemical, such as the polycyclic aro- and cancers. matic compounds--i.e., the Pullman electronic Important facets in these efforts, which depend theory; and some structural characteristics of the in part upon a more exact and detailed informa- members of these chemical groups, as well as of tion on the causative mechanism of carcinogens, some carcinogenic aromatic amines--i.e., the for- are associated with the selection of tile proper ani- mation of ortho-hydroxymetabolites. Whereas mal species suitable for the screening of chemicals some of the general type theories have also been for carcinogenic properties and with the extrapo- used for explaining the action of carcinogenic lation of observations made in animals to man in metals, such as the sulfhydryl theory and the hy- both qualitative and quantitative respects. pothesis on the formation of intracellular protein The decisive significance which specific mctabo- complexes, only Warburg's theory of cellular lites, formed by some species but not by others, anoxia and the theory on the formation of protein possess in determining the occurrence as well as

the site of a carcinogenic response has been strik- alterations in carcinogenic properties and relative ingly illustrated by the role which ortho-hydroxy- potency of several chemicals which result from a derivatives of certain carcinogenic aromatic shift in the position and the relative length of their amines, such as fl-naphthylamine, 4-aminodi- sidechains (polycyclic aromatic hydrocarbons: phenyl, and benzidine, play in the production of benzpyrene, dibenzanthracene) and occur subse- bladder cancers in man and dogs, and in the ab- quent to the introduction of fluorine into the ring sence of such neoplastic reactions in mice and rats (aromatic amino compounds) (Miller and Miller) in which these metabolites are essentially absent. (49). The development of cancers at other sites in these The increased reliance of the modern economy species, when given the aromatic amines men- on products of the chemical industry and the tioned, on the other hand, indicates that these spe- growing awareness of the carcinogenic nature of cies apparently produce metabolites which have some of its products make an early acquisition of

TABLE TARGET ORGANS OF CANCERS PRODUCED BY AROMATIC AND AZO COMPOUNDS IN DIFFERENT SPECIES

MAN DoG RAT MOUSE CI~EMICAL Bladder Liver Intest. Bladder Liver Intest. Bladder Liver Infest. Bladder Liver Intest. Benzidine X? x x 3-Naphthylamine -Aminodiphenyl x 9-Dimethylamino- azobenzene x LAminofluorene X X X -Aeetylaminofluorene x V-Hydroxy-~', 3-azotoluene ~,S'-Dimethyl- azobenzene IN. N-Diacetyl-o- aminoazotoluene -Amino-2',8-dimethyl- azobenzene

t~cetyl-o-aminoazotoluene X X ~-Toluidine Chrysoidin ?onceau R Dil Orange XX Drange SS Ponceau 3R

an affinity to and exert a carcinogenic action on an adequate knowledge of the basic factors under- other organs such as the liver and the intestine. lying, modifying, and controlling chemical car- Because of these shifts in target organ (Table 2) cinogenesis an urgent necessity. The availability and in carcinogenic response to various aromatic of sufficient factual data which may serve as amines by different species, experimental results in guides for avoiding the development of carcino- animals would become more meaningful, as far as gens in the production of new chemical compounds man is concerned, if the fundamental biologic would protect the chemical and related industries principles underlying these fluctuations were against engaging in research which might prove known and could be systematized, permitting to be needlessly costly, when it inadvertently thereby a more valid and reliable extrapolation of leads to the development of carcinogenic com- the results of screening procedures to man than is pounds. possible and justifiable at present. Additional advantages would accrue from such POTENCY OF CARCINOGENS AND "SAFE" DOSE knowledge, not only to the study of the environ- The emphasis which has recently been placed mental cancers but also to the future development upon the determination of the absolute and com- of noncarcinogenic economically important chemi- parative potency of carcinogens in experimental cals by industry, if the reason were known for the animals, for the purpose of making educated

guesses at their so-called "safe dose" to man, has aromatic amine, namely, !~-acetylaminofluorene, resulted in uncovering the many methodological administered orally to rats, elicited cancers in difficulties existing in this respect and in demon- various organs (liver, intestine, ear duct, lung, strating the distinct lack of fundamental facts for etc.) in most of the treated rats within a year arriving at a "safe dose" which is safe for the (Bielschowsky et al. [3]; Morris et al. [54]), whereas great majority of members of the human popula- dogs given this chemical by the same route re- tions at risk--i.e., mainly the general public and quired for the development of cancers of the blad- the general consumer of industrial goods. der and of the liver a minimum exposure period of Abundant experimental experience has clearly over 5 years (Morris and Eyestone) (55). shown that the absolute tumor yield, as well as the Recent experiments with a number of hexava- length of the latent period for carcinogenesis by a lent chromium salts have shown that the physical particular carcinogen, may vary in wide limits not properties, i.e., the degree of water solubility of the only among different species but even among dif- individual compounds, control both the tumor ferent strains of the same species and among the yield and the length of latent period (Table 8). two sexes of the same strain, although identical The relative biologic availability of carcinogens conditions of exposure are being used. Almost 100 when in contact with the host organism, therefore, per cent of dogs, for instance, developed bladder influences the potency of a carcinogen by control- cancer within ~ years when given optimal doses of ling either the relative amounts of carcinogen re- ~-naphthylamine by month, whereas only about leased within standard periods from depots or by 10 per cent of mice fed this carcinogen showed, determining the length of time it stays in contact within this period, cancers of the liver (Bonser et with the tissues at any one site because of its al. [5]; Hueper et al. [41]). Another carcinogenic excretion or removal rate.

TABLE 3 CANCEROUS RESPONSES AT THE SITES OF IMPLANTATION OF SEVERAL C]JROMIUM COMPOUNDS IN THE THIGH MUSCLE AND PLEURAL CAVITY OF RATS

CUMULATIVE TOTAL OF CANCERS/NUMBERS OF S~s RATIO AT MONTHS AFTER START LATENT PERIOD

ROUTE C(}MI]OUND 85 ~ATS Per cent 0-3 4-6 7-9 10-12 18-15 16-18 19-~1 22-24 ] 25-~7 Mean Minima I yield [ Chromic chromate I.M. 11/~0- 16/16 ir162 I 7O I.P1. 0/34 8,/~3 15/15 !r ~8/5 ~3/5 ~5/~ !~6/0 i 75 Calcimn chromate I.M. 0,/32 5/~25 8/~ 8/~0 9/13 9/9 9/7 9/0 25 I.P1. 0/8~ 1/80 16/10 ~0/0 i 60 i Sintered calcium I.M. 0/84 5/;~7 7/0-5 8/~q* 9/18 9/11 lO/4 1~/0 85 chromate I.P1. 0/33 13/16 17/9 , 17/6 17/s 17/1 17/0 50 [ Strontium I.M. 1/38 3/~9 9/~0 13/11 15/4 15/o 45 chromate I.P1. 0/~8 ~/~6 7/~0 13/9 14/7 16/4 16/3 17/o 5O J Barium chromate I.M. 0/34 0/38 0/31 0/30 0/'~7 o/17 0/14 o/7 o/o 0 I.P1. 0/'81 O/30 1/~0 1/14 1/8 1/5 1/0 5 14 14 Lead chromate I.M. 1/33 1/~8 1/~ 1/18 1/12 I.P1. 0/84 0/3~ 0/+30 1/~o s/15 18 16 Sodium dichromate I.M. 0/38 0/81 0/~5 0/~0 o/16 0 1.el. 0/~6 0/~4 0/~1 0/~0 o/11 0 Chromite roast I.M. 0/84 0/3~ 0/3~ 0/~7 0/15 1/lO 1/8 1/~ 3 19 i 19 residue I.P1. 0/32 1/~8 3/r 3/18 5/15 5/lO 5/0 15 13 i 1~2 Zinc yellow I.M. 1/34 9/~6 11/~ 13/16 18/12 16/9 45 6 5 I.P1. 0/33 1/32 7/t3 17/11 ~1/6 ~/3 65 10 6 Chromium acetate I.M. 0/34 0/38 0/30 0/~0 1/17 1/17 1.6 16 I.el. 0/34 0/83 0/31 0/34 0/18 0/16 1/15 19 Sheep fat I.M. 0/3~ 0/80 0/~3 o/15 0/lO o/6 0/0 I.PI. 0/34 0/8~ 0/30 o/~ 0/18 0/11 O/5 0/0 I

From the results of recent experiments under- carcinogenic agents by different members of the taken for comparing the relative carcinogenic ef- general population, since it consists not only of so- fectiveness on mice of a potent carcinogen, 3,4- called normal individuals but also of a consider- benzpyrene, when standardized amounts were ad- able proportion of metabolically abnormal ones ministered subcutaneously in a single injection who may possess a reactivity to carcinogens differ- with that obtained when the same total amount of ent from that of the normal group. carcinogen was given by repeated monthly injec- The importance of the reactive status of the tions, it appeared that the effects produced de- host organism in determining the potency of envi- pended not only on the amount administered but ronmental carcinogens and, consequently, any also on whether it was given in a single dose or in calculation which one might dare to make in regard multiple doses. The carcinogenic response under to a "safe dose" has recently received added atten- these conditions increased when the total dose was tion by the demonstration of a greatly increased administered in increments (Chart 1). susceptibility of newborn mice to carcinogenic Of distinct significance in regard to the deter- polycvclic aromatic hydrocarbons (Pietra et al. ruination of carcinogenic potencies was also the [66, 67]). Since previous experiences with a trans- observation of a plateau effect seen in mice given 3,4-benzpyrene by single injection after an optimal 90 I I I I I I quantitative exposure had been reached. In con- E- z 80 trast, there was a continued rise in the cancer ~...~ Administered in yield with a progressive increase in the total dose 70 .-,"" 12 monthly doses - of carcinogen injected when it was given in frac- ~ 60 f - tionated doses (Payne and Hueper [65]). Since a / k- / low-level, recurring exposure to a carcinogen, ac- m / cording to these findings, is more hazardous than 50 -- // / / a single exposure to the same total amount, and O3 40 - / because man sustains, as a rule, the first type of g I exposure to environmental carcinogens, any po- I Administered in tency rates obtained in experimental animals by a I.-- 20 _ /f o single dose _ single administration of a carcinogenic test material would probably give results with little or no I0 / significance to man. The possible importance of a third factor which -~5: o / I I I , I I. may determine the outcome of potency studies of 0 0.I 0.2 0,3 0.4 0-5 0,6 0.7 carcinogens was suggested by the results of experi- TOTAL DOSE OF" BENZPYRENE, MILLIGRAMS ments on the character and type of metabolites CHART 1.--Production of tumors in mice with varying appearing in the urine of rats following an oral amounts of benzo[a]pyrene in single and repeated monthly administration of different amounts of a certified doses. Per cent of mice with tumors and total dose. food dye, Citrus Red No. 2 (Conway and Lethco [8]). It was found that the number of demonstrable placental transfer of urethan from pregnant mice urinary metabolites increased with an increase of to their offspring resulting in an early and accen- the dose of the dye given and that there occurred tuated appearance of puhnonary tumors in the a shift in the quantitative relations between the young has a similar connotation, experimental po- chemically different metabolites under these ex- tency determinations with prospective application perimental conditions. In view of the fact that the to man must take these observations into proper chemical character and the relative quantity of consideration. In fact, infants and children, if individual metabolites of urinary carcinogens these findings in animals should apply also to man, seems to influence the carcinogenic response pro- would be particularly vulnerable to prolonged ex- duced in the bladder by some of the known car- posures to rather small and perhaps minute doses cinogenic amines, it is probable that purely quan- of environmental carcinogens present in food- titative factors may decisively influence not only stuffs, including the maternal milk, in the air, and the outcome of experimental potency studies but in drinking water. Because of their prospective also the degree of cancer hazard from such chemi- long lifespan, infants also face the additional lia- cals in exposed human populations. These observa- bility of a long latent period, usually necessary for tions, moreover, illuminate the frequently raised weak carcinogenic exposures to result in manifest problem concerning the existence of marked dif- tumor formation. There is an additional health .fere~:ces in the susceptibility to environmental hazard from such intrauterine exposures of the

fetus to carcinogenic agents, such as x-rays, radio- furnish an adequate justification for conducting active substances, trypan blue, and others, because comprehensive epidemiologic investigations on they may result in the development of congenital population groups exposed to this agent for explor- malformations. ing the existence of a similar environmental cancer These observations and considerations of a hazard to man. methodologic nature, as well as the absence of any A similar connotation has the observation of dose-response curves for human carcinogens in any epidemic-like appearance of cancers in animals, experimental animals, do not justify the claim that especially if they are food animals and if they be- any valid conclusions can be drawn from dose- come exposed to environmental factors, particu- responses obtained with a few experimental car- larly dietary constituents, which are identical with cinogens in experimental animals on the reactivity or similar to those introduced into the human food of environmental carcinogens of all kinds and of supply. While the occasional appearance of can- all types of contact in members of the human pop- cers in domesticated and wild animals, including ulation. The control of environmental cancer haz- fish exposed to human carcinogens, such as radio- ards could easily be made by the adoption of a active matter, petroleum oils, and arsenicals, had "safe dose" of carcinogens into a lottery of human previously been reported, the scope of such envi- lives. ronmental pollutions to animals and man was Added to the methodological objections to this demonstrated by the recent observation of an epi- conccpt must be the fact that the exposure condi- demic of primary liver cancer among rainbow tions as to source, variety, and total dose of envi- trout kept in hatcheries throughout the eountry ronmental carcinogens are, in most instances, not (Hueper and Payne; 2 Rueker, Yasutake and Wolf adequately controllcd or even sufficiently control- [71]). It was found that such cancers occurred in lable for keeping the carcinogenic burden within animals as young as 6-7 months old and affeeted set limits as far as the individual is concerned. The about 80-90 per cent of brood trout kept for over "safe dose," if adopted, therefore, would become 3 years. The evidence indicated that the carcino- because of these circumstances a most unrealistic genic agent active in the production of these liver standard without any practical significance. cancers was evidently highly potent and apparent- Finally, it must bc emphasized that thcre does ly acted upon the very young animal. A prelimi- not exist any correlation between the carcinoge- nary assessment of the circumstances under which nicity of a chemical and its toxic properties. The this epidemie has made its appearance suggests degree and type of the toxic reactions of a chemical that a dietary factor (arsenical amebieides, sul- therefore do not provide any qualitative or quan- fonamides, oxidized fatty acids, antioxidants, vita- titative index of its prospective carcinogenic quali- minie and proteinie imbalanees, etc.) is to be in- ties and its relative potency in man or animals. criminated, which is eontained in or associated This fact deserves special mention, because phar- with the processed fish feed introduced into the macologists not sufficiently familiar with the spe- industry some years ago. cific aspects of chemical carcinogenesis have con- This tentative explanation is made rather prob- tended that bioassays of chemicals for carcino- able because of the fact that various chemicals in- genic reactions arc equivalents or modifications of troduced into animal and human foodstuffs and chronic toxicity tests. dietary deficiencies have been shown to elicit primary cancer in experimental animals (chlorinated III. EPIDEMIOLOGIC ASPECTS hydrocarbon pesticides, such as DDT and Ara- In the past the initial recognition of environ- mite; fungicides, such as thiourea and thiourea mental and especially occupational cancers and derivatives and thioacetamide; the sweetening carcinogens by cpidemiologic observations was agent, phenetyl urea [l)ulcin]; the flavoring agent, subsequently confirmed by appropriate experi- safrol; the food contaminant, selenium; the pesti- mcntal observations. During the last few years this cide, arsenic; several food dyes, oil orange E; oil sequence of events has been reversed in coimection yellow HA, butter yellow; and dietary methionine with the demonstration of carcinogenic hazards and protein deficiencies). Since some of the various from cutaneous contact with hydrogenated coal dietary ingredients mentioned are not only present oils produced by the Bcrgius process (Huepcr [3s in many of the foodstuffs used for human con- Sexton [74]) and with respiratory contact to mus- sumption but are also stored in the hmnan body tard gas (Heston [s Case and Lea [7]; Bcebe [s and thus capable of exerting a prolonged and pro- Yamada et al. [76]). The experimentally induced gressively accentuated action, the occurrence of a occurrence of cancers in animals by the use of a Unpublished observations, ])rs. W. C. Hueper & W. W. chemical with economic importance should thus Payne, National Cancer Institute, Bethesda, Md.

catastrophic cancer epidemic among rainbow trout which is generally recognized throughout the should provide a most forceful stimulus for organ- world, has been challenged by some American izing comprehensive epidemiologic studies on the investigators (Eckardt [~0]) who followed in this incidence and site distribution of cancers in human respect the lead given some years ago by Gehr- populations especially strongly exposed, for some mann (~4). reason, to the various dietary carcinogens to be Through such practices the false impression is suspect. This occurrence also furnished additional supported that occupational cancers are uncom- justification for an extension of the rather limited mon (Eckardt [~1]; Oettel [61]) and that, for this efforts of screening food additives and contami- reason, this particular but highly important kind nants as well as processed foodstuffs for carcino- of environmental cancer is only of limited impor- genic properties, so as to avoid setting the stage for tance as a public health problem. The fact is that a future repetition of a similar cancer epidemic according to world-wide experience the study of with some man-made carcinogenic environmental occupational cancer hazards deserves greatly in- contaminant. Since Japanese investigators recent- creased attention not only because they elicit im- ly demonstrated the carcinogenic action of the portant and often fatal industrial diseases, but also antibiotic actinomycin which produced sarcomas because the special circumstances related to expo- at the site of subcutaneous injection in mice (Ka- sures to carcinogenic agents present for occupa- wamata et al. [44, 45]) as well as of penicillium tional population groups greatly facilitate the islandicum which contaminated rice and elicited demonstration of the action and sometimes of the carcinomas of the liver when fed to rats (Miyake character of an industrial carcinogen. Such a car- et al. [51]), antibiotics used in the processing of cinogen, through its subsequent introduction into foodstuffs or formed in them by fungal contami- the general human environment, might also repre- nants should be included in experimental and epi- sent an environmental carcinogen which then has demiologic investigations of this type. usually a rather diffuse distribution and possibly An additional and probably the most promising widely scattered carcinogenic effects not readily field for greatly intensified epidemiologic efforts is shown by available epidemiologic methods. Epi- presented by the occupational cancer hazards. In demiologic studies on occupational cancer hazards, comparison to the epidemiologic evidence avail- therefore, may provide the key to the recognition able on the occurrence and incidence of occupa- of environmental cancer hazards. tional cancers American epidemiologic-statistical Retrospective epidemiologic studies are indi- data are highly defective, if not pitiful, and, there- cated for the multitude of occupational population fore, if taken at their face value, misleading and groups whose members have been exposed for not adequately reflecting the actual situation. This many years to the various known carcinogens. Such deplorable situation has recently been complicated studies are especially indicated whenever the by the publication of two occupational cancer available evidence for a particular carcinogenic studies in which objectionable methods were em- hazard has remained totally or mainly restricted ployed. In industry-inspired epidemiologic studies to non-American sources, such as cancers in hema- on the liability of railroad employees and of work- tite miners and foundry workers, in nickel smelter ers in asbestos operations (Kaplan [48]; Braun and workers, in employees of asbestos mines, mills and Truan [6]) epidemiologic conclusions have been textile plants, in miners of arsenic-containing ores, drawn, therefore, which do not conform with the arsenic smelter workers, and insecticide makers results of other properly conducted investigations and users, in uranium ore miners and millers, and which contain the incorrect allegation that an chemical and pharmaceutical producers and users increased liability to cancer of the lung of the of various aromatic amino- and nitro- compounds worker groups analyzed could not be demonstrat- and their users in industry (particularly rubber ed (Mancuso; 30'Donnell [60]; Doll [18]). This lack plants and processing and preparation of food- of an adequate number of trustworthy and com- stuffs), makers of synthetic estrogens and the pro- petent epidemiologic studies on occupational can- ducers and users of estrogenized animal feeds, em- cers in the United States is also responsible for the ployees of oil refineries and carbon black and car- fact that the eminent carcinogenic role of benzi- bon electrode plants, and workers on gas retorts in dine in the causation of cancers of the bladder, gas plants and coke ovens, as well as the numerous industrial users of coal tar and pitch. 3Personal communication on asbestosis cancer of the lung Prospective epidemiologic investigations are presented before tim Meeting of the American Academy of Preventive Medicine, March 1961, Dr. Thomas F. Mancuso, needed for the even more numerous occupational Chief, Industrial Hygiene, Ohio Dept. Health, Columbus, populations engaged in the manufacture and use Ohio. of the many potential human carcinogens for

which, at present, any type of human evidence is lung may have played in the development of can- lacking. Retrospective and prospective epidemio- cers in tuberculous lung (Bal6 [1]). logic studies can most profitably be pursued at In the interpretation of the statistical data ob- present on worker groups of great stability (long- tained from epidemiologic studies of occupational term employment) who are employed in factories groups it is unrealistic to adopt the concept that located in rather small communities and represent- "It is scientifically unsound to attribute a given ing their main local industrial establishment. type of cancer to an occupation unless it can be Such surveys on human populations undertaken established with statistical significance that the for the discovery and assessment of occupational incidence of this type of cancer among employees cancer hazards should be supplemented by long- is higher than in the general population, or in an term surveys on wild and domesticated animals employee group comparable in all other character- living on the ground and in bodies of water in the istics except the occupation" (Eckardt [19]). Such vicinity of industrial operations with carcinogenic decisions do not depend entirely on the outcome hazards, since industrial effluents released into the of statistical investigations but require also the air and into bodies of water near such plants may application of sound medical judgment concerning contain carcinogens which may elicit carcinogenic the symptomatic and pathologic manifestations responses among such animals. In fact, observa- noted in members of worker groups suspect of tions of cancers among these animals may serve being subjected to an occupational cancer hazard. as early warning signs of the existence of an indus- Individuals exposed to benzol and ionizing radia- try-related environmental cancer hazard to man tions, for instance, exhibit a hematic syndrome breathing the air, drinking the water, and eating reflecting strikingly the ambivalent aplastic and the plants and fruits grown in the soil polluted hyperplastic effects, including leukemia, produced with carcinogenic chemical dirt from nearby in- by these agents upon the blood-forming tissues. dustrial plants, and means of motorized transpor- Since the entire range of such reactions can be tation. The reported more frequent occurrence of elicited with these agents in experimental animals lung cancer in dogs living in urban areas in the there can exist no reasonable scientific doubt con- U.S.S.R. than in those of rural regions, if confirmed, cerning the causal relation between contact with furnishes a good illustration of such correlations, es- benzol and ionizing radiations and the subsequent pecially since they would point to the importance development of leukemia, despite the fact that the of carcinogenic factors in urban air pollutants as presently available epidemiologic data may not be significant agents in the causation of this particu- entirely sufficient to support such a conclusion. lar type of cancer (Leake [47]; Hueper [31]; Hueper The objections raised lately by several commercial- et al.). 4 ly interested parties to further consider arsenicals In the etiology-specific interpretation of such as human carcinogens because of the absence of statistical data, when applied to cancer of the lung adequate epidemiologic and experimental evidence in man, it appears wise to consider the proved in support of such a concept, held for many years polyetiology of many cancers, including lung can- by numerous competent and experienced derma- cers, as well as the probability that several car- tologists and industrial physicians, also totally dis- einogenie and co-carcinogenic factors might com- regard the characteristic symptomatic pattern of bine in elieiting a cancerous response. The results chronic arsenic poisoning presented by the type, sequence, and location of cutaneous changes pre- of recent epidemiologie and pathologic observations ceding the development of cancers of the skin, have revived the former interest in the relation of lung, and liver often seen in individuals who were tuberculosis and cancer of the lung. In view of the exposed to arsenicals for occupational, medicinal, fact that the oral administration of the sedative, and dietary reasons. urethan (Jaff6 [4~]) and of the tuberculostatie iso- A serious shortcoming of the presently available nicotinic acid hydrazid (Mori et al. [5s resulted in epidemiologic-statistical methods is related to the an excessive development of pulmonary adenomas fact that the information obtained by such proce- in mice, it may be indicated to investigate with dures usually relies on the demonstration of ab- statistical methods the possible role which the normalities in the quantitative pattern of the can- various types of medications administered for dif- cer panorama found in the population group ex- ferent reasons to persons with tuberculosis of the amined, i.e., as a rule an incidence rate of a certain type of cancer which is excessive in relation to that 4 W. C Hueper, P. Kotin, E. C. Tabor, W. W. Payne, H. found in a standard or control population. How- Falk, and E. Sawicki. Carcinogenic Bioassays on Air Pol- lutants. Presented at the 58d Annual Meeting of the Air Pol- ever, conclusions drawn from such comparisons lution Control Association, May, 1960. Arch. Path. (in press). are subject to the vagaries of the so-called "stand-

ard" cancer rates, since these vary within rather a registry of patients who received parenteral im- wide limits for different population groups accord- plants of such plastic materials for a subsequent ing to region and occupation. If one should give epidemiologic assessment of possible late carcino- full credence to the claims of the advocates of the genic sequelae around such implants appearing cigarette theory of lung cancers, they vary for some 10-30 years after such deposits were made. these cancers also according to the prevalence and As a matter of wise precaution, such studies may intensity of the smoking habits observed by the also be extended to persons wearing plastic den- members of the particular population group ana- tures, since it is important to ascertain whether or lyzed which, in turn, are alleged to determine their not a prolonged mucosal contact with such plastics predominant histologic variety. "Standard" can- might be related to a delayed formation of cancers cer rates thus are rather arbitrary values, which, in the oral cavity. when indiscriminately and improperly applied, This brief outline on the facts, the concepts, and might obscure the demonstration of an occupa- the many unsolved and controversial problems of tional cancer hazard. environmental carcinogenesis and cancers has An example of such an obliterated correlation served its purpose if it has conveyed adequately is being offered by the gradual disappearance of the message that the field of environmental cancer the formerly marked discrepancy in lung cancer research represents not only one of the most im- incidence rates between English coke oven and portant facets of cancer research but, at the same gashouse workers exposed to an inhalation of coal time, also one of the most rewarding and imme- tar fumes and the English population in general, diately useful ones. With the availability of in- beconfing lately exposed to an increasing degree to creased funds and increased interest in these as- carcinogenic constituents present in industrial air pects of cancer control especially by prophylactic pollutants and in automobile exhaust (Hueper and preventive measures, it may be hoped that the [31]; Doll [18]). Similar objections apply to the foreseeable future may see perhaps a repetition of validity of data on cancer incidencc in so-called the successes which this approach brought to the normal control groups, which can also be selccted control of communicable diseases. in such a way that they may or may not differ fundamentally from the test group as far as cancer REFERENCES rales are concerned, although they are apparently 1. BAI/), J. Lungenkarzinom und Lungenadenom, p. 363. chosen by the generally accepted rules. The deci- Budapest: Verlag dcr Ungarischcn Akademie dcr Wissen- schaften, 1957. sion concerning the absence or presence of an occu- ~. 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Carcinogenic Properties of ~-Amino-1- Naphthol Hydrochloridc and Its Parent Aminc--~-Naph- benzol, estrogens, urethans, and others, it appears thylamine. Brit. J. Cancer, 6:41~-~4, 195~. to be important that considerable epidcmiologic 6. BRAUN, ]). C., and TiiUAN, T. D. An Epidemiological research be conducted on the carcinogenic rela- Study of Lung Cancer in Asbestos Mincrs. Arch. Indust. tions of various chemotoxic disease manifestations ttealth, 17: 634-53, 1958. 7. BRU~'NER, H. Expcrimentelle Ausloesung yon Tumoren characterized by degenerative manifestations, durch Implantation yon Polymethyl-methacrylat bei Rat- such as aplastic anemia, agranulocytosis, liver de- ten. Arzncimittelforsch. 9:396-99, 1959. generations and necroses, functional and anatomic 8. CASE, R. A. M., and L~'A, A. J. Mustard Gas Poisoning, thyroid hypoplasias, and cutaneous atrophies, Chronic Bronchitis, and Lung Cancer; Investigation into which represent either direct chemotoxic reactions Possibility That Poisoning by Mustard Gas in 1914-18 War Might Bc Factor in Production of Neoplasia. Brit. J. or chemoallergic responses. Prcv. & Soc. Med., 9:6~2-7~2, 1955. The rapidly growing industrial, dietary, cos- 9. CONWAY,W. D., and L~.THCO, E. J. Metabolism of Citrus tactic, and medicinal use of macromolecular Red No. ~2--an Oil Soluble Food I)yc. Abstracts of Papers, chemicals, such as especially plastics and water- 139th Meeting American Chemical Society, St. Louis, March ~21-30, 1961. soluble carbon and silicon polymers, which have 10. Cou~-ClLON DnUGS. Withdrawal of Iron-Dcxtran Comt)lex displayed carcinogenic properties in experimental (hnferon). J.A.M.A., 175:836, 1961. animals, also seems to justify the organization of 11. ])ELANEY CANCER CLAUSE: t[EARING8 BEFORE TIIE IIo(:sn

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W. C. Hueper

Cancer Res 1961;21:842-857.

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