Document VQvvyxw60x8J9YXp1nae01zj

Occupational carcinogenesis i Cessre MaJtoni Iflimiodi Oncologia 'F. Acdaru'tmdCentro Tumori, Bologna, Italy Occupitional carcinogenesis is one of the most interesting, tragic, important and difficult fields is oncology. It is interesting from the scientific point of view because it represents, dramatically, an experiment in carcinogenesis made on humans and it may teach us a lot about the natural history' of rumours. It is magic from a human point of view, because work which is per e a natural necessity of life, should not, at least, cause cancer. It is socially important because oncogenic factors increasingly are produced and diffused in occupational environ* meats. Moreover from the factories they spread to the general environment, so that they come to be an ecologial problem. Finally, occupational carcinogenesis is a difficult field to approach, because the care of the workers' health is often in conflict with the product* he interests of the factories. Industry has done a lot lot experimental carcinogenesis, related to occupational can cer; often however the result is merely to prove the carcinogenic effect in animals of agents which have already proved to be carcinogenic for man; this is equivalent to saying that many people die of cancer but some make their living from cancer. On the other hand emotional arguments should be avoided. Thus I am aware that speaking on occupa tional cardnogsnesis is a complex and difficult task. Experimental carcinogenesis did not start with the experiment of Yamagiwi and Ichi kawa in 1915, but rather in the 16th century with the observation of the so-called `mountain disease* in miners of Joachimisthal This disease was recognized at the end of the last century as pulmonary carcinoma, which we now know is due to radio-active pollution, present in those mines. In 1775 Percival Pott in `Chirurgical Observations' de scribed a cancer of the scrotum in chimney sweepers and he correlated it with the black soot. In 1 94 Tinna reported on the frequency of skin cancer found in maritime workers, and he considered it due to excessive exposure to sun light. In 1895 Rehn, a surgeon from Frankfurt, reported at the congress of the German Society of Surgeons, 3 cases of bladder turn sum found among 45 workers from a factory which produced fuchsine. He thought that the rumours were caused by aniline, but in fact it was shown, sevpral decades latex, that they were due to othet aromatic amines. In 1902 at a meeting of the Medical Society of Hamburg, Frieben presented a case of a cutaneous tumour found on the hand of an employee of a factory producing X-ray apparatus. This employee used his hand for radiological demonstrations. The frequency of reports on occupational cancer has been increasing with the increase o: fniunriahmtion. mainly cue to the progress of chemistry. The most important thing to do in occupational carcmogenesis is to try to recognize occupations which may re present an oncogenic risk, and to identify the agent or agents which cause the risk, and qtt,- tc try to assess the degree of risk. If the nsk is related to an agent already known to be c-iojiiir for man, :*s detection in the occupational environment should be considered ruiririen: for undertaking preventive measures. On the other hand if the risk is related to agents, whose effects on workers have no: yet been studied and are therefore not yet known, then we hzvs to evaluate the risk they represent for workers. This can be done by means of epidemiological investigations and experimental testing. Most oncogenic occupa tional agents have been identified on the basis of retrospective epidemiological studies. The propsss is and the development of this branch of oncology should facilitate systematic experimental testing of agents heavily released in the occupational environ- UCC 088214 msit. In other wards epidemiologies! evidence in men should be avoided. Experimental :er-i on ere lie more relevant to man, the more they reproduce the condition* of r-.-jt- exposure and eventually induce in animals the tame tumour* that they induce in - - - t tiii olsc, results of experimental tests may be considered largely equivalent :: epidemiological evidence in man. On the other hand if an agent causes any kind of tumour in animals, in whatever experimental conditions, it should be considered potentially carcinogenic for man. To consider an agent definitely carcinogenic for man on such a basis, would be an excess, but no time should be lost before retesting it in more appropriate conditions. To reproduce experimentally the conditions of occupational exposure is often difficult and costly, r rrthrrmort we hare to consider that the number of agents in the occupational environ ment ts large and tamearing. Thus, new agents to which workers may be exposed should be submitted first to the easiest and quakes: tests, however incomplete those tests may be. Then, for those agents indndng tumours in the experimental animals in these conditions, more precise and sophisnated experimental tests should be devised. The validity of experimental testing and the prerequisites for validity have been a matter of long discussions in international T a XI V i Incidence of Etbcuicneous sarcomas in rets, following local injection of some inorganic pigments Treatment No. of animals Chromium yeDc-w Head chromate) Chromium orange fiead chromate) Molybdenum onage (and chromate and molybdenum chromate) 'jr-iiag yeSow tadmjtm sulphide) r;r red ttror cradii iron vrilcw iiroa ciide) Ccarrols 40 40 40 40 40 40 ' 60 No. of tumours 26 26 36 IS 1 0 0 meetings and exposure contir rat of compou some idea of th In Table 1. the subcutanec that chromium From what hr conditions, she visibility of apparatus is qt able to find ax inhalation of ; experimental u With this chloride mono first) of peat resin, as a co; mediate, and results on thes Zymbal gla spontaneously Only 3 cas Dawlev) have 1 and river angi< nephroblastor angiosarcomas Although tumours have sidered in our Zymbal gk often mulriph Epidemiolc workers. Wou these tumour value of exp; agents and w before' any n: Another e working pop cancer precur cytology am among work: posed to* chi groups of wo: To evalua'. agents, we m: 1. a direr plastic respor Z. the on' to develop w: 3. the on their effects. According la/ dcfiiL UCC 088215 3 meetings and commissions, but of course, in the meantime the existing occupational exposure continues. Also, imperfect testing, for example the subcutaneous injection in the ra; of compounds, to which man is exposed mainly by the respiratory route, may give seme idea of their potential oncogenic risk. In Table 1, data are reported on the induction of tumours (sarcomas) at the site of the subcutaneous injection of some inorganic pigments. From these data it clearly appears that chromium and cadmium pigments should be considered riskier than iron pigments. From what has been said before, the compounds shown to be carcinogenic in these conditions, should now be tested by inhalation. The latter way of exposure implies the availability of a complex apparatus for continuous inhalation of controlled doses. The apparatus is quite rare, as we discovered when we wanted to build one and we were not able to find any model is our own or any neighbouring country. Now as apparatus for i-v ala tips of gaseous compounds has been functioning for more than two years in the experimental unit of our institute (Fig- 1 ) With this apparatus we are now performing a carcinogenicity.-bioassay of vinyl chloride monomer (VC) and of vinyl acetate monomer (Va), which are (particularly the furt) of great industrial importance. VC is used in the preparation of polyvinyl chloride resin. as a copolymer in saran and other plastics, as a solvent and as a chemical inter* mediate, and it is it present produced at a rate of 12,000,000 tons per year. Early results on these bioassays are shown in Table 2. Zymbal glands carcinomas, liver angiosarcomas have never been observed as occurring spontaneously in our breed of Sprague-Diwley rats. Only 3 cases of spontaneously occurring Zymbal glands carcinomas in rats (Sprague* Dawiey) have been recorded in 1962. To our knowledge, no spontaneous nephroblastomas and tver angiosarcomas of rats have been reported in the literature. As far as we know, nephroblastomas have never been reported to be experimentally induced in rats; liver angiosarcomas have been induced in this species by dicthylnitrosamine. Although liver is the preferential site for onset of angiosarcomas, such kind of rumours have been observed in other tissues and organs: therefore VC should be eon* ncered in our experimental conditions generally cancerogenic for endoihelia. Zymbal glands rumours and nephroblastomas may be bilateral; liver angiosarcomas are often multiphocal. Epidemiological investigations and medical controls should be undertaken on exposed workers. Would such neoplastic neoplasia unhappily be found in man, given the rarity of these rumours in both animals and humans, it would be a precise indication of the high value of experimental testing ur predicting the oncogenic potential of environmental agents and would strengthen the recommendation on the necessity of such bioassays before any new industrial compound is produced and widespread in large scale. Another means cf revealing the oncogenic risk of an agent is to examine the exposed working populations with methods which make it possible to assess the incidence of cancer precursors. The incidence of such precursors has been studied by us by exfoliative cytoiogy among asymptomatic, apparently healthy workers exposed to risk, namely anteng workers exposed to aromatic amines (urine cytology), and among workers expcsef to chromates (sputum cytology). The incidence of cellular atyptas in these two groups of workers is shown in Tables 3 and'4, It far exceeds the expected incidence. To evaluate in medical and legal terms the risks represented by occupational oncogenic agents, we must consider that: 1. a direct relation exists between dose (amount and length of exposure) and neo plastic response; 2. the oricogenir agents produce mainly non-reversible changes, which may continue ;*v*)op when the exposure is interrupted: 2. the oncogenic agents (occupational or generally environmental) may be additive in their effects. According to our knowledge the occupational carcinogenic agents may be classified as: .c, definite orenogens, when epidemiological evidence exists, TAI11.K 1 ftrliminnry results of carcinogenicity bioatsay of rlnyl chloride monomer (VC) and of vinyl acetate (VA) (l-rom C. Haltont, (1. I.efemlne and U (inatano, in press) fit mips and Irealmcnl Animals (Spragtte-I)awley rals) Tolal Survivors Zymhal glands carcinomas (A) No. Animals wtlli lumouts Nepbroblas loinas w No. Angiosarcomas IJvcr (C) No. Ol her siles No. Ollier type and/or site No. Tolal No. 1 VA 2,50(1 ppm. 96 13 _ _ __ _ . II VC 10,000 ppm. 69 - 13 3 6 - 5(H) 27 Ill VC 6,000 ppm- 72 5 3 3 HD) HD 18 IV VC 2,500 pprn. 74 16 2 4 6 3(E) 1 (L) 16 V VC 500 ppm. 67 15 2 3 5 2(F) 1 Ol) 13 VI VC 250 ppm. 67 20 - 3 1 2((!> 2 (N) 8 VII VC 50 ppm. 64 35 - - -- - - VIII Mo Irealnrenl 64 33 - - -- - - Tolal 577 139 22 16 26 8 10 82 (A) Mclaslasrs In lung. (II) Melaslascs lo liver and/or In lung mil spleen. (C) Melaslases In lung. (D) Angiosarcomas In subcutaneous fibrosing angioma. ([) 2 iniiaIninmilml angiosarcoma* (I neat In spleen and I neat lo ovary); I ossifying angiosarcoma or neck. (I7) 1 pulmonary angiosarcoma; I angiosarcoma of ulerus. ((>) I tnlrabdominal angiusartoma (ncal lo spleen); I kiliilhnraclc ossifying angiosarcoma. (II) 2 cymbal glands adenomas; I neurilemmoma of Hie car; I mammary carcinoma; I cysloadenncarclnoma or ovary. (I) Sebaceous gland careInnina ol skin. (L) Zymbal glands adenoma. (M) Minimal deviation he patoma. (N) I cymbal glands adenoma; I salivary glands carcinoma. TAIII.lv 3 Freipienry of cellular atyplas among workers expoted to aromatk amines in 4 North Italian dye-tinfffactories I TAMl.F 1 I'tiijiirnrv W n#iW atyphts annuit muKm exposed to aromatlr atulnei In 4 North ttmUmn dye ' /// farlmtes Faclnty No. or workers iimln con 1 ml Cytologlcal classes (Papanicolaou) 1 III 11 11-111 III IH-IV IV IV-V V A 212 4A in 114 14 71 1- 1 ! II 159 5A 21) 49 25 5l 1- - C 40 II A 72 Al 2- - iD 41 ir> 13 91 -- -- " iIt j| Total 472 122 A9 179 43 20 3 4- 1 i . TABLE 4 Frequency of adenomatous typical and atypical hyperplasia, and of squamous metaplasia and dysplasia. In workers exposed to chromium com pounds in one Northern Italian factory Tjf|e of occupation |jcnf,lh of taposiiie 1 cngtli No. Typical adenoma lout Ity petplasla No. % Alrpieal adenoma tout hyperplasia No. % Squamous metaplasia No. % Squamous dysplasia No. % Production of Dp to J 25 3 12 --_ 24 96 4 16 eliminate) and fi-M 14 2 21 17 12 A6 3 21 ilicluoinales II 15 12 2 23 2 23 12 92 4 30 Ovei 15 l7 - - 16 IS AA 4 23 ! 1 olal 69 9 13 57 63 91 15 22 Production of chromium pigment Up to 5 6-10 M-IS n*ct 13 14 l 7 17 1 6 A 1 12 A 2 23 --- -- -"-- 14 100 14 A2 6 75 A too -_ 2 12 l 12 2 25 Total 47 5 in -- 42 S9 5 10 tj HI j ! ram i I: * i i i rrr \ | \ i i \ j U C C 088218  V 1 . 6 ft) highly guspected carriaogerrs, when strong experiment*! and/or tome epidemio logic*! evidence is present, (cl potential carcinogens, when experimental data give some indication of carcino genic action of a compound on an experimental animal. According to their effects, the carcinogenic agents may be classified as strong or medium. Toe agents, which have been definitively proved or ere suspected to be oncogenic for -M-) ca an epidemiological basis, are listed in Table S, together with the target tissues and the dep-ee of evidence. The list of the agents present in the occupational environment, which, on an experimental basis should be considered highly suspect or potentially carci nogenic for man, is reported in Table 6. TABLE 5 Afents proved or suspected to be oncoftnic for workers on en epidemiological basis Agents U.V. radiations X-rays Uranium ore Arsenic Asbestos Evidence + + T (+) A. Chromium Nickel Iron ore Bis-chloromethyl ether Benzene lsopropylie oB Soot, tan, mineral oils, cutting oils Carbon black Mustard gas Aromatic amines * (+) A <+> - - Tumours Skin carcinomas Sinn carcinomas Leukaemias Pulmonary carcinomas Skin carcinomas (lung ardnomas) Lung carcinomas Fieural mesotheliomas (abdominal malignancies) Lung carcinomas Lung carcinomas Carcinomas of nasal and paranasal cavities Lung carcinomas Lung carcinomas Leukaemias Carcinomas of paranasal cavities Skin carcinomas Lung carcinomas laryngeal carcinomas Bladder and upper urinary tract carcinomas f Aftr.:: sjsctaed to be ccr.ncfenc for H-o'kers or an experimental bests Beryllium Cadmium Cobalt Lead Selenium Zinc Carbon tetnchloridt Chloroform Vinyl chloride Pesticides (DDT, aldrin. dieldrin, Aramite, DMDT, AmiioL Tniuram) Thiourea and related compounds Tannins Detergents Alkylating agents Niuos*mines Aro-dyes Oestrogens In Italy ca (a) expo: produced; (b) expo (c) expo workers in fa (d) in fai (e) in fat (ft in the In our co tioned work' , chromate fa; workers in a who were b Province an among worl workers had fuchsine, 3,: , and benzidi > cardnogene: ! The metl 1. cone ! 2. up t< i risk; j 3. legisl > have been i especially if 4. meat be producet ! Public Heal: 5. spec preneoplast risks throug It is my epidemiolo mainly loc; 1 We know t some way i TABLE 1 Factory A B C D E Total i I In 1 are i I UCC 088219 7 la Italy carcinogenic occupational risk exists for workers who are: (c) exposed to chromates, manly the ones working in lactones where chromates are produced; (b) exposed to nickel, mainly the ones exposed to nickel-carbonyl; (cj exposed to asbestos, mainly the ones who extract it from its natural source, or workers in factories where asbestos is used for manufacturing; (d) in factories making shoes, purses and raincoats, exposed to benzene; fej in factories producing carbon black from mineral oils; and (f) in the dye and rubber industries, exposed to aromatic amines. In our country occupational tumours have been observed in many of the above men tioned workers. 21 lung carcinomas have been found among less than 200 workers in a chromate factory in Northern Italy. Pleura] mesotheliomas have been discovered among workers in asbestos mines. A number of leukaemias have been found among shoe-makers, who were heavily exposed to benzene, in factories in Lombardy (Vigtvano), Bologna Province and Tuscany. The incidence of bladder and other urinary tract carcinomas among workers in 5 Italian dye-sniff factories are shown in Table 7. Is these factories workers had been exposed to 0-napbthylamint, benzidine, o-naphthylamine, Auramiae, fuchsint, 3,3'-dithlorobenzidine. Now in our country the production of ^naphthylamine and benzidine has been withdrawn. One may conclude that prevention of occupational carcinogenesis is a very urgent problem. The methods of prevention may be summarized as follows: 1. correct experimental testing of all newly used agents; 2. up to date epidemiological data from Tarious categories of workers exposed to risk; 3. legislative measures forbidding the production and the utilization of agents which have been shown to be oncogenic on an epidemiological and/or an experimental basis, especially if the said agents are strong carcinogens; 4. measures of technical protection, when weak or doubtful carcinogens continue to be produced or employed; these protective measures should be periodically examined by Publie Health Inspectors; 5. specific medical checks to make possible, on the one hand, the early detection of preneoplastic lesions and tumours, and on the other, the quantitative evaluation of the risks through the incidence of these changes. It is my opinion that the value of medical checks is mainly to evaluste the risk that is epidemiological. Early detection of occupational tumours which, as already shown, are mainly located in the respiratory and urinary' tract, has been, 1 think, over-emphasized. We know that these rumours art multicentric. In other words all the target apparatus is in some wav affected by the carcinogenic process. TABLE 7 Frequency cf cxrcinomai of the urinxry tract among workers of 5 Itelien dye-stufffac tories exposed to aromatic amines ri ;:erv A B C D E Total Total No. of exposed workers ;se 386 213 135 135 1.155 No. of workers with carcinoma E.idct: Rena] pelves and ureters i: 1 8* 5 4U - a- 71 15? 7 Total 18 92* 44 4 8 166 In 1 ease bladder and upper urinary tract tumours were coexistent. UCC 088220 8 Concerning the urinary tract, in a systematic histological study, I have seen that in patients with bladder rumours, dysplastic and cancerous foci may be detected from renal pelvis to urethra. Therefore it is obvious that in such conditions early diagnosis can achieve very little. We may diapose some tumours quite early, but on the basis of 15 years' experience with periodic checks of workers exposed to high risk, I doubt that periodical medical examination has a real bearing in saving people with occupational cancer although detected early, or in prolonging their life span. Thus my position is in sharp contrast with those who claim to `protect* (!) workers exposed to carcinogenic risk with medical examinations. 1 do believe that the potentialities of medical examinations should be evaluated at an international level In conclusion, 1 would like to emphasize the need of a close collaboration among scientists, public health services, workers unions and industries, to evaluate the risks and to devise preventive measures for avoiding or minimizing occupational tumours. References Friebea (1902): Fortschr. Rbntgawm, 6,106. Pott, P. (1775): In: Oururgisal Observations relative to the cataract, the polyps of the nose, the can cer of the scoaim, the different lands of ruptures and the modification on toes and feet. Hower, Quits and Poliins, London. Unna, P. G. (1 94): In: Histopatholope dec Hautloankheiten, p. 719. Hinehwald, Beilin. Yamapwa, K. and Ichikawa, K. (1915): Miru med. Fak. Tokyo, 15.295. *