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THEOOORE VOORHEES, JR. 0'CC T GI*L NUNiCH '202' 002 3230 "OVINGTON & BURLIN 1201 PENNSYLVANIA AVENUE. N. W. P.O. BOX 736 WASHINGTON. D C. 20044.73 12021 662-6000 TELEFAX 13021 092-0201 TELEX: 00 - 503 ICOVUNG W5MI CABLE. COVLtNG September 17, 1996 LCCO^-CLO MOUSE CL^ZOM ST*CCT LONOON WIT BAS CNCLAMO ^ClC^lQK 44 171-4^9 M54 TCLCr*V 44 171 499 *U*3CLS COMCSFO*^CNT O'^'CC 44 AVCNUC DCS ABTS WUSSCLS 1040 BCLO'UM TCLCF^MC 31 j 9lt 9800 TCLCFAI S3 I 903 I5 VIA FACSIMILE Dr. Charles H. Powell Cohrssen Environmental Inc. 1990 Lombard Street Suite 200 San Francisco, CA 94123 Dear Dr. Powell: Enclosed is a copy of Cesare Maltoni's lecture on his vinyl chloride experiments presented at the Bologna Symposium on April 9-12, 1973, as published in Cancer Detection and Prevention Volume II (Excerpta Medica 1974) Please let me know if you have any questions. Sincerely yours, TV/dld Enclosure / Theodore Voorhees, Jr. f bcci^yMr. Sweeney (w/o end.) Mr. Spears (w/o/ end.) PPG 188 Occupational carcinogenesis Cesare Maitoni htuuco dt Oncologia 'F. Addam'and Centro Turnon. Bologna. Italy Occupational carcinogenesis is one of the most interesting, tragic, important and difficult fields in 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 tumours. It Is tragic from a human point of view, because work which is per se 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 ments. Moreover from the factones they spread to the general environment, so that they come to be an ecological problem. Finally, occupational carcinogenesis is a difficult field to approach, because the care of the workers' health is often in conflict with the product ive interests of the factones. Industry has done a lot for 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 1 am aware that speaking on occupa tional carcinogenesis is a complex and difficult task. Experimental carcinogenesis did not start with the experiment of Yamagiwa and Ichi kawa m 1915, but rather in the 16th century with the observation of the so-called mountain disease' in miners of Joachimsthal, 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 tn 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 1 894 Unna reported on the frequency of skin cancer found m maritime workers, and he considered it due to excessive exposure to sun light. In 1895 Rehn, a surgeon from Frankfurt, reported at the congiess of the German Society of Surgeons, 3 cases of bladder tumours found among 45 workers from a factory which produced fuchsine. He thought that the tumours were caused by aniline, but in fact it was shown, several decades later, that they were due to other 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 of industrialization, mainly due to the progress of chemistry. The most important thing to do in occupational carcinogenesis 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 also to try to assess the degree of risk. If the risk is related to an agent already known to be oncogenic for man. its detection in the occupational environment should be considered sufficient for undertaking preventive measures. On the *ther hand if the nsk is related to agents, whose effects on workers have not yet been studied and are therefore not yet known, then we have to evaluate the risk they represent : r 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 progress in and the development of this branch of oncology should facilitate systematic experimental testing of agents heavily released in the occupational environ- C. Mai[oni men:. In other words the need of epidemiological evidence in man should be avoided. Ex perimental tests on animals are the more relevant to man, the more they reproduce the conditions of human exposure and eventually induce in animals the same rumours that they induce in man. In this case, the results of experimental tests may be considered larzeiy equivalent to 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. Furthermore we have to consider that the number of agents in the occupational environ ment is large and increasing. Thus, new agents to which workers may be exposed should be submitted first to the easiest and quickest tests, however incomplete those tests may be. Then, for those agents inducing tumours in the experimental animals'in these conditions, more precise and sophisticated experimental tests should be devised. The validity of experimental testing and tne prerequisites for validity have been a matter of long discussions in international TABLE ! Incidence of subcutaneous sarcomas in rats, following local injection of some inorganic pigments Treatment No. of animals Chromium yellow (lead chromate) Chromium oranae dead chromate) Molybdenum orange Head chromate and molybdenum chromate) Cadmium yellow (cadmium sulphide) Iron red 1 iron oxide) Iron yellow (iron oxide) Controls 40 40 40 40 40 40 60 No. of tumours 26 26 36 13 1 0 0 PPG 190 Occupational carcinogenesis meetings and commissions, but of course, in the meantime the existing occupational exposure continues Also, imperfect testing, for example the subcutaneous injection in the rar of compounds, to which man is exposed mainly by the respiratory route, may give some idea of their potential oncogenic risk. In Tabie 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 mat chromium and cadmium pigments should be considered riskier than iron pigments. From what has been said before, the compounds shown to be carcinogenic m 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 in our own or any neighbouring country. Now an apparatus for inhalation 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 chior.de monomer (VC) and of vinyl acetate monomer (VA), which are (particularly the first! of great industrial importance. VC is used in the preparation of polyvinylchloride resin, as a copolymer in saran and other plastics, as a solvent and as a chemical inter mediate, and it is at 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, nephroblastomas and liver angiosarcomas have never been observed as occurring spontaneously in our breed of Sprague-Dawley rats. Only 3 cases of spontaneously occurring Zymbal glands carcinomas in rats (SpragueDawley ) have been recorded in 1962. To our knowledge, no spontaneous nephroblastomas and liver angiosarcomas of rats have been reported in the literature. As far as we know, nephroblastomas have never been repotted to be experimentally induced in rats; liver angiosarcomas have been induced in this species by dicthylmtrosamine. Although liver is the preferential site for onset of angiosarcomas, such kind of tumours have been observed in other tissues and organs therefore VC should be con sidered m our experimental conditions generally cancerogemc for endothelia. Zymbal glands tumours and nephroblastomas may be bilateral, liver angiosarcomas are cften mulnphocal Epidemiological investigations and medical controls should be undertaken on exposed workers Would such neoplastic lesions of kidney and liver unhappily be found in man, given the rarity of these tumours in both animals and humans, it would be a precise indication of the high value of experimental testing in predicting the oncogenic potential oi 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 of revealing the oncogenic risk of an agent is to examine the exposed working populations with methods which make it oossible to assess the incidence of cancer precursors. The incidence of such precursors has been studied by us by exfoliative cytology among asymptomatic, apparently healthy workers exposed to risk, namely among workers exposed to aromatic amines (urine cytology), and among workers ex posed to chromates (sputum cytology). The incidence of cellular atypias m these two groups of workers is shown in Tables 3 and 4 It far exceeds the expected incidence. To evaluate m 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 oncogenic agents produce mainly non-reversible changes, which may continue to develop when the exposure is interrupted, 3. 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: ia/ definite carcinogens, when epidemiological evidence exists, PPG 191 M a lto m 192 TABLE 2 Preliminary results of carcinogenicity bioassay oj vinyl chtoriile monomer (VC) and of vm if acetate monomer ( VA) (From C. Matumi. C. I.efemine and L Gualano. in press) Groups and treatment Animals Toial Survivors Zymbat glands carcinomas (A) No. Animals wrlli tumours Nephroblastomas (B) No. Angiosarcomas Liver (C) Oihei sues No. No. Oilier lype aml/of site No. Total No. 1 VA 2,S00 pptn. 96 IS II VC 10,000 ppm. 69 - 13 3 6- 5 (II) 27 Ill VC 6,000 ppm. IV VC 2,500 ppm. V VC 500 ppm. 72 5 74 16 67 15 5 2 2 3 8 1 (0) 1 (0 18 4 6 3(E) 1 (L) 16 3 5 2 (E) 1 (M) n Vi VC 250 ppm. 67 20 - 3 1 2(G) 2 (N) 8 VII VC 50 ppm. 64 35 - - -- - - VIII No treatment 68 33 - -- Total S77 139 22 16 26 8 10 82 (A) Mclastascs to lung. IB) Melastases lo liver and/or lo lung ami spleen (C) Melastases to lung. (D) Angiosarcomas in subcutaneous libiosmg angioma (E) I intrabdominal angiusarcumas (1 next lo spleen ami I next lo ovary), I ossifying angiosarcoma of neck flj I pulmonary angiosarcoma, I angiusaicoina of uterus. (G) I inirabdominai angiosarcoma (ncm to spleen); I inttallioracic ossifying angiosarcoma. (If) 2 2ymbalglands adenomas. I ................ miaul the car; I mammary carcinoma, I cystnadenucarcinorna of ov,nv (II Seb.n roue *l out........ ..c. o 7 11 * Occupational carcinogenesis PPG 193 lutuiiu UM l i.'i uitul I s.iliv.iiy gl.iiith l ji unum a TAM) 1 / rtyui rn i tf t i ttufaf at VfHifl nutting in vAiv* cv/ajwi/ in tinnnutn umntr\ in huimn th 4 Muff Jttt 1 aitoiy A 11 C 1) Total No ol workers under control 232 159 40 41 472 t l tl 4H 46 5H 20 11 8 16 IS 133 89 < ylul<i}EU.U italVtfS (l'j]).l/IKohniH II ii in 114 14 49 25 73 91 179 43 III III IV 71 51 81 - 20 3 IV 1 1 2 4 IVV - TABLE 4 trequeue v> of adenomatous typical anti atypical hyperplasia, and of squamous metaplasia and dysplasia, in workers exposed to chromium com pounds in one Northern Italian factory Type of occupation Production of chromates and dichrotnates Production or chromium pigment Length ol exposure (yeats) Length No. Up to 5 6 10 11-15 Osei 15 25 14 13 17 Total 69 Up to 5 6-10 1115 Over IS 14 17 8 8 Total 47 Typical adenomatous hyperplasia No. % 3 12 3 21 3 23 9 13 17 |6 l 12 2 25 5 10 Atypical adenomatous hyperplasia No. % -- t7 3 23 16 57 -- -' --- -- Squamous metaplasia No. % 24 96 12 86 12 92 IS 88 63 91 14 100 14 82 6 75 8 100 42 89 Squamous dysplasia No. % 4 16 3 21 4 30 4 23 15 22 2 12 1 12 2 25 5 10 tj (b) highly suspected carcinogens, when strong experimental and/or some epidemio logical evidence is present, (c) 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. The agents, which have been definitively proved or are suspected to be oncogenic for man on an epidemiological basis, are listed in Table 5, together with the target tissues and the degree of evidence. The list of the agents present m 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 Agents proved or suspected to be oncogenic for workers on an epidemiological basts Agents U.V. radiations X-rays Uranium ore Arsenic Evidence 4+ (+) Asbestos + Chromium Nickel Iron ore Bis-chloromethyl ether Benzene (sopropylic oil Soot, tars, mineral oils, cutting oils Carbon black Mustard gas Aromatic amines 4* * <+) 4- + (*) 44f 4- Tumours Skm carcinomas Skin carcinomas Leukaemias Pulmonary carcinomas Skin carcinomas (lung carcinomas) (liver tumours) Lung carcinomas Pleural 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 TABLE 6 Agents -o Beryllium Cadmium Cobalt Lead Selenium Zinc Carbon tetrachloride Chloroform Vinyl chloride trJ to be carcinogenic for workers on an experimental basis Pesticides (DDT. aldrin, dieidrin, Aramite, DMDT. Amtzol. Thiuram) Thiourea and related compounds Tannins Detergents Alkylating agents Nitrosammes Azo-dyes Oestrogens Occupational carcinogenesis 25 In Italy carcinogenic occupational risk exists for workers who are iai exposed to chromates, mainly the ones working m factories where chromates are produced, id; exposed to nickel, mainly the ones exposed to nickel-carbonyl, io exposed to asbestos, mainly the ones who extract it from its natural source, or workers in factories where asbestos is used for manufacturing; id) in factories making shoes, purses and raincoats, exposed to benzene, le) in factories producing carbon black from mineral oils; and ,'p 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 m Northern Italy. Pleural 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 (Vigevano), Bologna Province and Tuscany. The incidence of bladder and other urinary tract carcinomas among workers in 5 Italian dye-stuff factories are shown in Table 7. In these factones workers had been exposed to (3-naphthyIamme, benzidine, a-naphthylamine, Auramine, fuchsme, 3,3-dichlorobenzidtne. Now m our country the production of (3-naphthylamine and benzidine has been withdrawn. One may conclude that prevention of occupational carcinogenesis is a very urgent problem. TABLE 7 Frequency of carcinomas of the urinary tract among workers of S Italian dye-stuff fac tories exposed to aromatic amines Factor;, Total No. of exposed workers \ B C D E Total 286 386 213 135 135 1.155 No. of workers with carcinoma Bladder Renal pelves and ureters 17 1 87 5 44 _ 4 71 159 7 ' In 1 case bladder and upper urinary tract tumours were coexistent. To tal 18 92* 44 4 8 166 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 various 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 TMbLc 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 nsks through the incidence of these changes. It is my opinion that the value of medical checks is mainly to evaluate the risk that is ePidemiological. Early detection of occupational tumours which, as already shown, are jjjamly located in the respiratory and urinary tract, has been, I think, over-emphasized. e know that these tumours are multicentric. In other words all the target apparatus is m sme way affected by the carcinogenic process. PPG 195 6 C. Mattortt Concerning the urinary tract, in a systematic histological study, I have seen that in patients with bladder tumours, 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 diagnose some tumours quite early, but on the basts of 1 5 years' experience with periodic checks of workers exposed to high risk. I doubt that periodical medical examination has a real bearing m saving people with occupational cancer although detected early, or in prolonging their life span. Thus my position is m sharp contrast with those who claim to 'protect' (!) workers exposed to carcinogenic risk with medical examinations. / do hehcvc that the potentialities of medwul examinations should be evaluated at an international level. In conclusion, l would like to emphasize the need of a dose 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 Frieben (1902): Fortschr. Rontgenstr., 6, 106. Pott. P. (1775): In: Chirurgical Observations, relative to the Cataract, the Polypus of the Nose, the Cancer of the Scrotum, the Different Kinds of Ruptures, and the Modification on the Toes and Feet. Hower, Clarke and Pollins, London. Rehn, L. (1895): Arch. klin. Chir., 50, 588. Unna. P. G. (1894): In: Histopathologic der Hautkrankheiten. p. 719. Hirschwald. Berlin. Yamagiwa. K. and Ichikawa. K. (1915): Mitt. med. Fak. Tokyo. 15. 295. busmess/corporate department ENVIRONMENT HEALTH & SAFETY DATE 03/25/98 ORGANIZATIONAL UNIT SAFETY & HEALTH ]RE-PPG JOB HISTORY COMPANY AND LOCATION JOBTTTLE FROM FUNCTIONAL PREFERENCES TO 1 2 1 ZDUCATION__________________________________________ 0feil?iL V|?" CINcfTO W DEGREE IN PROGRESS ____________________________________ fflfRci CREDOS EARNED REQUIRED OTHER ACHIEVEMENTS. ACTIVITIES. TRAINING 1 2 3 4 5 0 7 a 9 10 m PROFICIENCY LEVEL OFESSIONAL SOCIETIES AND ORGANIZATIONS MEMBER STATUS YEAR PPG TRAINING COURSES 1 2 3 4 s 6 7 9 10 YEAf OFESSIONAL LICENSES AND CERTIFICATES ISSUING AUTHORITY RELOCATION INTEREST YR. RECDJEXP. POTENTIAL INTEREST: YES NO GEOGRAPHIC PREFERENCE: ANY AREA U.S. CANADA D LATIN AMERICA EUROPE ASIA PACIFIC RK EXPERIENCE AND KNOWLEDGE CATEGORY DESCRIPTION FUNCTIONAL AREA vl7~ ACTION YRS. EXP. LASTYR B ID 346208934 POWELL,CHARLES H 1897 TILTON DRIVE GUALALA CA 95445 PPG FLSA CATG ORIGINAL HIRE DATE LATEST HIRE DATE CONTINUOUS SERVIC1 E FR 08-01-77 08-01-77 20 YRS 8 KOS PPG 197 PLEASE SEE REVERSE SIDE FOR UPDATE INSTRUCTIONS