Document Gy5vLr3wbxNR9G0zR1E0nVZY

FILE NAME: Exxon (EXX) DATE: 1973 Nov DOC#: EXX047 DOCUMENT DESCRIPTION: Journal Article - Recent Developments Industrial Pathogens - Journal of Occupational Medicine m Review Article Recent Developments in Industrial Carcinogens Robert E. Eckardt, M.D., Ph.D. T h e topic of carcinogens is one about which there is much confusion and also much misunderstanding. This in turn leads to the development of fears and apprehensions. As in clinical medicine, the word cancer in industry immediately seems to lead to despair, whereas our approach should be straight forward and intelligent. I think of cancer in industry just as I do about any other potentially toxic problem in in dustry. What w e need when a problem develops is knowledge-- knowledge of the process, knowledge of the chemistry, knowledge of the exposure. The more w e know the more likely we are to arrive at satisfactory solutions. In this respect, then, cancer in industry is like any other problem solving. First, w e have to have some knowledge of the experimental methods used by oncologists to test for carcinogenicity. In the case of the skin, the tests are relatively straightforward. You w ill note that I say "relatively" because in fact even a skin car cinogenesis test has many elements that may serve to com plicate it. Thus w e know that mice, hamsters, and rabbits do develop skin cancers in response to chemical agents painted on the skin, while rats and guinea pigs seem to be refractory, and monkeys are resistant, taking long periods to do so. Thus the mouse has generally become the animal species used in this type of experiment. Painting is usually done three times a week. If done more frequently the material applied may so severely damage the skin as to make interpretation of results difficult. If done less frequently the latent period for cancer development may be so long that the animals die before developing cancer. Painting should be done w ith a minimum of rubbing to avoid damaging the skin. Some workers even use a micropipette so that no rubbing at all Is done, just letting the material spread over the shaved skin in an accurately measured dose at each application. The animals should be weighed periodically because if the material being painted is toxic it may interfere with their growth, and w e know that this in turn w ill interfere with tumor development. Because a skin-painting experiment takes so long-- up to two years-- people are always looking for shortcuts. They want a chemical test or an accelerated biological test that w ill give them an answer in a few days or a few weeks. However desirable this may be, so far none of them have held up when examined closely. Thus it was found that some carcinogens would cause atrophy of the sebaceous glands of the skin, and this was once proposed as a "quickie" test However, in a study of 130 compounds, Bock & M und1 found that some car cinogenic compounds did not cause sebaceous gland atrophy, while some non-carcinogenic compounds did. Some chemical Dr. Eckardt is Director, Medical Research Division, Esso Research and Engineering Company, Box 45, Linden, N.|. 07036 904 tests may have limited application, but because of the wide variety of chemical compounds that have been shown to haw carcinogenic activity it would be anticipated that no single chemical test would have universal applicability. Suffice it to say that an expert panel convened to advise the Food & Drug Administration concluded that there were no truly satisfactory short-term tests that had been sufficiently proven that they could substitute for long-term carcinogenesis tests.2 Some people have recommended that the material to be tested simply be injected or implanted subcutaneously into rats or mice. This has the advantage of a known dose and minimal handling of the anim als.3 But this method so tar has been shown to produce malignant tumors (sarcoma! in response to cellophane, Dacron, polyethylene, polyvmd chloride, silastic, Pliofilm, Nylon, polymethyl methacrylate- polystyrene, Saran, Ivalon, Kel-F, Teflon, silk,4 and glass covw slips.5 In our hands, w e found that a complex oil shown tobe carcinogenic to the skin when painted caused a local absce* when injected subcutaneously which subsequently sloughed out without tumor formation. Thus this route of testing ma* have limited application, especially if tumors are produced at a site distant from the site of injection, but if sarcomas at the* of injection are the only tumors formed, interpretation of the significance becomes extremely difficult. Another suggested test Is that of implanting the-material * the bladder of mice. This suggestion arose, I believe, from a entire misconception. Thus in the study of bladder tum ors curring in workers in the dye industry, beta-naphthylamii* when administered subcutaneously, w as shown to product bladder tumors in dogs but not in mice. In searching ford* reason for this discrepancy it was found that both man and dogs excrete 2-amino-1-naphthol as a metabolite of ** naphthylamine in their urine, whereas mice do not O' Georgianna Bonser, in England, concluded that maybe bit* naphthylamine was not the carcinogen after all but d* metabolite 2-amino-1-naphthol was. To test out this theory d * impregnated small wax pellets with 2-amino-1-naphthol V * implanted them surgically into the bladders of mice. 5/ enough, the mice developed bladder cancer. However, sequently it has been shown that cholesterol, glass, ***** acid, magnesium stearate, hexadecanol, octadecand, *' naphthalene6 (the old-fashioned moth ball) all produced bj*| der tumors and cancers when implanted into the der. None of these are suspected of being carcinogenic, this test does not seem to be a very sound one. ' f Ml Incidentally, these studies of the metabolism of naphthylamine have led to extensive metabolic studies brisk scientific arguments about what truly is the carciodr" ^ agent. O ne school supports the 2-amino-1*naphthol meU<** ilte- -:.r -S-Ji. of the wide iwn to have it no single Suffice it to ood & Drug satisfactwy in that they s .2 iterial to be reously into n dose and ithod so far (sarcomas) e, polyvinyl nethacrylatt I glass covet shown to be oca I abscess tly sloughed testing may reduced ate as at the she ition of theh m'5 material b> ;ve, from r tumors C* ahthylamine, to prodi ching for d * jth man wd lite of ben do not 0 maybe be#* all but lb* iis theory she Su# - sub stearic and bbdblad- Thus as the carcinogen, whereas another believes that hydroxylation of the nitrogen atom of the amino group (so-called N hydroxylation) is the carcinogen, w hile yet others believe dif ferent metabolites are the true carcinogen. These studies have been fascinating from a biochemical standpoint and have served to keep many cancer biochemists hard at work in the laboratory but probably do not have much practical im plication for industrial cancer prevention. However, the studies of the implantation of cholesterol, glass, stearic acid, and other materials into the bladder, previously mentioned, may have serious practical con siderations for other studies. Thus diethylene glycol and other materials are claimed by some to be a carcinogen on the basis that they have produced bladder cancers in mice. However, such tumors and cancers never developed unless first a blad der stone was produced. The question then arises-- is the chemical a carcinogen, or is the stone the carcinogen? It is in teresting to note that the first experiments with cyclamates were undertaken w ith such bladder implantation techniques and had to be discounted until feeding experiments were com pleted. Even now the cyclamate picture is not clear because there is some question that the experimental animals may have been infected w ith bladder parasites. It is w ell known that Bilharzia, a bladder infestation of humans by Schistosoma hernatobium, is associated w ith bladder cancer. In Egypt, where Bilharzia is endemic, bladder cancer incidence is quite high. The Schistosomes enter the body through the skin from water in which the Egyptians are walking in caring for their fields. From there they enter the bloodstream and ultimately end up in the bladder. Incidentally, the secondary reservoir for the Schistosoma hernatobium is the snail, and much work Is going on trying to find an agent that w ill kill the snail without producing other undesirable ecological effects. The approach is like killing the mosquito to eliminate malaria. Another approach that has been recommended to try to shorten the necessary test period for carcinogens is the use of newborn or very young (suckling) m ice.7 It was suggested that an increased incidence and earlier appearance of malignancies could be obtained from a single injection of potent car cinogens. However, newborn rats did not respond in the same way as newborn mice.8 Rather, they responded like adult mice. Further, more complete studies have shown that this test method probably has few true advantages.9 It may be that the use of newborn or very young mice was predicated on the ab sence of detoxifying enzymes in the newborn w hich sub sequently appear as the animal ages. It is known that a benz pyrene hydroxylase exists in the gastrointestinal tract,10and it is further known that newborns are frequently lacking enzyme systems that are present in adults. Even today, however, there ate those who strongly urge the newborn as a test animal system. Turning to experimental lung carcinogenesis, it is now beginning to appear that multiple factors are probably necessary to produce lung cancers in experimental animals. Thus in rats a combination of repeated influenza virus in fections plus ozonized gasoline11 or sulfur dioxide and benzo(a) pyrene12 or 7,12-dimethyl-benz(a) anthracene plus india ink13 or, in hamsters, hematite plus benzo(a) pyrene14 all have led to lung cancer production. The evidence indicates that pure polyaromatic compounds like benzo(a) pyrene are rapidly removed from the lungs. However, when introduced with particles or with SO 2 w hich may impair the ciliary Journal of Occupational Medicine/Vol. 15, No. 11/November 1973 removal mechanisms, residence time within the lung may be much prolonged, and it is this increased residence time w hich the experimentalists believe leads to the production of lung cancer. This experimental work on lung cancer is in its very early stages, and it is too soon yet to draw definitive con clusions on it. One very interesting lung cancer experiment in rats was that conducted by Laskin et a/.15 These workers exposed rats to 0.1 ppm of bis(chloromethyl) ether six hours per day, five days per week for a total of 101 exposures. Nineteen out of 30 rats so exposed developed squamous cell cancers of the lung or can cers of the nasal epithelium. O f interest in this connection is that subsequently in a chemical plant in California where bis(chloromethyl) ether was produced several cases of lung cancer were reported. I have only seen newspaper-type reports of these cancers in these chemical workers, so I am not able to comment intelligently further on them. If in fact this is so, it may represent the first time the detection of a carcinogen by laboratory tests has subsequently been followed by the ap pearance of cancers in humans. Usually epidemiological studies have shown the presence of cancers in humans, and this in turn has led to an intensive search in the laboratory for the carcinogen. It is of interest that these workers have also been able to produce lung cancers in experimental animals w ith 2,3-dichloro-p-dioxane, ethyl bromoacetate, and epichlorhydrin,16 although these are weak carcinogens. The demonstration of weak pulmonary carcinogenesis in animals with these compounds should alert everyone to minimize human exposures to them and to follow workers exposed to them with extra vigilance. For completeness it should be mentioned that pulmonary carcinogenesis in anim als has been demonstrated for beryllium,17 nickel carbonyl,18 and radioactive materials.19 In terestingly enough, inhalation pulmonary carcinogenesis has not yet been demonstrated in experimental animals for chromates20 or asbestos,21 although the former has produced malignancies when injected intramuscularly or intrapleurally,22 and the latter has produced pulmonary fibrosis (asbestosis) when administered by inhalation21 and malignancy when given intrapleurally23 in animals. Finally, various epoxides, lac tones, and peroxy compounds have been shown to have a car cinogenic potential.24 W ith this far-from-complete review of experimental car cinogenesis w hich has been given only to emphasize the com plexity of the problem, I should now like to turn to some in teresting recent epidemiological work. I shall not try to cover skin cancers in coal tar workers, mule spinners, cutting oil users, wax pressmen, and the like, lung cancers in chromate workers, nickel refining, or asbestos workers (other than in sulators), bladder cancers in the dye industry, nasal cancers in nickel refining and isopropyl alcohol manufacture, or bone sar comas in radium dial painters because these have been covered in my book25 or other works. Presumably w e are discussing recent developments. Much publicity has been given recently to asbestos as a pulmonary carcinogen and producer of pleural or peritoneal mesothelioma. Actually pulmonary cancer in asbestos workers has been recognized for 25 to 30 years.26 The condition was catapulted into prominence by the observations of Wagner27in South Africa among miners and processors of asbestos and especially by Selikoff and his coworkers28 among insulation workers. What has made Selikoff and his associates' work 905 unusual has been their use of union records to study this con dition. Because insulators usually don't work for one single employer, but rather move from job to job wherever work is available and thus work for multiple employers, it was very difficult to obtain any kind of picture of what their health ex perience had been except through union records. When these were examined it was found that of 632 workers w ho entered the trade before 1943 and were traced through 1962, 45 had died of cancer of the lung or pleura. O nly 6 to 7 men would have been expected to die of lung or pleural cancer if the nor mal incidence had prevailed. Another interesting observation has been that the incidence of lung cancer among asbestos in sulation workers who smoke cigarettes is far greater than for those who do not smoke." It is to be hoped that the industrial hygiene measures introduced among these workers w ill soon have this situation under control.30 There is still some dispute among workers in this field of whether the asbestos is a direct carcinogen or whether its carcinogenicity is due to certain oils that may be present in the asbestos naturally or through con tamination.31 32 O f perhaps more concern has been the ob servation that asbestos bodies can be found in the lungs of a very high percentage of people w ho come to autopsy and have never been exposed to asbestos in their w ork.33 Although this is of concern to many people, no one is yet prepared to say what its significance is. It is important not to jump to as-yetunwarranted conclusions on this observation, as I have often heard Dr. Selikoff say in talks on the subject. As many people suspected, lung cancer incidence among uranium miners has been shown to be increased.34 Again, the risk seems to be much higher among smoking miners than among nonsmoking miners. There have been 62 lung cancer deaths among 3,414 white miners and two among 761 non white miners. There seems to have been established a doseresponse relationship w hich may hopefully permit the elimination of this disease in the futute. Recently an outbreak of bladder cancers occurred among workers in the electric cable industry.35 This apparently resulted from the former use of beta-naphthylamine as an an tioxidant in the rubber sheathing used on the cables. Since this material has not been used by the rubber industry as an an tioxidant since about 1945, it is anticipated that these tumors w ill soon disappear. However, it does point out the long latent period that can occur, and that in searching for etiologic agents in occupational cancer it may be important historically to go far back into the processes to find the responsible agent. Among 8,047 workers in a metal smelter works, 147 res piratory cancer deaths among 1,877 total deaths vvere report ed.35 The causative agent in this case was believed to be ar senic trioxide exposures by inhalation, although some relation ship to SO i exposures was also demonstrated. This recalls the association between sulfur dioxide and benzo(a) pyrene in animals demonstrated by the NYU group and previously discussed.12 A real surprise has been the demonstration in England37 of an increased risk of nasai cancer occurring in woodworkers in the furniture industry. This seems to be associated w ith the use of hard woods. To date, no one has come forward w ith a good guess as to what the causative agent might be in this situation. Undoubtedly/this observation w ill lead to extensive laboratory studies, both chemical and biological, in an attempt to un cover the causative agent. The accumulation in the literature of cases of leukemia 906 following benzene exposures38-41 leads to the inevitable con clusion that benzene is a leukemogenic agent, particularly in cases that have previously displayed a panmyelopathy.44 Although this had long been suspected, the data reported in the literature was not sufficiently convincing to establish the leukemogenic nature of benzene, However, the more recent observations seem to establish this association beyond a doubt. More recent observations of chromosome changes in workers exposed to benzene45 46 lend further weight to the leukemogenic nature of benzene. In any event, in our own operations w e are proceeding as if benzene was a leukemogenic agent, eliminating exposures wherever possible and reducing them to the lowest possible level where com plete elimination cannot be accomplished. It has been reported47 48 that lung cancer incidence in fluor spar miners is 29 times the expected rate. It was found in this situation that radon and radon daughter exposures are in ex cess of the maximum permissible concentrations and it is believed that this is the cause. In this respect, these lung can cers are similar to those seen in uranium miners and in the old Joachimsthal-Schneeburg mines. : A study of lung cancer among coke oven workers in the steel industry49 showed that they suffered a 2-1/2 times in creased incidence of that disease. This increased to five times among men w ho worked topside on the ovens, and to ten times if they worked five or more years fulltime topside. It is likely that exposure to very high levels of benzo-a-pyrene and similar polycyclic aromatic compounds occurred, although it is quite possible, due to the complex chemical nature of coal tar, that other promoting or co-carcinogenic, such as phenols or nitrogenous, compounds have contributed to the increased in cidence. Undoubtedly, intensive chemical and biological studies of this situation w ill be undertaken w hich w ill in time elucidate the causative agents and their comparative significance. I have tried to develop for you tonight some of the more recent developments in experimental carcinogenesis as applied to industrial problems, and some recent epidemiological studies of industrial cancers. I believe our approaches to oc cupationally induced cancer should not differ from the ap proaches w e use in any potential occupational toxicity problem. W e should study and become intimately acquainted with the processes involved, not sim ply by Studying engineering or flow diagrams, but by actually getting out into the work place and observing just what is done. This w ill give us some idea of the personal hygiene of the workers involved as w ell as possible industrial hygiene measures that may be ap plicable. W e should conduct appropriately designed toxicological tests, in this case carcinogenic tests, un derstanding fully the limitations and pitfalls of any such tests w e conduct. W e should carefully examine the workers in volved to detect early signs of exposure or early pre-cancerou* changes. Thus appropriate urine or blood analyses for nickel <* chromium, or for phenols in the case of benzene exposures should be made. In some cases early biopsy or Papanicolaou smears of appropriate secretions should be undertaken. M every opportunity, w e should stress the avoidance of un necessary exposure. I can think of no area where' the cooperative efforts of industrial hygienists, industrial nutses and industrial physicians can have a more salutary effect th* in the control of industrial carcinogens and thus in the cootm* of occupational cancers. Recent Developments in Industrial Carcinogens^/EcMf* Ref* j. l!v M 2 : for S<) f! th4 npl !. (. rarcir. 4. f li-em- 3. 5 * Ap/ : 6. B i mto t! 7. P heme n. t. : , inogr 9. T. ;!-racer 10 \ rstroir ! 1. V ! "t ex i | e 0 7 .| 120 ! : ollutai l 70 | 13. S j '3 1305 | 4. s- ; :'>n hat : 15. I i Iialaiii n. : 16. In i ; >?allh 5 1 0026: 17. V, ' -xicolo ' -meets. --rgy < ; '"SS, |p 8. Su " mors ii ' <`hol 4f 9. I K : '-eting < 20. Sipi - iremical' '-ch [nvi 21. Wa20 I. 196 ' 22. Pay ' '-mpoun' 23. 5mi> t'ifed by 74 Van Journal of i References 1 Bock FG, and Mund R: A survey of compounds for activity in ihe suppression of mouse sebaceous glands. Cancer Res 18:887,1958. 2. 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