Document Y75pLXmjLr4o53dwE4Zr0jQV

't ` ,* i________________________ ^^ ASSOCIATION Quarterly VOLUME 17. NUMBER. 3 SEPTEMBER 1954 ' 4 Z+Q ocptonoffr, iSZo ? :' Conduiiofl the effects are reversible, although in severe 2I .' !S 'T'hqle EXISTS a continuing need to have a coordinated, objective appraisal of radia tion hazards to develop a definition satis factory to health officers in government and cases recovery may require years (in man). No threshold limit defining the level for safe exposure has yet been set. Acrylamide represents an interesting industry and to legal authorities. Having de demonstration of our current inability to fined a "hazard," appropriate controls can be predict the grave physiologic consequences more dearly spelled out on the degree of from chemical structure; the closely related competency of the supervising personnel. amide, propionamide (CHsCHjCONH2), is used as an .animal feed supplement. Here, In the Field of Toxicology again, is another striking case of the addi tion of a second double bood in the molecule to form a conjugated system with confer HER3ERT E. STOKINGER, Ph.D. ence of remarkable toxicity. Another well- Occupational Health Program known example is the 44-fold greater toxici U.S. Puoiic Health Service Washington, D.C. ty of crotonaldehyde compared with its saturated analogue butyraldehyde (Skog, Acta Fharm. Tox. 6, 299, 1950). Less well' known, but equally striking is the highly IN THE BRIEF space allotted to review recent lacrimatory power of conjugated unsatur developments in the field of industrial ated nitrocompounds such as 1 nitroiso- toxicology, those subjects have been selected butylene compared with the unsaturated but that appear to be of interest, either because not conjugated isomer, l-nitroisobutyl-2-ene of the unique character of their response or which has no marked lacrimatory powers. their indications of importance to industrial The potent irritating capacity of the di health. In the vast field from which to isocyanates discussed below are other ex choose it is obvious that other selections amples of the effects of conjugated unsatur might have been made equally as well. ated compounds. Examples could be multi New Hazardous Compounds plied almost endlessly. * As a new group of monomeric substances A CSTLAitlDE, CH==CH-CONH-, a chemical used in foam rubber, lacquers and for other 1 intermediate of great potential useful purposes, the aromatic diisocyanates, es ness for the formation of polymers and pecially 2, 4-diisocyanotoiuene (TDI), 1. copolymers, plasticizers, dispersants, and 5-diisocyaconaphthaJene, and 1, 4-di- other purposes, has the unusual property of isocyanobenzene present interesting toxico being insidiously neurotoxic at relatively logic properties. Although extremely inert low levels of intake, while at the same time in polymeric forms, and possessing a very showing unremarkable toxicity from acute low oral toxicity 1-3 g/kg,* these aromatic doses (oral LD50, 170 mg/kg).1 Acrylamide isocyanates, particularly the naphthalene is lexicologically remarkable in other ways, derivative, are exceedingly irritating to L It shows practically no species- rnriz the upper respiratory tract, producing his tion; effective doses for the cat, deg, and tologic changes in animals at 0.09 ppm and rat were essentially the same. death at 1 ppm upon repeated inhalation ex 2. Its physiologic effects are produced posures. Man also responds at exceedingly equally readily by any route, oral, skin or low concentrations with evidences of allergic eye. ^ sensitivity such as asthma at air levels well 3. X definite quantity of acrylamide will below 1 ppm. Peculiarly sensitive individu produce the characteristic central nervous als may snow responses below 0.1 ppm, system syndrome of disturbed gait, postural which is below the odor threshold of toluene tremors, visual and auditory hallucinations diisocyanate for many individuals. and muscular atrophy, irrespective of the A level of 0.5 ppm of TDI produces throat dosage schedule used. irritation. The tentative threshold Limit has 4. There is an anamnestic response, in been set for TDI at 0.1 ppm. In our present that following cure, leaser amounts of state of Imowledge it is believed that the acrylamide recall the syndrome. Fortunately upper respiratory tract is first involved i following ia.TA-acoa oi .cw -- the isocyanate, pulmonary edema occurring reported.* only at far higher TDI concentrations. Ail It is recognized that the boranes are but evidence to date indicates no other type of additional examples of noometal hydrides systemic involvement from the isocyanates such as phosphine, arsine, stibiae, hydrogen if the respiratory tract itself is free of in sulfide, etc., which are characterized by volvement. Moisture greatly reduces the their exquisite toxicity. toxicity of 1. 4-diisocyajiobeiuene presum Although ozone is by no means a new ably by hydrolysis and destruction of the compound, two factors have been shown to unsaturated conjugated system. have remarkable effects on modifying its Three boron hydrides, diborane, penta- toxicity, exercise and pre-exposure. Exercise borane and decaborane have received con during exposure to ozone has been shown by siderable toxicologic and pharmacologic the- research work at Occupational Health study.M Used as high-energy fuels these Fieid Headquarters^ U.S.P.H.S. to enhance boranes are highly hazardous by all practi markedly the toxic effects of ozone; simul cal routes of entry into the body. taneous, intermittent exercise during a 6- Diborane a gas at room tempera hour exposure to otherwise noa-injurious ture (b.p. --92lsC) differs from the others concentrations of o2one (around 1 ppm by in toricoiogic action in possessing no neunK voLj proved lethal to rats and mice. On the toxic properties presumably because of its other hand, pre-exposure to the same non- ease of hydrolysis; it is however, acutely, injurious levels of ozone, without exercise, subacutely and chronically injurious to the resulted in a rapid development of tolerance Jungs, producing congestion, edema, and. to multilethal doses of ozone that persisted hemorrhage in higher doses and in the kid for at least four weeks. The tolerance which neys it leads to the production of tubular developed within 24 hours, protected the casts. The threshold limit of exposure- has lungs from the pulmonary edema and been tentatively set at 0.1 ppnr; this is con hemorrhage common to lethal exposures but siderably below its odor threshold of from did not abolish the characteristic spasmodic 2-J ppm. breathing or the narcosis. Pentaborane (B-H9) is the most hazard ous of the three boranes. This liquid, (b.p. New Industrial Cencerigens. 5SC) whose vapor in a two-hour exposure at JT"HSS is a tendency to belittle the carcino 14 ppm results in immediate death of mice, genic potentiality of many substances on at lower concentrations, produces symptoms the basis that carcinogenicity in animals is of weakness and tremors indicative of no proof for carcinogenicity in man. It central nervous system involvement but would seem a more reasonable view to re without the lung involvement seen with di gard all such, compounds at least potentially borane. Cumulative effects are seen with carcinogenic in man. low repeated doses. Skin absorption is a Sufficient work on beryllium now seems possible contribution to the over-all toxicity. to have.been done in one laboratory (Sara On the basis of hazard from the vapor and nac), at least, by Vorwald, Schepera and its severely toxic effects, a tentative thresh- Scheeltf to establish beryllium as a carcino has been set for this compound of gen in the rat. Inhalation of beryllium sul 0.1*1-ppm, No medical preventive or thera fate for several months (six) produced peutic effective agent for this compound has eventually what was interpreted as an yet been developed.; complete protection is adenocarcinoma of the lung. The cancer has afforded by airiine gas-masks or a mask been successfully transplanted subcutane cartridge layered with soda lime, silica gd ously in rats, whence it metastasized to the and activated carbon.7 lung and the lymph nodes of the mediasti Decaborane presents a toxicity num. Inhalation of beryllium phosphor picture rimliar to, bat siightiy less than that (13% Be) produced in three to six months of pentaborane but as it is a solid, it pre lesions in the Jungs which appeared to be sents less of a hazard than pentaborane; ac squamous cell carcinoma. The beryllium cordingly its tentative threshold limit has cancer has not been produced by other been set at 0.05 ppm. The cardiovascular workers although it is not rat-3train de- i t i * 3i2 Septeiriber, 1 pendent in the hands of the Saranac workers. Alkaline phosphatase inhibition appears to be the first step in the physiologic process leading to tissue changes. It is believed that the Be(OH)*, a form through which all beryllium compounds pass in the fluids of the body, initiates the reaction. The lack of success of other workers elsewhere to re produce beryllium cancer is still disturbing, however. Doll10 has found that the incidence of lung cancer among* 105 English asbestos workers employed more than 20 years was tenfold that in the normal population. Cartier'1 studying- over a nine-year period 4000 asbestos miners in Canada, involving" _ 123 cases of asbestoaia, 40 of them with autopsies, found six of these have bron chogenic carcinoma- Seven cases of lung' cancer were found among asbestos miners with no asbestoais. - With such relatively small numbers of cases one must be extremely cautious in, drawing the conclusion of a causal relation ship between exposure ^nd the disease. Snegireff and Lombard'12 several years ago pointed out in a study of lung cancer in ar senic plants involving similarly small num bers of cases that cancer deaths in any decade could have by chance been either far leas than in the population as a whole or several times more than found in the plant. The question to resolve then in the asbestos exposures, is whether a 10-foid greater in cidence of lung cancer is large enough to be significant when dealing with small samples of this sort. Before a final decision is -reached it would seem well to wait until a more impressive number of cases has been documented. Moreover it seems to this - author that the question of the nature of the asbestos in different localities and the associated minerals such as chromium and ' nickel, both recognized cancerigena, seem to have been too little considered. Asbestos is a fibrous form of several different species of minerals, a point commonly disregarded. Hydrocarbon Products of Combustion ABCQfOCE?nc hydrocarbons have now been shown to be present among the exhaust products of diesel and gasoline engines,13 and in the air of English14 and American cities.15 These products have been shown furthermore to produce akin tumors in mice. Although these findings were made :n c necticn with community air poilu: studies, diesel and gasoline engines are u in many industrial operations. Efficient : innocuous operation of a diesel engine fr an atmospheric pollution view has b pointed out as possible, moreover, withe costly engine redesign.13 The fact tha: man lung cancer has not yet been proven arise from the inhalation of these hydroc bon products should not act as a deterr* to an active program to reduce the air c: tamination of working areas from t: source. Recent figures on lung and brooch cancer from smokers and nonsmokars urban (Liverpool) and rural areas1* sm definitely an urban "factor." The benzp rene content of the air of urban areas w eight to 11 times greater than in the ru: areas, a ratio which corresponds with : estimated mortality ratio among nc smokers in these areas. Although the ecus relation seems tenable, it should not considered proven, as a considerable part the evidence rests on the statements of *J widows of the deceased as to their sznokir habits. Sledder end Skin Cancer TT has NOW" been repeatedly found that amino diphenyl produces carcinoma < the urinary bladder of dogs fed this sui stance,17"19 the last of these confirming n ports being that of Deichmann in 1256. Th cancer was predominantly squamous i type and was produced from total dose ranging from 3Qg (English workers) : 113g, 3 to 10 g;kg (American workers;. Th British investigators consider 4-amir diphenyl as a more effective bladder car ciaogen than either benzidine or 2-acsry aminofiuorene, and at least as potent a. beta n&phtbylamine. A resurvey of the British chemical dye in dustry30 produced statistical evidence tha: bladder tumors are associated with the manufacture of the dyes auramine or ma genta, (aminodipneayl and aminotriphenyimethane dyes (but do not necessarily arise from contact with the finished dyes them selves. Aniline, however, has been definitely excluded as a causative agent in bladder tumors, at least in the British chemical in dustry over the years 1910-1952. Straight-run distillates21 and higher boil- Industrial Hygiene Quarterly . rr-i*-* w-f* f l September, 13SS the difference from a number of foreign in vestigators familiar with trichloroethylene exposures. The consensus of the foreign investiga tors, Ahimark (Sweden), Truhaat (France), Grandjean (Switzerland) and Soucek (Czechoslovakia) in answer to the above four questions, was that neither impurities in^the trichloroethylene nor faults in sam pling and analysis of the air are believed to. account for the differences. They believe rather that their more' thorough medical evaluation, especially neurologic examina tion, tend to account for their appraisal of trichloroethylene as a more severe hazard to health than considered elsewhere. An swers- to the more difficult fourth question of the role of national idiosyncracies were either not forthcoming or were admitted not to have been studied. The question may have air important bearing on the problem, however. Evidences of geography or na tional differences affecting metabolism of an industrial agent have been obtained from a comparison of vanadium ore workers in Peru and in America.** * Measurable changes in fingernail cystine occurred in Peruvian workers at^irinary levels above 10/ig/I whereas levels greater than SOfig/1 were required before changes of similar magnitude were found, among U. S. vanadium workers. In defense of the U. S. position of 200 ppm thresh old limit for trichloroethylene may be- cited the unbeiievabiy low air values ob tained by the European workers in the area of trichloroethylene degreasers (Grand- jean),23 the use of trichloroacetic acid as a means of evaluating safe exposure levels (Aairoark)37 and the lack of objective evi dence in the U. S. of injury among tri chloroethylene workers chronically exposed over a `period of many years. Further ex ploration, both medical and toxicologic is needed to clarify this important question. Rerereneas L Gocx. H. Toxieity at AcryMaiida. Lectar* 4*. U MeCtanaf LAboratPrioa. ClnanaaM, Ohio. 1964. 2. Tuba. 2. F. ZaPT. 2. at ai: Tstierty at tbo Dliwykaat^. DusuMb at Kenoriat Laboratories. Claannul, Ohio, February. 1954. 3. Kjlaocow, E. S.; Tojtiatr end Health H*a*rd at Bom* Hydrioo*. AMA ArcA lad. Myg. >5 Oer*p. Med1:514, 1M. 4, Sn*g.r. /. I.: Suhaoute Toxicity at DaeabormAe- and Protaborane Vapora. AMA ArtA. lad. Ht9. 4 Ocm*. MaA. 10:305. 1954. I L Aeau Toaieity Studio* at DmboaB*. AMA AreA lad. Hemlh. 11:132, 1955. C. IZ Litmat at Repeated Do*a* at Doeaborane for Laboratory Anirnak AMA ArtA ImA HaallA 11:135, 1955. . 7. Hiu. W. S. Svtxutr. J. L.: Gao-Maek Pmtutlaa araiaat trafaorua AMA Arab. ImA Htg. tt Ocrwp. Med- 10:59. 195A. 5. Wau9bm. B. IUchaadsok, 2. A-- gaooB, 0. 2a Cardlo-auiAr Action* at Decaborana. J. PAorea, ppt, .fherati- 114:357. 1965. 9 Sc*Era*. C. W. K.: Oof-yUlum Cancer la the Rat Rnonod at InduatriaJ Syrian* Foundation Annual HhW (a*. PUt*burph. Koventbar, 1955. 10. ^<-4. JL: Mortality fnua Lunc Cabear ia A*bi Ua Workara. SAC J. ImA MaA. 12:51, 1955. It, Cartu, P.: Clinical Obeervatloea at AabeBtooia ia. Via* aad Mill Worker*. .IMA Artk. 1mA. ffamltA 11:204. 1955. 12. Sues:*.iff, t- a. Lu*KAa, O, M.: Araenic and Caneor. AMA Arek. UA H*g. A 0<np. MaA 4:199. 19SL IS. KwTW, P_ Fauc H. L_ Tuoxax. ML: Aromatic Zydroeartaa* 1IL C*re:ooanlaty of Ezbauat Crncu. AMA Arek. lad. HerUtX. 11:112. 1955. 14. Wtua, Jt. E.: Benxopyrene Content at Town Air. Sn'L J. Camcrr. 4:5. 1962-- ' 15. Ckamios, La Privet# Communication to Author. 1ft. Stock*. P_ Caothia. 2. 3C; Luay Cancer Data Rato* aoionf Smor* and Xvaamukem. SnC MaA J.. XI (Oslobar 15) 1955. pp. 924*929. 17. Kutru. W. C-; Henat Development in Zaviron-- nontax Caneor. AMA Arek. PalA. 55:350. 1954. It. WALrect, A- L- Wicuajcs. M. R. C~ Roacxnt. D. C.: Turnon at Urinary Bladder ia Docs after Iaeatioa at l-AminubipheoyL tint. J. 1mA MaA 11:105. 1954. IS. Ducmkamn. W. S. at ati Camiaosoaia Action at ^AmiAobiphrari ia tho Do*. AMA Arek. imA Haaitk. 13:5. 1954. 20. Case. R. a. M_ Pxaxsok. 2. T.: Tumors o< tho- Uriuarr Bladdar ia Workmen Eancod ia '^o MabuIao* tar* at Cortaia Dymraff ia SritAJa IL Snt. J. !*A Makm 11^13. 1954. 21_ Woueuouas. D. Im lawtn, J. 0.: CoApaaitioa at Stmcat Rub DiaoUataA. J. H*g. (Caah.). 45:121. 1950. ZL Sami. W. SL_ SUKeauaa D. A_ Sucoiba. X.; Eaprim*atal Aaiy*a at tho CAmioo**nie Activity of Cortaia Fotreiouta Produeta. AMA Arek. laA Hygm 4:299, 1951. 22. ChuscxsUA.^K. C^f.D.: OeeapatieaAi Expoaur* W Cutri"*' J --v.v. 70:450. 1954. 24. CtLAAN. 2. P. W, VfcusU2tQ*rreK. S. D.t CutUrt* 'Oi aaa Squamoua toil CAmiaoaa. Jnt J. 1mA MaA. 12:2*4, 1945. 25. 8tUtu<4tA4C. D. 2.1 UaBabJUbod Report*. Occu pational HoJth Pioid HaadauArtora. Clacianati. Ohio. 3ft. 7usk, 2. Tm at aX: Toxicity of tho Product* formed by tho Thoraial Dccempoaibaa of Cortaia Orraate SuMtAAcos. A1HA 0*ar^. 14:154. 1954. XT. AKLAABK. A. Triton. I_; Should tho I AQuwabio Coacntnooa at Trichloroochyiono and Similar Suhataacaa b* RodueodT SarkycA w .Vera. HlO. ndaor^ 34:155. 1955. 22. MousrTAiK. T_ StockBi. T. R. 2a Srorrwca*. H. E: StudiM ia Vanadium Taxicoiotr TTL Fincomail Cyaaao ma aa Earky Indicator- of Metabolic ChantTM ia Vanadiunt Worker*. AMA Arek. ImA HaAJA 12:494. 1955. 29. CaAxnjaAjr. n. at ai: Inwtiraaioao into t&o Ef- faca of Ezpoaur* to TrichioroethywB* la Meeaanieai lartrtnna. 5nL J. 1mA MaA. 12:131. 1955- * ! . i V