Document qkrqXob61O9RxYGoo3MpgjQw5

f&tjfdrixer* aiehe letzte Seitc. n efkheediree tee lest page. kt. . Jcrreddjd) geschfitit. Obering eafphotomechaaDchcR) i Fault- und FeRisebsendung ignvria* -bkibea rorbehal^eltiycridf2)tifuspttficke #bnd3tn Zwicken, i defilr Rwischeck 'dee Vetweming*-Brscfagriben 17-21 und deia -lead der Venicherungswirt* iweitefeO Vftbtadea ta die iteioea'-Venaerfc flber die tamg dee Gebtihreo.durch ; Blast doe Mark* un Wert V. ' . cS~i>V/--! fca-iv... Vud^erivs7T.il.* *. - togiscae Domrauchufi- Aedoboefltr.'Aoost. Zpidemiolotiul 13< (fid .Voekomiaab EJru'ge v-fr-' catrepce. Some Aspects 144 Paitikel. ! tTarficlc* . if ....... 159, g timer besondcrer Be* Mirtdlung: Ein Lite- Wcrniion lo (he Cocar-' pey ........................... 149 185 i: ' /-actA-mf tkbe ). Um.<b!pftt *s Zb!. Bakt Hy*, I. Abt. Orig. B 166, 113-135 (1978) / Naylor Dana loirltute for Disease Prevention, American Health Foundation, Valhalla, New York 10595, U.S.A. Identification and. Reduction of Carcinogens in the Respiratory Environment1 Identifizienug und Redaction von Reipirationakarzinogenen Dietrich Hoffmann and Ernst L. Wynder With 7 Figure* Abstract Epidemiological studies have implicated three factors in the overall increase of lung cancer - tobacco, especially cigarette smoking, ucba*-&fiUunon and, to a lesser extent, certain industnaf imuiiiLUfk envifnrlm.nft tam data were discussed on carcinogenic industrial Inhalants, and on the possible effect of urban pollution. The reduction of pol lution and that of specific environmental agents is stressed. Laboratory studies on the identification of carcinogena incigarette smoke and their reduction toward the "less harmful cigarette" repiesent a part of this aspect. Zusammenfassung WShrend dee lenten drei Jahrzchnte isr In den meisren entwickeireo Lindern ein starker Anstieg des Lungenkrebses beim Manne beobaehtet worden. Dec gleichzeitig aniteigende Tabakkonsum, besondetl in Form von Zlgaretten, wie auch anwachsende Lufcverunreini* ( gung in den Srldten und in begnazrem Male, die Enrwieklung newer fndnstrieaweige, sind ` in epidaniologischen Aibeitcn als bedeutende Faktoren fur die steigende Lungenkrebirate. gensnnt worden. Auf dem Gebiet des Berufskrcbset erkonnte man innerhalb der letzten Dckade, dafi Chlormethyllther Bronchiilkarrinome indurierca kann, dafi Vtnylchlorid AngiosuUomc m der Leber hervorruft, und dafi Chioropren wahrscheintich fttr Kaninome der Lungr wie auch der Haut verantwortlich ist. Auch Benzol mufi als potenzielles Leukacmogen an* gesehen werden. Alle dicse Beobachturgen haben zu verscharfcen arbeitshygicnisehen Vorschriftcn gefiihrt. 1 Hcrm Professor Dr. Adolf IKttenandt zum 75. Geburtstag gewidmet. Presented at the J6.Tagung Deutsche Gcscllsehaft fur Hygiene und Mikrobiologie, e. V., Liibeck'Travemiinde, September 24-28,1977. Supported by National Cancer Institute Grant CA 12374 end by American Cancer Society Grant BC 54. S ?.hl Bakt. HI Abu OHf. II 1*4 ) 1 ' * i t AP00012603 114 ' D.HomiANN and LLXTrNM* ' Retrospektlre 'Unrersuchutigcti hahcn such gOTcigt, daft Rcrufsumwdt and Zigarmen/raiKhen synergisiwch wirkcn. So bcvrcht x.R. cin hohcrn Rkiko fur Rronchiafkrcbs miter ", Ashest-Arbcilcrit, die hiicImi, alt untef sofeben. die nicht rauchcn oJn uatcr Aritritem atU>crhalh der Ashcst-lndustric, die rauchcn. Ahnlkhc Beweise fur Synkarzhwgcncsc gibt a hei Urangnibcn-Arbcitcrn, die rauchcn, gegcnBhcr totchcn, die nieht rauchcn. Audi dkr Bcohachruttg vm ,,Stadtfnfcioren" in der vcrplcichctxlen Lungenkrebsstatistik bei Rauchcm in Stndlcn gegenfiber snlchcn to liindlkhcn Gcbiclen, deutet auf Synkarzinogenesc von Urawdikarzinngrncn dot Menseben bin. In dicscm Faltc hewertet man lichen wndiKiltnet anderen Faktoren dicLufrvcrnoreinignngin den GroSstadren als Synkaninogen zum Tahakrauch. AnahrtiseKe und biologische Studien mit Extnktea voo JLuftverimrcmiguiigEpartikelB, die In 3 USA-GroSstidten gcsammdt wurden, haben gezeigt, daS PAK fast ausschlicSIkh fur die im Tlcrversuch bcobachtetcn Kaninome reranrwortltch wares. - Eine Reduktion von karzinogenen KoMenwasserstoffcn in dcr Luft rochrarer Grofiuidtc tat wShrand der letzten 10-15 jafire dutch Uiustcllung von Kohlc auf Olbcizung und durch spczitischc Re duktion der lovischen Abgasc von Otto- und Diesdmororen erzielt vrorden. Tahakrauch enthdlt auch karzinogenc KohlenwasscrstofFc, jedoeh stellen die kamnogenen Vcrbmdurgen dieter Stoffklattc im Rauch nur einen Teil der Gesamtakttvitat dar. Eine Reduktion der karzinogenen Wirkung det Tabakrauchcs mufi Jcshalb auch von etner Reduktion dcr cokarzinogencn odcr tnmorfordernden Rauchkomponentcn bcgleitct werden. - Da fur Tahakrauch nach uattstuchen Erbebungen fiir das Lungcnkrchsrtsiko, wie auch Im Ttcrcxperimerit cine klarc Rcrichimg zwiichcn Dost* und Virkung festgestellt wurJc, war cine Reduktion dcs Tccrgehaltcs dec Zigarcttcnrauchcs dcr ertte Schritt zu einer RisikovcrtnindcnWR, Glcichzettig wtirdc aucheinc Reduktion dcs Nikoiins und anderer phyuologischcr Noxcn angestrebt. Die Filtcrxigmitc war das ersle Entwickluugsprodukr in diecer Richtung. Darttbcrhinaut hat man aher auch durch Sdektran von Tabakarten mtt Hcimischungen von Tahakstcngcln und Tahakfoltc (tefconsrituiert aus Tahakstaub) Vcrandcrungen dec Tabakrauches bewirkt, die sowohl gcringere Mengcn Teer pro* duzicren als auch geringerc tsmorerzcugemk Wirkung dcs Tccfcs zur Folge haben. Stall* srisch ergeben sich erste Anzrichen emer'eifblgreichen Verminderung dec Lungcnkrebsritiko* fiir Raucher der ,,rnodifizicrtcn" und Filterzigaretten. Jedoeh bleibr die Enthalrung die sichcrrtc Risikovcrmmdcning. Introduction In 1912, ADLER published a monograph on lung cancer (1). The rare occurrence of the disease then prompted the authors to ask: "la it worthwhile to wrirc a monograph on primary malignant rumors of the lung?'* Today, cancer of the respiratory tract is one of the most common causes of death in developed countries (45). In the United States, the United Kingdom and the Federal Republic of Germany, for instance, respiratory tract cancers arc now the most common cause of cancer death among males. In 1966-67 lung cancer constituted about one fourth of all male cancer deaths (24.8%) in Vest Germany (48).* A detailed study of the eptdemiolofpcal history of luog cancer illustrated that environ mental factors play a crucial role in the incidence rate of this disease. Thirty years ago, more women than men died of cancer; the reverse is true today. This remarkable change is due mainly to a sharp increase in the iuddence of lung cancer in men (Fig. 1). Prospective and retrospective studies have implicated three factors in rhe overall increase of lung cancer - tobacco, especially cigarette smoking, urban pollution and, to a minor extern, newly emerging industrial environments (Tabic 1). The epidemiological studies which dianomiMid the dramatic MH-rcMe ih lung cancer provided the mam impetus for the chemical-analytical studies and bioassays in tobacco and air pollution carcinogenesis and for laboratory studies of occupational factors involved in cancer of the respiratory tract. In addition to these research activities, increased emphasis has bees placed m the reduction and removal of carcinogens from the Human respiratory environment. _ ' *; r ' ' * Carcinorcns hi the Ri-plr.it.it} Tn* ns FEMALE UMS ----V--L-A-E--O-C--H`^IIMIMYtVVai -mB1-I|N1C>,ff0ftTr *V H t . IMt Fig. 1. Time trends for cancers reportedly related ro tobacco smoke and other air pol lutants; U.S white. Abb. ]. Zcitlichcr Trend fur Krcbserkrankungcn, die rermutlicb auf Tabakrauch unJ anderc luftvcrunrcinigcndc Stoffe zurbckzufiihreR sind. Table 1. Relative'contribution at suggested carcinogenic inhalants ro cancer death rates1 Tabelle 1. Rclativer Bcitrag dervorgeschUgenen karzinogenen Inhalatezu den krebsbedinpten Stcrberaten Cancer site Tobacco smoke Polluted air Occupational environment Respiratory tract Oral cavity Larynx Lung Gastrointestinal tract . Esophagus Stomach Pancreas Liver Genitourinary tract Kidney \. Bladder 'V . Prostate . V- -:; ++++ ++++ ++++ +++ -- ++ - +++ - +++ _ -- +> ? *-. . .. i. . - _ 9 + w -- -- + +. 4- . ? - . .`JBiaatt deaths as percentage of total cancer deaths at specific site: + + + + i stn;. - "0.0%.- APOOO12604 - "* * ' - **: n -i.e* i v-;': * 7> !.' !/ Xtei*-: 116 D. Hoffmann and E.L. Wynn** fndwitrial Oircinopcticsts Carcinogenic stimuli in occupational respiratory environments appear ro have relatively little effect on the overall incidence of human cancers (Table 1). Hicoenson lias estimated that cancers related to occupational factors amount to less than I */ of all cancers (21). Whatever influence docs exist, it must be separated from the tumorigcnic stimulus of tobacco smoke (24). Nevertheless, for specific industrial groups, certain exposures to inhaled pollutants are of obvious impor tance, especially since such exposure is usually preventable. The major industrial respiratory carcinogens are listed in Table 2. During tlic last decade, several new industrial carcinogenic inhalants have been identified. These are volatile alkylating agents and reactive monomers which are characterized by the vinyl-group. They are widely used for the large scale pro- Table 2. Epidemiologies! and experimental evidence for carcinogenicity of industrial inhalants Tahcllc 2. Epidemiologist:he und expcrimentelle Nachwelse fur die krebserzeugende Wirkung indusukller Inhalate Carcinogens Site1 Evidences Epidemio Experi logical mental Aromatic amines Arsenic Asbestos Benzene Beryllium Chloromcrhyl ethers Chloroprmc Chromate Coke oven fumes Isopropyl oil Mustard gas Nickel Radioactive aerosols Vinyl chloride Wood dust Bladder (1895) . Skin (1820, Bronchi (1951. / Bronchi (1935, Mosothelium (1955) Haematopoietic system (1936) Lung (1954) Bronchi (1966) Skin (1972) Lung (1972) Bronchi (1936) Note (1953) Bronchi (1971) Kidney (1972) '. Nasal cavity (1946) ' Bronchi (1925) Bronchi(1933) * Nasal cavity (1933) Lung (1879) Angiosarcoma nf the liver (1974) Nasal cavity (1951) + 4- 44 44- 44 44 4 > 44 4 4 44 ? 44 4 4 44 44 44 44 ' 44 44 _? 44 44 ? 4 .4 4 _ 44 ? 44 ? ? 4 _44 44 44 ? * Number in parenthesis is the year the agent was first suspected ro be a human car cinogen. * + + = established, 4 MgEurive, - w negative, ? - qtiestionable'or hot . f ' Carcinogens in i!c Ui duction of inexpensive polymeric plastics and liquids. Ctiioroineilij1) ethers, rirnl chloride and chloropttne (Pig. 1) ate tnay>t representatives of ibis group of wuln- strlal carcinogens. ci-ch,-(5-ch, Methyfchloromethylcther CM ME a-CH.-0-CHi-a Brs(cliloromvtbyl)ctber BCME a Ct-CH-CH, Vinyl chloride VC CH,-C-CHCH, Chloroprene Fig. 2. Volatile industrial carcinogens. Abb. 2. FlUchtige indut.trtelle karzinogette Slide. Bisfcbloromethylfetlter Scientists at New York Univetsky repotted in 1968 and 1971 that bis(chloromelhyl)ethcr (BCME) induces tumors in the skin of mice and bronchiogcnic cardnomas in die lungs of rats which were exposed to concentrations as low as 0.1 ppm (32, 34, 53). Subsequently epidemiological studies on an industry-wide basis in the United States have disclosed some 30 cases of lung cancer in association with BCME and chlorontethyl/methyl ether (CMME) (41). Among 14 cases in the first report 12 had confirmed oat cdl carcinoma, four were younger than 40 years and none was older than 53 years, thus demonstrating that these chloromethyl ethers are powerful carcinogens (14). Ia the U.S.A. BCME and CMME are now recognized as human cardnogcns (42) and their industrial use has been practically stopped. Recently the possibility has been discussed that BCME may be spontaneously formed from formaldehyde and hydrochloride. This applies not only to certain industrial environments but also to the general environment. Vinyl chloride (VC). VC was also first found to be carcinogenic m laboratory studies and was then shown to be responsible for inducing angiosarcoma of the liver and likely also to elkit bronchiogenic carcinoma in workers (50). Up to 1975 about 50 cases of angiosarcoma were recorded among VC and polyvinyl chloride (PVC) workers in the. chemical industry, including a few cases in Germany (28, 50). Studies of the environment of VC and PVC plants have shown pollution of the air up to 33 ppm of VC at a distance of 0.5 km (10). A recent study of cancer mortality among populations residing nest VC polymerization plants suggests an increased risk of dying from CN5 and lymphatic cancer (28). Today most VC and PVC factories must observe vety strict standards of pollution control (USA 1 ppm), and air and water effluents from these plants are monitored. Nevertheless, greater preventive efforts arc needed, especially since the combustion of chlorine-contain ing organic matter leads to the formation of VC (22). jJlbd oaremogcnic, industrial inhalants in Table 2 include benzene. In 1974 the >'e-sj j!y . . . v - AP00012606 HR. D.Hoffmanh and E.L.Wvwder ; . . . Deutsche parsdHtngsgefReinschaft (8) and the International Agency for Research * -oh Cancer (30) did not consider benzene as a carcinogen, In the meantime several epidemiological studies including one survey of 28,500 slioe-workcrs (2) and one . study on benzene workers (29) have suggested lcukemogcnic activity of benzene. In this context it is of interest to note that according to a study in the United States of America and in Sweden, chemises face an increased risk of death from malignant lymphomas and leukemia (35). We concur with the U.S. Nattuoal Re search Council which stated in 1976 '`Based on available literature, if can be con cluded that benzene may be associated will) leukemia. Therefore, benzene must be considered as a suspect kukentogen" (51) In the U-S.A. 1 ppm is considered to be the standard limit of exposure for benzene (40). Coke Oven Effluents Coal tar was shown to be a skin carcinogen as early as 1875 by VOLKMANW (54). Kckardt reviewed the world literature on this subject in 1959 and estimated the total number of skin cancer in coal tar workers to exceed 3,000 (9). The very base studies on coal tar by Cook ct al. in 1933 which led to the isolation of bcnzo(a)pyrunc as the first organic carcinogen (7) were followed by many studies which have shown that polynuclear aromatic hydrocarbons (PAH) are the major carcinogens in coal tar (Table 3). In 1936 sixty one eases of lung cancer were reported among workers of one stcH company in Japan (31). Since then, lung cancer has also been observed in coke oven and gas retort workers in England, the U. S., Canada, and Norway (27). However, it was not until 1971-72 that detailed background information became available for coke oren workers who developed lung cancer (37,43). At that rime Lloyd and his group found that these workers had a ZJ times higher risk to develop tung cancer than the general population. Ait especially high risk with 6.9 times that expected was found for the loaders on topsides of coke ovens. Although data on smoking were absent, it is unquestionably clear from die study that coke oven workers face higher risks of death from lung cancer. A study of the high concentration of PAH in the coke oven effluents during the loading periods strongly supports the concept that carcinogenic hydrocarbons at least contribute to the high incidence of lung cancer (46). In recent years new exhaust systems and preventive measures have significantly decreased the risk of exposure to carcinogenic PAR The next step which is now under way in the US.A. is the environmental pollution control of the effluents from these coke ovens. Recently, relatively high concentrations of PAH have been found in the dir of the surroundings of these plants (11). Although it is nor likely that the PAH-eontaimng effluents alone will lead to an increased risk for bronchtogcnk carcinoma in nonsmokers, rite contri bution of these aerosols to the total burden with environmental carcinogens of persons residing near coke ovens must be considered. Asbestos Another example of combined exposure to two environmental carcinogens is found in asbestos workers. Employees in the asbestos industry have long been known to have a high risk for mesothelioma of the pleura and peritoneum and a somewhat higher risk for bronchiogenic carcinoma. HAMMOND arid Sf.ukoff Carcinogens in the KuiwaMtj Lmuoii.t^-.: Table 3. Carcinogens in coal tar Tabelk 3. Karzinogenc Stoffe in Kohlcmecr .119 TOhciui>f.0P3*ene ++ D!benI>lanlhritcve 1+) DibCTttlajil MftmTM ++ BemafilfloatUtlKM Bladder carcHiotf** .CCll1*I, rcL tu. TkWdiw /-V^VKW* l.NkpMhyW""" tria tGnW>W > wewr amwil" * **" documented in 1973 that asbestos workers who are also cigarette smokers face a significantly higher risk for lung cancer than the nonsmoking asbestos workers, or cigarette smokery outside the industry (18). In recent years, several investigators have keen concerned with (he exposure of the general population to asbestos dust from construction sires, brake linings, and from polluted air in the vicinity of asbestos factories. Lancer and Seucoff identified chrysotile in the lungs of New York City residents without occupational exposure (33). Bohug and Hain reported 38 cases of mesothelioma between 1950 and 1968 in residents in HAmburg-Bergedorf where an asbestos factory is located (6).. These observations make it possible to tlveorize that the inhalation of air .polluted with asbestos particles, may increase the lung cancer risk of cigarette smokers And workers exposed to other carcinogenic inhalants even further. APOOO12607 |i) P.llOhlMANN jih! E.LWtN1)ER. liwriM.scJ efitiits should be made to protect the workers, as well as the city residents from asbestos dust exposure, since the material is still widely employed as insulating material. Nitrosjwincs Today more than 100 ntrrosamincs are known to be carcinogenic in expert-' mental animals (38}. Yet, We are stilt missing the direct evidence that the nitrosraincs cause cancer id man. In view of ihc fact char nicrosamines arc carcinogenic to the usual laboratory animals, as well as to monkeys, birds, amphibia and fish, and because of similarities in the metabolism of N-nirrosodimcthylaniinc in human ami animal tissues in vitro, there is a strong possibility that some nirrosamines arc carcinogenic to man. These considerations alone dictate that great caution be exercised in the indus trial use rtf uitrosamincs and that these agents be excluded from household goods and from food. The example, the carcinogenic N-nitrosodtcthanolaminc (38, 45} has been found up to 3 / in syntltetic and semtsynthctic cutting fluids and up to 200 ppb in certain cosmetics (12, 13, 53}. Epidemiological studies have not thus fat been undertaken to evaluate the role of this nitrosamhte and certain volatile nttrosamiucs as possible risk factors in occupational environments. The thermal energy analyzer (TEA) represents a new analytical tool which increases our capacity to determine traces of nitrosammes in environnwnt.il agents down to 10s*g (15). The application of TEA-techniques to the examination of general and occupational environments as well as to detection of N-nirrosamincs in body fluids will further elucidate our knowledge on the importance of nitrosainiiws in carcinogenesis. In t'ivo formation of nitrosammes from amines and nitrile is possible and is also substantiated by a recent report of induction of squamous cell carcinomas in the lung of rats given high ora) doses of hepramctliylcnciminc hydrochloride and sodium nitrite (36). Other Industrial Respiratory Carcinogens It is certainly beyond the scope of this discussion to present data on some or all other known ot suspected industrial inhalants with carcinogenic potential (Table 2). For detailed information we refer to the subject Literature (9, 27,44,47). We will, however, emphasize a few points. During the last few decades we witnessed a significant reduction of rhe cancers caused by industrial agents alone. Despite the fact that, even in the most industrialized nations, occupational cancers account for merely a few percent of all environmental cancers, we must consider their occurrence as a neglect of society. A fresh approach of scientists toward the elimination of occupational cancer is needed. For example, factories with large volume production of plastics and other polymers from reactive monomers with vinyl configuration may represent new carcmotsvttk environments. This area needs our attention. The exposure of the workforce, or even tint of the general population, to small amounts of certain specific chemicals alone may not represent, a carcinogenic hazard, however, these trace compounds increase man's burden with agents which have to be detoxified m vn-a, or else will induce irreversible cellular changes. Examples arc the significunily higher risks for lung cancer of uranium miners and asbestos workers who arc .iKo i ig:ircuc smokers. >. *W \ U. -V- ' Vtr-Jii.'...'1 f .i? Carcinogens * llic t<cs.pir.u,i.y Iwrono s.i Ait Pollution Urban air pollution may well represent another factor which contributes to tltc carcinogenic burden of man In industrialized countries. Thu effect of atmospheric pollution alone on the induction of respiratory cancer is difficult to evaluate because of the overriding effect of cigarette smoke {44, 32). Lung cancer, however, does occur more commonly in cities, and in fact, a committee of the National Academy of Sciences estimated that urban dwellers may have twice as high an incidence rate of hing cancer as those in rural areas (39). Epidemiological Considerations A number of retrospective and prospective studies have been concerned with the relative influence and nature of the "urban factor" in the etiology of lung cancer. It appears chat the urban factor is not only a consequence of atmospheric pollution, bur also of several variables (Table 4). Table 4. Contributors to the "urban factor" in respiratory carcinogenesis Tabetic 4. Stoffe, die bet der atrmingsbedmgtcn Krcbsenfstchimg aim ltSi,idcifchen Faktor" beilragen More accurate reporting and recording of death certificate* Higher degree of atmospheric pollution More industrial exposure More cancer diagnosed and treated Different immigration/migration patterns Differences in socioeconomic factors More cigarette* smoked Investigations of these various contributions to the "urban factor" in respiratory carcinogenesis do not eliminate the role of polluted air. Within each urban/rurul grouping, lung cancer death rates increase strongly with cigarette smoking and show always somewhat Higher rates for the city smokers (Fig. 3; 17). Atmospheric pollution appears to offer a reasonable explanation for the persistence in the urban-rural ratio of lung cancer. It appears to us chat air pollution contributes to man's burden with carcinogens and, as such, may increase the risk to develop lung cancer for cigarette smokers and possibly for asbestos workers (17, 49). Laboratory Studies The findings from bioassays and physiocbcmical studies arc equally significant to the epidemiological data in relating atmospheric pollution to rhe pathogenesis of respiratory cancer. Thc-ctucidation of the mechanisms leading to lung cancer induction remains primarily the domain of the physical ami biological sciences. In environmental carcinogenesis, demonstrable parallelism between epidemiological data, and laboratory findings add to both. Carcinogenesis bioassay data from -TS..-:- v . 122' - D.Hoffmamh auJ E.L.Wtndhk r Carcinogens in the Rerpitatory l.tv.'i;.>.'<uicrl 123 100 f- Cl WMrV 0 i: I 25 sapoo* m^mwj>vm .mi_> n.. Ki Ctfjot SOmtvTom IQJX0SOOOO Fig. 3. Age-standardized rates for wdt established cases of bronchtogetiic carcinoma, by rural-urban classification. Rare* for cigarette smokers arc compared with those for men who never smoked regularly (17). Abb. 3. Altcrsgcnormte Vote fsir ruchgcwiesenc Falie des brtmebogeneo ICarzinoms, nach cincr Land/Stadt-bezogcncn Eintrilitag. Die Haufigkcitswerte fur Zigarcttcnrauchcr 1 werden mit denen verglichen, die bei anrcgelmifiig raudienden Atannern auftraten (17). I I I InMn EM APD MndMI-t-t-tf-M--r1 1------ ------- 1 ['Mr* lq 1I 11 UMMl 4N-MM Ml-WON Mm*** <Mttr 1____`____J___ ,,____ L M-MMM EH** l*yr lukforta ler 1 C.* 4ncimi dher 1 bpa T i t 6 mammalian species with air pollutants lend support to the concept tlt.it air pollution represents one factor in the increased risk of urban dwellers (<> develop lung cancer. Above all, laboratory studies offer tlic possibility of reducing tlie emission of potentially harmful carcinogens into our environment. Extensive studies in many laboratories have shown that the particulate matter of urban pollutants contains the majority of the respiratory carcinogen (25). For the identification of the carcinogens, die organic particulate matter of air pollutants sampled in a number of cities was fractionated (Fig. 4). The total organic matter and the aromatic, neutral subfractions of these air pollutant concentrates induced papillomas and carcinomas in the skin of 50-95 */# of the mice. The insoluble and acidic portions and the aliphatic and oxygenated neutral subfractions were inactive as complete carcinogens. The basic portions were not tested since they amounted to only 0.55-3.4 /* of the total organic matter. A detailed chemical analysis of the aromatic neutral subfraction revealed the enrichment of practically >11 of the PAH from the total particulates in this subfraction and also revealed the presence of at least six known carcinogenic PAH in the organic pollutants. In the bioassayed organic particulates from four different locations in Detroit and New York, the concentrations of the strong carcinogen, bcnio()pyrcne (BaP), varied between 0.011 and 0.035*/# and of the weak carcinogen, beirz{a)awhracene (BaA), varied between 0.017 and 0.06 */, Using chemically purified BaP as positive control, we estimated that 45-55 V# of the carcinogenicity of the total organic particulates and of the aromatic neutral subfractions could he explained by BaP alunc. From the bioassays of the organic particulates, one can conclude that polluted atr contains trace amounts uf carcinogens. 'Fhc most important types of these carcinogens are the active species of the PAH group. BaP is the most active compound of this group. Minor carcinogens are ara-hcferocyc/ic hydrocarbons and certain types of epoxides and peroxides. However, the total amount of carcinogens in urban pollutants is very small. The highest amount reported for the U-S. is 74 fjg BaP in 1000 m* polluted air. Taking this value, if one stayed outdoors for 24 h, there would be approximately 0.9-1.5 /rg BaP in the air one breathes (11--20 ms). The average value for a U.S. city is more near 0.07-0.12/rg. These very low values certainly appear in line with the human data showing only slightly elevated lung cancer risk for the urban nonsmoker and a somewhat more derated lung cancer risk for the urban cigarette smoker compared with rural cigarette smokers. Whatever the demonstrated increase in the relative risk factor for lung cancer caused by present day urban pollution, the established presence of poten tially harmful carcinogens in the atmosphere should increase our efforts to remove the agents to whatever degree possible. Aaocpriton Mr* porta Hit n.s* Sources for.Atmospheric Carcinogens FI MfMX mam an n tactpi "iton'mwi Ft Awiuit mam Ll vim fracta | a.n 1 Fig.4. Separation schemeof organic par ticulate matter from air pollutants (De troit) (25). Abb. 4. Trennungsschema ftlr orgartinhe Partikel in Luftvenmreinigungen (Detroit) (25). i Carcinogenic PAH are formed primarily during the incomplete combustion of organic matter'by a few distinct mechanisms. The prevailing pyrolytic route for PAH is the initial formation of C,H-tadicats in zones with highly elevated tem peratures O 600 "Q and the subsequent combining of C, H-radicaU to the thermodynamically preferred aromatic hydrocarbons including those of carciimgenjchydrocarbbiuwiih four to six condensed aromatic rings (Fig. 4). This route AP00012608 AP00012609 tJ4 J), t llllTMANN .ind.l,,WrMDT.R if cnluiicvJ during the burning of precursors with an aromatic ring system. These data suggest (hat all combustions can contribute PAH to urban pollution. It has Urn cminiared that in the U.S.A. alone 1110-1,000 metric tons of BaP arc emitted annually into chs environment from combustions (Table 5; 39). Although data for Other carcinogenic hydrocarbons are presently lacking, we can assume that their tout emission exceeds that of BaP by at least 3-5 times. Tahiti. Estimated benzo(a)pyrene emissions in the United States (1972)' Tabetic 5. GescMtzte Abgabe rots Benzpyren in den Vereinigren Staaten (1972) Source type Emissions MTfyr Stillinnary sources Coal, hand-stroked residential furnace Coal, intermediate-sire units Coal, steam power plants Oil, residential through steam power type Gas, residential through steam power type Wood, home fireplace Enclosed incineration - apartment through municipal Vehicle disposal Forest and agriculture Other open burning Petroleum, catalytic cracking Asphalt air blowing Coke production Mobile source (20-2S MTlyr)* Gasoline-powered automobiles and trucks Diesd-powered trucks and buses Tire degradation 300 7 <1 2 2 25 3 25 11 10 310 <1 (0.06)-170 11 <J 11 t ' 1 U.S. Environmental Protection Agency, 1974. ! Other estimates 40-50 MT/yr (5). The nation-wide estimates cannot be applied to individual areas. For example, she major emission sources for the coal mining and steel producing states are coalfired furnaces, coal refuse burning and coke production. In our major cities, motor vehicles contribute significantly to the PAH atmospheric burden. This applies specifically to downtown areas of New York City and Los Angeles. The only motor vehicle data available for Detroit show a surprisingly small contribution of 5 V of the BaP in the downtown area, tS Vs of which was located in the freeway area and *12 Vs in the suburban atmosphere (25). Reduction of Atmospheric Carcinogens In recent years, some progress has been made in reducing urban pollution. London represents one example of such progress after her citizens suffered through air pollution episodes iu 1952 and 1952. Since then, the British Government and N. Carcinogens *'* B5 V*1*-*' tltc city have enforced strict regulations for industry and a clu-hgo from etui to oil heating for private and public bousing. The United Kttigdont has, furthermore, made emission control devices mandatory. The maximal emission value* for motor vehicles per km are 4.2 g of hydrocarbons and 48 g of carbon monoxide; the U2j. standards arc 2.1 g and 24 g, respectively (3). These regulations led to a significant reduction of gaseous air pollutants, especially of the dlia-toxic sulfur dioxide as well as to a reduction of particulate matter, including that of carcinogenic hydro carbons (4). In the U5., many communities and countries have enacted new ordinances which set limits for the sulfur content of coal and heating oil. Industries have shown initiative in controlling the emission of pollutants. Nevertheless, new control measures arc still needed. As discussed under "Sources for Atmospheric Carcinogens", coal refuse burning represents still a major source of atmospheric pollution iu the coal-mining states. Coal refuse is a major by-product of the coal mining industry resulting in large dumps or heaps of rocks intermixed with small pieces of coat. Unfortunately, on occasion, these dumps can sclfignite and emit very dense smoke for weeks. Hopefully, the mining industry will increase the use of coal refuse for tilting abandoned mine shafts or find new applications for this by-product and thereby reduce a major source of atmospheric pollution. In the last decade, some cars have been equipped with emission control devices. These devices have been estimated to reduce the emission of PAH by 85 V (Table 6; 39). The central reason for the lower PAH yields from current emission controlled vehicles is the shifting from rich carburation (285 */ carbon monoxide) to clean carburation (0.9-1.4 / carbon monoxide). However, aging of an internal combustion engine can increase PAH emissions. Hangeorauck et al. reported five times the BaP emission for a car after 50,000 mi of operation (19). A significantly higher emission of PAH aUo correlated with an increased nil consumption (Table 7; 26)4 Hopefully, future developments will make annual emission rate inspections mandatory in all states for cars, trucks, buses, and mo torcycles. The measure should significantly reduce atmospheric pollution in urban communities. In recent yean, the public has been increasingly concerned with the emission of lead from gasoline engines, which brought about the introduction of low-lead fuels. In order to keep the anti-knock number high, the aromatic portion (benzene. Table 6. Automotive bcnzo(a)pyrene emission factors (19) 1 Tabetic 6. Benzpyren-Ahgabefaktoreo fur Kraftwagen (19) Source \ Uncontrolled car (1954-1964) 1966 Uncontrolled ear 1968 EtAission-controlled vehicle . Advanced systems Berao(j)pyrene Emission factors (/rgjgal of fuel consumed) 170 45-70 20-30 < 10 II.HOfFMAHH and E.L. Wvnijex ' TaMt 7. Emission tales of polvnndtftt aromatic hydrocarbon* (mm a gasoline engine TalK-fli- 7. Ahgabcwc/Tc fur pcdyzyfcliscbe arontariwhc Kofilcnwasscrstotifc bci BenzinnNHorm (ii) "Tar" emission (g/hr) (p/gaj fuel) "Tar" analysis (ppm) BaP* IMA* Pyrene Fluor anthene StaadarJ run* Run with high ail consumption1 1.4 1Q.J 2.2 4.8 100 ISO 566 925 2400 1330 4l()b 1200 11 qt/JMQmi. 1 qr/200 mi. * Quantitative values ( 5%) determined by isotvpe dilution irchniaue. miTM- RiP.tCr*' and ma.w, respectively. BaP = bciuo{a)p) rene; BaA ** bcnzfajnmhraccne TaMe 8. BaP Fuels L (15) and BaA Emission Rates from a: Gasoline Engine Operated with Afferent Tabdlc stojfen 8, Ahgabewerre fur BaP und BaA bci Benzinmotoren mit experinicntclEefl Trcb- Fuel (pg) BaP Gasoline 2,3,4-Trimethylpcnrare 2,4,4-TrimeibyH'pentcfte .soot o-Xylette plus 50% benzene 25% 2,4,4-TrimiihytpeMtaric plus 25% isopenranc pins 50% xylene 9.6 2.6 0.7 25.8 9.0 One-minute rim. BaP = bvnzofajpyrene} BaA - benz(a)amhraceiK 0<S) BaA 17.3 0.8 0.4 563 313 toluene, and xylenes) in tome of these fuck has been significantly increased. Ex perimental engines operated only on aromatic fuels have demonstrated that this will increase PAH emission (Table &). The recent practice of synthesizing ko- octance (anti-knock number 100) from cracking gases and adding it to gasoline will eventually reduce the aromatic portion in finds. Carcinogens in the Rcpirat-.y 1?? of progress already achieved, as well as in regard to future developments in me thods of prevention of cancerous diseases related to smoking. Y-'c have to re cognize that educational efforts and smoking cessation techniques arc only par tially successful, in addition, data have dearly indicated that tire kwr the edu cational status of an adtdt the more likely he or she is to smoke. We have to face the reality, therefore, that in decades to come, we will have tens of millions of cigarette smokers in the U.S.A., as well as in the BRD. On the basis of these considerations, we concur with the statement by Dr. G. Com of the U.S. National Cancer Institute "to leave millions of smokers to their fate is neither humane nor economical" (16). The answer, therefore, for these people who continue to smoke is the "Less Harmful Cigarette''. Tumorigeiiic Agents in Tobacco Stnoke The development of the less harmful cigarette will be based primarily upon our knowledge of the toxic constituents of tobacco smoke. The predominant role of lung cancer among smoking-related diseases has focused attention on the carcino genicity of tobacco smoke. Animal studies conducted in numerous countries have demonstrated carcinogenicity for cigarette smoke and mainly for its particulate matter, commonly known as MtatN. Fractionations and bioassays have revealed that tobacco smoke contains trace amounts of carcinogens, which act as tumor initiators, cocarcinogens and organ specific carcinogens (Tables 9 and Jflj 17, 57). Whereas, most tumor initiators in "rar" have been identified, current studies arc directed toward determining the chemical nature of the neutral and weakly addic cocarctnogcns. Several of these compounds are tobacco specific, and their piecursoia in the tobacco leaf can be selectively removed through the breeding of new tobacco varieties and/or by extraction and treatment of the tobacco. Since little is known about the organ-specific carcinogens in tobacco smoke, their role in tobacco carcinogenesis needs to be examined. It was shown that to bacco proteins give rise to traces of several aromatic amines in die smoke. Com pounds of this type are known animal and human bladder carcinogens, /f-naph- rhylamtne being the best known representative of the group. The presence in the smoke of volatile nttrosamincs and nonvolatile nitros- amtnes, such as the tobacco specific N'-nttrosooomicorine, which are derived from tobacco alkaloids, appears to be an equally important factor. These compounds do not exist in fresh, green tobacco, but their formation occurs during tobacco curing as well as during smoking (20). Nitrosonomicotinc is an organ specific carcinogen which induces esophageal tumors In rats as well as litng tumors in mice and in Syrian golden hamster 120). Other tobacco specific tiirtosamincs and their carcinogenicity arc currently being studied. .Reduction of Tumorigatidty and Toxicity of Cigarette Smoke Tabncco Smoke The formation of organ specific carcinogens during tobacco curing, their par tial transfer into the smoke and their formation during smoking provide a frame For more than a quarter century, epidemiological data have causativcly linked work lor intervention towards their reduction in the smoke. These efforts ate tobacco smoking with lung cancer (26). I himan studies have also shown a reduc sctll in their early stages. Significant progress has been achieved in the uonsdec- tion it* risk fur lung cancer when cigarettes with reduced "tar" yield have been tivc reduction of `'tar" and nicotine, m the selective reduction of several carcino I smoked for 10 years or more (56). It a the purpose of this discussion to define the less harmful cigarette in terms of its chemistry and biological activity on the basis genic and cocardnogenic agents and of toxic smoke constituents such as carbon monoxide and hydrogen cyanide. AP00012610 12S D.HomtANM and E-L-Wthreh . Tabic 9. Major toxic agents in the gas phase of cigarette smoke* (imaged) . fabdlc 9. Gro&re toxrsche Staffc in det Gasphase dot Zigarcttcnrauchs (ofme Alrerung) Carciaop^nS in ihc lAivir.itu'.w.'.i l-'J Table 10. Major toxic agents in the particulate matter of cigarette smoke* (inu&uJ) Tatxdk tO. GroSere toxischc Stoffc In den Partikeln von Zlgarcttenreueh (ohne Aliening) Agent Biological Activity1 Concentration in 1 Cigarette Range Reported U.S. Cig.* Agent Biological Activity* Concentration m t Cigarette Range Reported U.S. Cig* Dfincihyliutrosanuae C 1 - 300 ng 13 ng Ethylmethybirroumine Dtcthylnitrocamine Nttrosopyrrolidine Other Nicrosamincs (4 compounds) Hydrazine Vinyl Chloride Urethane Formaldehyde Hydrogen Cyanide Acrolein Acetaldehyde Nitrogen Oxides (NO*)1 Ammonia Pyridine Carbon Monoxide C C C C C C TI CT. CoC CT, T CT CT T T? T> T 0.1- 10 ng 0 - 10 Bg 1 - 42 ng 0 - 20ng 24 - 43 ng 1 - 16 ng 10 - 35 ng 20 - *>Pg 30 - 200/1% 25 - 140ps 18 -HflO/tg 10 - 600/ir 10 - 150/rg 9 - 93 pg 2 - 20 mg 1.8ng 1J ng 11 ng 9 Bcnz(a)pyrenc S-Methylchrysene Bcnzo(i)fiuoranthcnc 32 ng ling 30 ng 30 pg Benz(a)anthraccne Other PAH {> 20 compounds) Dibcnz(a,j)*cridinc Dibenz(a,h)*cr)dine 110 PS 70 pg Dibcnz(c,g)carbazale Pyrene 800/rg Fluoranthene 350 pg 60/i% Bcnzofg, h,i)pcrytcne Other PAH (> 10 compounds) ion 17 mg I Naphthalenes 1-Methyltndoles 9-Afctfiylcarbazoles TI TI TI TI TI TJ TI T! CoC CoC CoC CoC CoC CoC CoC 1 May also contain such carcinogens as arsine, nickel carbonyl and possibly volatile Other Neutral Compounds CoC chlorinated oleins and nitro-olefins. 1 Biological activities: C carcinogen; BC bladder carcinogen; T1 tumor initiator; CoC cncarcinogen; CTcilia toxic agent; Ttoxic agent. 185 mm cigarette without filter rip bought on the open market 1973-76. 1 NO, > 9J% NO, n-st NO,. Catechol 3- and 4-Mcckylcatecbols Other Catechols (>4cocnpound) Unknown Phenols and Acids CoC CoC CoC CoC 1 Not toxic in smoke of blended U.S. cigarettes because pH <6.5 and therefore am monia and pyridiiKs are present only in protonated form. t N '-Nirrosonornicottne Other Nonvolatile Nitrosamlott 0-N aphthytaiuinc c c BC Undesirable tobacco smoke constituents can be reduced through the elimina tion of precursors by selection of specific tobacco varieties and plant components, also by selective filtration. Dose reduction can be effected by smoke dilution through air filtiation, or by reducing inhatabiliry. Table 11 presents the major methods which have been employed in an effort to reduce the biological activity of cigarette smoke. New concepts continue to emerge and together with the pre sently available techniques, they will further reduce the harmful effects of tobacco \ i Other Aromatic Amines Unknown Ni'ro Compound* Polonium-llO Nickel Compounds Cadmium Compounds Arsenic Nicotine BC BC C C C C T products. Minor Tobacco Alkaloids T Whether progress has been made in reducing the smoker's risk by modification Phenol CT of the commercial cigarette can be measured to some extent by chemical analyses CrcsoW (3 compounds) CT and in bioassays. However, ultimate confirmation must come from epidemiologi cal surveys. We would predict increasing consumer acceptance of low "tar" brands, lA 8 . 50 ng 0.5 - 2 ng J - 40 ng 5 - 80 ng > 3 - 10ng ? 0.7 ng 50 -200 ng 50 -250 ng 10 - 60 ng ? 1 - ICpg 0.3 - 0.9 pg 0.005- CUpg ? 40 -460pg 30 - 40/g ? ? 100 -250 ng > 0 - 15 ng ? 1 0.0J - 1.3 pa 10 -600 ng 9 - 70 ng 1 - 2J/ig 0.1 - 2.0 mg 0.01 0.2 mg 10 -200Ag 10 -150pg 20 ng 0.6 ng 10 ng 40 ng Sng 0.7 ng 150 ng 170 ng 30 ng > 6 PS 0.8 PS 0.1 pg 270 ng 32 pg ? > 250 ng > 20 n > i 3 > ? 1.5 mg 0.1 mg 85 pg 70 pg particularly if they could provide sufficient "satisfaction" for the smoker. Flavoring agents derived (com tobacco, from synthetic compounds and/or mixtures of (riant * Incomplete list. * Abbreviations feeBiological Activity, tee footnote 2 ot Table 9. extracts, enhance consumer acceptance. Such nootobacco flavor additives and. -i* Sec footnoted of Table9. 9 Zbh Salt. Mm-I. Ala. Orfe t US i- .m if rfU. .. * i . - AiriI'-'A".K.-' > 11J 1>.I Iovfmann and E.L. Wtnijer Table 11. Reduction of biological activity of cigarette smoke1 Tabdlc II. Vcrmiiw^nang Jer hiotngischcu Alauitfit ron Zigarctfcnraucb F Carcinogens in Htc IU p-fj-.-.r/ fc'.viroi.^i-s* Method Tar" Nicotine BaP Select. Biolog. Reduction Carcinogen Promoters Agricultural Aspects Tobacco Varieties (BrighMlurlcy) +++ + New Tobacco Cubtvars + + + > Leaf Position* + +p + ? > Selection by NO," + ++ ? Tobacco Processing F.xtraction: Organic Solvents* + 4- 4- ) Cut + > 3 Stems + + - + + + + Reconstituted Tobacco Sheets (RTS)* + + + 4- + Reconstituted Tobacco Slwcts (Paper Process) ++ + + ++ > Expanded Tobacco + + + + + + ? l Ctgarotte Production Porosity of Paper Perforated Fillers ++ +++ > > Cellulose Acetate Filter + 4- + Charcoal Filter* f + + + Additives: NO,"* + + + + Tohaccn Substitutes + + + 4- + + 4- + DDiyiiWMi O Now Fie. fi Fig. 5. USA. Sales weighted average deliveries of total condensate {dry) and nicotine pci cigarette 1954-1975 (55). Abb. 5. USA Umsatzbewertetc Durchschnitrsabgabcn von GesamrkonJensat (trocken) unJ Nikofin pro Zigarerte 1954-1975 (55). Fig.fi. Germany. Sales weighted average deliveries of total condensate and nicotine per dgarette 1961-1975 (55). Abb. fi.'Di-utschUnd. Umsatzbewertetc ITurdisehnittsahgabcn von GesamtkonJensat und Nikotin pro Ztgarette 1961-1975 (55). 'Reductions: + * -> 50%; + significant; insignificant; ? questionable; -- in crease; i unknown. * Data given for reconstituted tobacco sheen relate to those not made by the paper process. 'Reductions of "tar**, nicotine, and BaP are in general gteater with cellulose acetate filters than with charcoal filters. * Uisnl stalk position highesr reduction * Only of academic interest * Some RTS give high CO I their ronthtistioti products require testing with respect to (heir biologic activities. We Itavi* emphasized rite importance of sudt testing for a number of years since there is a dearth of information in this area. Concerted efforts of governmental agencies aiul institutional and industrial research groups arc needed to study these aspects so that (lie least harmful product can be offered to those who continue to smoke. * The Jaia from K. H. Whicr in Fig. 5 and 6, ate for sales weighted average . "ur* and nicotine delivery of U.5. and German cigarettes (55). A gradual ' reduction of *Tar" and nicotine has occurred, not only in the U.fLA^ but. also * * ^ f tl ,* - ... Vfw . Fig. 7. USA Deceasing concentration of benzo(a}pyrcne in the condensate of a leading non-filtercigarette (Hoffmann, 1952-15175). Abb. 7. USA. Aboehmende Konzentratton von Penzpyren im Kondensat einer fiihrcndcn fitteriosen Ztgarette (Hoffmann, 1952-1975). i'. ' AP00012612 ;*tiAd**-' 'sVlatprwci . 5vtfr AP00012613 JJ2 D.H9rnuNH and fi.LWrNDiai . in Austria, Canada, the Federal Republic of German?, France, Japan, Sweden, Switzerland, the Uniii'd Kingdom and other countries. Fig. 7 demonstrates the decrease in hciizo(n)pyrene values in the smoke of a popular representative Ui. cigarette since 1953. Bcnr.o[a)pyrcne has been chosen to indicate the levels of tutnorigcnic polycyclic hydrocarbon* in the smoke, and its reduction can be correlated with a steady decrease in tumorigeniciry of "tar*, in VS. cigarettes since 1950 (Fig. 5). incorporating all available technique* in cigarette manufacturing and assum ing that none of the flavor additives induce additional toxic effects, we propose certain limits for smoke components for a less harmful cigarette (Table 12). Some of the cigarettes sold in 1977 have, at least in some specifications, reached the suggested levels. We must realize, however, that these cigarettes constitute only a small percentage of current total sales. The data in Table 12 arc to he considered as a starting point for discussions. It is imperative that additional smoke components be evaluated in the continuing search for a less harmful ciga rette. , Table 12. Maximum concentrations of some selected toxic agents in the smote Tabdfc 12. Max. Konzentrarionefl einiper ausgcwihltcr Ciftstaffc im Rauch Toxic Component Maximal Proposed Concentration Total Particulate Matter* Nicotine Carbon Monoxide Hydrogen Cyanide Bcrao(a)pyTCe* Dimethyktirrosamioe* N'-NitrosonornieoCine Catechol Phenol Acrolein4 Oxides of Nitrogen 8 mg 0.6 mg 6 mg lOOf* 8 ng Jog 60 ng 90n 2on 30 US 100 pg * Total Particulate Matter Tar - Water - Nicotine. * Serves as indicator for tumorigcnic PAH. 5 Serves as indicator for volatile niirosnmincs. 4 Serves as indicator for organic cilia toxic agents. Conclusion In summary, we wish to stress that cessation of smoking is the best option, bttt ) a less harmful cigarette must be realized for millions of current and future smoken, and for those who do not want to gwe up smoking. 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