Document jNB455V4Lb8yqbRbeEyOLMQGk

FILE NAME: Asbestos Mining (ASMI) DATE: 1955 DOC#: ASMI027 DOCUMENT DESCRIPTION: Published Presentation from The Canadian Cancer Conference - Environmental Lung Cancer J V Canadian Cancer Conference \ ohirne Proceedings of the First Canadian Cant'cr R esearch C onference Honey H arbour, O ntario Ju n e 16-19, 194 Edited by R. \V. BEGG Department of Medical Research l niversitr of Western Ontario London, Canada 1955 ACADEMIC PRESS INC., P I BLISHERS NEW Y O R K . N. Y. A .."v . . ' ! !cr: Environmental Lung Cancer \Y. t H H 'P K R ' : A anamil I n s/ii.n cs i : Health, l ' u h i \ J L ' a 'C; sr i.' . r, a Health LJueatiou, ami C e l i a . Lethesda. Hai'Cata 'I he n r 't evidence indie.ami; the existence <>t causal relations between environmental factor- and the development of enneors of the lung was recorded in ! S7. when Haerting and Hesse (dot established the cancer ous nature o' the lung diseases prevalent among the radioactive ore miners m Fchneeherg. Saxonv. This discovert of historical importance .am! great present significance .attracted, at its time, little attention because radioactivity was still an unknown fact, .and cancers of the lung were comparative!! rare before the turn of the century, and, therefore, of little medical interest i Table 1 1. T a b u I. Frequency Hates of Lung Cancers m .lutnpsY Ma'crtaC 1852-1900 Autlb r Period R e in h a rd Fuchs W olf Passler W olf PeruU M archesam K ik u th Feikhenudd l^icchelniann Sehrt Marctic-sani 1852-1876 1S54-1S85 18/7-1884 1881-1894 1885-1894 1885-1897 1887-1896 1889-1899 1895-1900 1895-1901 18`'9 - 190.1 1886-1906 "Reference 140. X o of tiuiop^ies 8716 12.107 4172 9246 7228 -- 1946 -- 5022 7790 1741 .1.137 Total no carcin o m a" -- -- -- 870 _ -- -- 511 711 159 -- Lung cancers \l>-s no W of all car r o of all autopsie- 5 -- 0.057 S -- 0.0r>5 <) -- 0.21 16 1 81 0.17 51 -- 0 428 0 1 27 O.Ki 4 0.26 10 0 07 22 4 3 0.24 27 5 8 0.39 5 1 88 0.17 6 -- 0.18 When, alter W orld W ar I, a definite and progressive- increase in the relative frequence of hint; cancers in autopsv material became apparent t'fab le 111. some thought was given to the possible causes of this phenomenon Since the v idely scattered sources, the topographical!v ir regular appearance, and the relatively -hurt developmental period of these observations did not favor the action of hereditnn factors, the main a t tention m this m atter wa- g iw n to a consideration oi v a r i o u s em iro n meuta! lactors which, had made their appearance, or undergone marked 1S(. I \ \!k `</ \ M ! \ I \! 1 : \<. . \\ t I k- c 1`;ir i^ c.- i l m u i " llu- p ri.Pi -<!n ,'u U' \ ' M - I 'c i l 't 1ll V civill n u n n v n ' . a l a c P i r - | >nijH>-:<! h a t ' a n a w a - *' "U8 c.-ll n u 'ta p ia t h e i i r n n o h i a i m i c n - a a m !:8.-.1 v , n ! i ; K a l l n i r n , . i (`j a . l i ' i n i c , a n d 1' - t o v a r n i i b ' i i v i ' . !w a n 1 r-> > n - ia v. io.. > 9 >11. . i a n d c n v 1; T abi.k Ff F r c ^ u m r y K . r c s * I. ut:n C;-- r f ! , 1^00-1025 U./6'n,//" \ 11'.' ... I V t l<)<l N o .>T" <tP ' - l'ooa - 1 c . a . l n . - 1- Rc l!i; h Se> talir t K a r r : . ' ! ! ' t t a n K iku tu S t:u ' u ! i llcai'ii Prall,^ey iah-'t Rne-e Pej-i,-:Pc'.aclM a i v '.i.-.a m Rau P e r b i r .e r \i .ucr\.! S tach ci i,i Pr Qc\ u h r : U.l : rr.a Rrt. ak v*. .Ult Kan Per!,;,- l. CI P i ..!.-: M al.vra K i k i '. ' h ,iai aac- ick: i I ,1"! Pl!" " `i "v vMlirt II. r a l . . . u. er M a . . :- !'i k.i. Pi P -t ^ lir ; p . poo-ioo? 1900-1906 1900-19(17 1900-1911 1900-1911 1904-1908 1906-1910 1907- 1915 1898-1916 1908-191.1 1909-1912 1906-1916 1909-1914 1910-1914 1912-1914 1912-1914 1911-1911 1914-1918 1912-1922 1915-191/ 1914-1919 1915-1010 1915-1010 1910-1920 1918-1920 1012-192.1 lOln-1922 1915 102.1 1920-192! 1910 192.1 1920-1924 1921 192! 1920-1928 1921-1928 p(24 2002 -- - 19272 -- 2750 129/1 6908 5801 4754 4816 2547 866 -- 544R 1667 a*i45 5518 5240 4 f*xn P r (9 -- 5 ' k> -- 242l> I 949 0 :'> ,0 il;/ 74u 40 <, 51 -- * 954 52 -- Ol) 56o 12 715 20 ->f 5 -- -- 1287 60 692 55 5 80 29 -- 6 552 15 265 8 48 1 218 11 5.89 15 70 ; 554 21 5S0 27 557 16 102 24 94 5 146 16 7 ": 54 8 8)1 458 - 2.87 24 7r s (i2 2a 912 0, : i 1in l.iii'a caiu-ei - f r O .55 >,,a r P " f al ;am t i'-ai ^ 5 51 1 42 5 8 2.1 2 79 1 15 n <S4 4.51 4 8 4.05 2 7 2 2 2 08 : 0 5 54 11 25 7 14 5 7 4 8 > <; (, 12 ; 51 5 4 --4 9 - 4 4 75 4 ) > 1) 2 7 7 17 4 O 15 0 67 0 51 0 57 -- 0 11 0 9 0 46 0 45 0 5 0 15 0 51 0.54 0 11 -- 0 5.8 1.01 0 19 0 55 0 56 0 49 f) 50 0 5 0.51 i) nK 0.5 --- 6 90 0 57 0 5'i 0 n; IS S w . i~. n r i ; r i : K mental air pollutants. such a* (lusts containing silica, soot, smoke. and tobacco; dusts ;:.im r o a d s especially asphalted o r oiled roads: <xh. u t'l fumes of gasolir.! engines, irritative chemical fumes, vapors, and g ases: and war gases However, no definite or generally accepted conclusions were reached as to the role of these agents in the production of lung cancers and their rise in frequency. It was not until the third and fourth decade of this century that ad ditional well defined occupational activities and environmental agents were again related to the causation of cancer of the lung and other parts of the respiratory tract : i.e. the nasal cavity, paranasal sinuses, and larynx. Among these additions to the list of environmental respiratory cancers were the lung cancers among chromate manufacturers (1905). of asbestos workers (1935). of arsenic workers (1930), and of coke oven operators (1936), the cancers of the nasal cavity, paranasal sinuses, and lung among copper-nickel smelter workers 11932) : the carcinomas of the nasal sinuses among luminous dial painters ( 1931) : the cancers of the nasal sinuses, larynx', and lung among isopropanol manufacturers (1946) ; and cancers of the larynx and lung among w orkers exposed to lubricating oil sprat's or mists (1936, 1949 i (Table I I I ) . T he most recent and best advertised addition to this list is cigarette smoking. T able III. Agent Arsenic Asbestos Chromates N ickel Coal Tar Petroleum oils Isopropyl oil f fiacliodAtne chemicals Occupational Respiratory Carcinogens and Cancers Recorded p u n u a P ast ~5 Y e a r s Site of Xuniber of recorded case* cancer Discovered L'.S.A Other countries Total Lung 1930 7 16 23 Lung 1934 22 6 88 Lung 1932 75 65 140 Lung 1932 0 84 84 nare~ and 0 51 51 na^al sinu? Lur.s 1936 0 53 53 Lung and larvnx 1936 7 33 40 Lung 1946 1 0 1 larynx 4 0 4 nat'a} sinu> 6 0 6 Lur.jr ltt/V 0 625 t.25 na^al sinus 1931 3 0 3 This impressive evidence on the existence of occupational and ein runmental respiratory cancers, however, is not generally considered a- \alid 1>y all parties concerned with such hazards, nor is there am a g r e m u n t or reliable knowledge as to the relative role which these and o tlu r in- I \ V 11;\ M h \ I \1. I ! \ I . i \N i IS '1 \ir- '.mental agents assume m the can s.u a a: <a ca w .ir ot da re-] mwii >rv tract Tints. the medical director ot an m lj >'".ru . r 11 <'<. '.a : m in p a n v n-Ccmh c.\]irc'Srd great skeptieiwn a- to tin- actual n ie n t- ot the avail able data on industrial respiratorv cancer lit- urn!' Ile -Ktud. "1 have as '.et to see a single report m tile literature w ind; 'udicatc- that the in cidence ot hmg cancer, and 1 cmpha.-i/e the word 'incidence.' is higher for ;im particular industrial group Keen the chtww.Ut - tu d e - la n e oui \ shown an increased relative frequency of lung cancer, and lienee 1 feci that until incidence .studies have been done, we had better stav aw;t\ from commenting about lung cancers in industrial workers." Paralleling this categorical attack on the significance <>f industry-related environmental and occupational factors in the causation of respiratory cancers is the recent challenge presented by the proponents of the cigar ette smoking theory of lung cancer genesis. It is alleged bv these in vestigators. on the basis of statistical O' hlenee, that the great m a jo ritv ot lung cancers-- i.e. up to 96r 'r -- observed du rin g the last 30 vc-ars, as well as the recent rapid rise in lung cancer frequency, are attributable to cigarette smoking and the increase in this habit, respectively (T a b le I Y i. T s 3lE IV . Statistical Correlations B etw e en T " :>acco Strr.kir.o and 7 C Degree of Smoking Habit Anione bung Cancer Patients 1Males 1 A cr. nor> Highly Very exceed\e heavy X..U Heavy Moderate smokers Chiaretto, only. haJanre ;>iyv,vn! <ipar-i Sorta et al. (156) 18 3 50 0 \V>w!er and 12 2 14 6 Graham (187) 20 8 30.0 3S 2 124 1 8 DoU and Hill (42) 50 21 0 80.8 5X <6 5 1 llrc'Di\v rt al (24) 15.8 50 7 10 5 5 5 0 0 G-e ! 1 64) 80.0 87 0 21 0 10 5 2 0 C '> rtr.,ls - Wyiitlcr and Graham 70 11.5 85 6 80 5 14.6 Do!! and Hill 21 114 30 5 47 1 s.s nrf'hnv et al. 5.5 14.8 18 8 11 1 80.5 T h e obvious impression is produced by these far reaching claims that an elimination of the cigarette smoking habit would re-uh. within 15-30 year-, in a reduction of the number of lung cancers to a level prevailing before the turn of the century and the .advent of the cigarette. .smvc the two propositions outlined i-.c - - adherent' of >oUscijuence and are actively and vigorously propagateli in both the scientific and lav 1 l H) \\. . I l l I -1'I u press. tlu-\ (lest rve son, w.s consideration '1 lie acceptance oi either :.c both o1 these a:legations is bound to exert ;i pr<ifotind influence tip tin direction which the com m ] oi respirator\ cancer ha/ards will have w take in the immediate future, as well as upon the type oi epidemiologic .m.'1 experimental research work which should he undertaken on this si-ddec. during the coming years. Apart from the not unimpoilant matter of scientilic accuracy and cnliditv of these claims, thev also pose medicolegal implications of no mean proportions, which are of immediate concern to parties engaged in tile prosecution and adjudication of compensation claims. A critical and sober analysis of the evidence available o r the causation of respiratory cancers by environmental agents therefore a p pears to be of sonic importance and urgency for these reasons, and e s pecially in view of the continued alarming and progressive rise in cancers of the lung in all industrialized countries (Fig. 1 I- r\\ ik ii.N m i ' \ i vi Cii't'innsltinlml /:tv/'m<v (\nu-i : nut .it. .'. >' ' <u. . i. *,. c : !.:m : Among;' the v a r i o u s i >i i -t -r\atn a i - i;-.\- m u 4 e n v i r o n m e n t a l o r i g i n ot r e s j u r a t o rx cancers aid r n - in r e c a c v . 'hir-c u \ 1r` c u ed tin- marked variations m the lim e of on set of the 'alter pheni mumon. in its mten.sitv .and ni its ]>ro" r v s s i o n m d im - a n t c< - --tri <' 'tales. | . m \ i " a counties, regions. and comnutnities ( T a l k s \ ,.nd \ ! . I'isi 1 ' W h ile 1' v n n \ ' >.ihni t \ n . v . r !>,\ilh / Cm. , . J : s ' e - - in l"-!r, .>: C'-in!r Pi-alh IIni f r i n ` >>r a' s State Connecticut Illinois Mars land Massachusetts Michigan Xew H o New I(T'Cy New VoA Ohio Pennsv Kama Rhode I'laiid Florida Louisiana Missouri Montana Xobra'ka Alabama Arkansas Xcw Mexico Xorth Carolina Xorth Dakota Oregon South Carolina A ashmgton \Y\i a i l i n g huiustrianci'ii -/r 1<<46 8 5 8 1 6 5 10 4 5 7 7 4 o 7 10.2 6.0 6 7 8 1 .''tnti's tci.'/i Rrmnnal Iniiv. \trmhcn urn; 6 8 6 5 7 5 10 0 5 7 . In n n i/lnra: 4 0 4 6 2 11 5 1 s t, 4 1 4 6 5 1 4 6 11 1 8 2 8 4 10 2 7 1 10 1 0/ 11.6 7 5 8 4 74 7 4 S.A 0.4 8 8 8 0 5 1 5 4 4 0 4 0 4 1 44 s 7 4 2 i o N'uii. '1 lie d e a t h r at es t . i tlit- m a r 1646 v . i t t a ' i i - r i. 1 1 ! 4 11 *i :ian ( i s 1.HUt , 1'I. 1646. I .lire c1 i 11.itn C,l!t v I, ir ( ,eI s -,., ; ' , : t h o - e Ini till e e. i r 1*J4S u i u ;, m . !lie e et b\ : 6< , ,f I'D \\ . v I H ) l ' I ' K in X or\\;i\, !e>' ihan <'r i of all canrtTS in males involve the lung. the corresponding Ugure a i (meat Hritain is about 2 5 rr. Tlie onset of the rise in lung cancer nioriahtx did not occur m Italy until about 1030 ( l'H O 1C)25: lung cancer autopsy rate of all autopsies in Padua and Milan 0.07 1 uni Y l. M . .'denre >! Result atony (.,7/nvr. 1<J37 and 2-}7 /unv.s tor X u i s ctropohta n Centers, by n,',r /vr JOO/vnf Pofuhihon'i Pi unarv Mtr Male. Females Total ami env Percent Percent Pert, ent FY7 D47 increase 1957 147 increase 1937 147 increase Atlanta Xcw Orleans Dallas Birmingham I >en\cr San Francisco Chicago Pittsburgh Detroit Atlanta Xcw Orleans Dallas Birmingham Denver San FraneFco Chicago Pittsburgh Detroit Hrone/.dm' omf Luna 5.0 15 4 168 1.0 5 0 400 2 9 8.9 267 15.1 59 1 198 2 8 4.2 50 7.6 20.8 174 5X 2<>ft 592 0 5 6 4 1180 3.1 17 2 455 4 5 18 9 .320 2.1 5 9 86 5.5 11 0 253 y.i 21 0 141 4.2 8 1 93 6 6 14.8 124 15.6 54 ,3 120 5.9 8 1 108 9 8 20 8 112 5.5 29.5 122 4.5 7 0 63 8 8 18 0 105 9.7 26.1 169 4.9 5 5 12 7 5 15 6 114 15.6 52.0 154 2.5 57 148 7.6 19 0 150 Larynx 1.4 4.0 186 0 3 0.3 -- 0.9 2 0 122 11.5 149 52 0 4 1 0 150 5 6 7 6 36 ' 2 5 5 66 1.5 0 4 75 2.3 2 7 17 1.4 4.0 186 0.0 1 3 -- 0 7 2.6 271 20 4 1 105 0 0 0.0 -- 0.9 2 0 122 4 5 8 8 96 0 2 0.8 500 2 4 4.6 92 6 7 7.0 4 0.4 0 6 50 3 5 3 7 6 4.4 8 0 82 0 4 0.8 100 2.4 4.4 83 3.5 6.4 85 0.4 0.3 --25 2.0 3.4 70 flP>iometrio Section National Cancer Institute and 0.13'^.; 1928-193,S in Venice Cl.5 ' / ). T he rise in lung cancer mortality lagged in rural districts of D enm ark by ten years behind that of Copenhagen. Stocks <164/ found that the local incidence rates of lung cancer in England and Wales during 1921 and 1939, and 1946 and 1948, jrevealed a general relationship to the extent and density- of built up area us expressions oi atmospheric air pollution through smoke from cliimnevs (Table V I I j . Similar observations were reported for England and Wales by kctinaway and Kennaway 96) covering the period 1946 W49, and comparing lung cancer mortality rates of (renter London with those ot larger towns and rural districts (T able V JII ). T he etiologic significance rN \ I KO.N M l.\ I M . s 'il these epidemiological findings is indicated by the recent dem onstration of 3.4-benzpyrene in the pollutants of the air of -everal English cities hv W aller (180), and of the particulate phase of the air of Los A nodes. California, and of the exhaust of gasoline and diesel engine-, by Kotin f t aI. ( W . l O O i . T aki.k \ 11. Lutuj Cancer M ortality t,ui / V / w /n O e ;; Groups of adjacent towns o u t 200,000 <n'nijnc-fl d u eliiniis .London and Suburban A re a 150 Lirmintihair. and Suburban \ n a ! 24 Manchester ami Suburban A rea 1.0 Lnerpooi and Suburban A rea U,2 Leeds and Suburban Area 122 Sheftichl -th 12-1,000 ov. t upied ihvtdhngs l.v \ c u i a-tle at a <iate^head with 87,000 <H'ttipicd d i,v 11 4 Xfifirenau- of <> towns witJl nOOOO !: ) X5,0(i(l in': d -' t b u m - 11.1 \uttrep.ite of s towns with d0,OOO to 50,000 o c c u p u d flue -hni^s lu? \wKrrjratc ot 12 towns with 2(),(Mli| lu 40,000 o c i u p n d -Iul jhn^s 104 SKt'l efaite of 1.1 town- with 20,000 to 20,000 i m h ^ u ! A -' h mj - 1nu V'fm< c a n of i tiwiis with k ss than 20,000 i v t u n o d L-. h u e ' S' ; "kl<ft n iii't LS 1 '4 V . l . I l l Kl'KR T aw t \ i i i no i'' of Fm. <} d>;j Aj m h .c, Lnglami and Hol es- 7`t/o - VO" Typo O OHiinni 'llt\ Greater 1a'IhK>,\ Ct*nnt\ hin Other ml un di-tr'ct s Kural tli" Tr'ot"s "Refer nee Of), Lung cancer rano-:nuni hcr of peratMK pn k]Ticino one death Males Females 100 100 12'< 137 160 136 233 183 Larynx cancer ratio-numbcir of persons producing one death M alls Female^ 100 ion 123 c 5 148 50 170 42 T h is i r r e g u l a r e p id e m io k Igic p a tt e r n e x h ib ite d by lung c a n c e r s fo r different regions and population groups conforms more closely with that shown by industrial developments than with one which might he ex pected :ii the result of a carcinogenic action of a single environmental factor, such as cigarette smoking. This interpretation of the data on the general epidemiologic behavior of lung cancer is supported by evidence on hand on the frequency of these tum ors among members of special occupational groups, for some which well defined exogenous carcinogenic contacts arc known to exist (Tables 1 X -X II t. T a b l e IX . L io .g C ancer Death R ale per 1,ij00 Deaths of .11! Causes Jor seeen In dustrial Grout's in O h m , 1)47, A m o n g 5,309 M ale Cancer D e a th s" Industry Iron and steel Transportation Agriculture Rubber and plastics Stone, clay, glass XonTcrrou-' metal Mining and quarrv ing Total "Reference 118. Respiratory cancer 2.18 2.61 0.82 2.34 0.66 3.22 1.3.3 1.76 J Operating railroad workers inhale carcinogenic jtolycvclic hydrocarbons contained in the sooty exhaust of diesel engines and coal and oil burning locomotives. The employment ratio of operating railroad workers was 1 :4. T h u s about 75r r of the lung cancers occurred among the operating group representing about 2 5 r}, of the total number of employees. Ross (147) recently stated that there occurred during the period 19.1.5 to 1952 an almost tenfold increase in the relative frequency of death from 1<K> \\ . l . I K ' K I ' I R T aw.i' XI. I,he-: i ahO'] T w . :i, ckk\ . hie 'Hi; ( :(\i ikers Luntr cancer's Railruail P tno-l T ot 1 r:o hmi; c111 A 1040-150 >, r. 10.19-1040 104 operating KR workers Xo. A 24 K.l 59 57 wj end X 'ratine .Vo.>oo,> Lung; cancer* nonoperating RR workers Xo. % 5 17 15 14 Ltlilir c. until(`tenmined RR \\ i Vers Xo. <c -- - -- .10 2Q lung cancer am ong the m e nibers of the B roth erh ood of R;lilroad. T rainmen. Dunner and Hicks (45) recently called attention to two additional specific worker groups, namely boiler scalers and grain dockers, who seemed to have an excessive liability to lung cancer. It may be tossible that contact with chromate containing scale, if chromates are used as antirusting agents, niav account for the observations of boiler scalers. The presence of fungicides or other chemical additives or contaminants may have to be considered in relation to the lung cancer liability of grain dockers. Conclusive Evidence on Environmental Respiratory Carcinogens The demonstration of special lung cancer hazards produced by a number of well defined exogenous chemical or physical carcinogens has so far been achieved for only relatively small and circumscribed worker groups It is well recognized, however, that similar contacts exist for other and often very large industrial groups which either have as yet not been surveyed or about which records of investigations undertaken in the past are not available in published form. Since many of the occupational respiratory cancer hazards extend in some form and to some degree to the general population through contact with industrial wastes released into the a t mosphere, with gasoline and diesel engine exhaust, dust from tarred and oiled roads, and the abrasion of rubber tires, or the handling and m e of consumer goods (paints, sprays, antirusting agents), it can justly he concluded that the actual scope of the environmental respiratory cancer . problem may be of a magnitude only faintly discernible from the recorded -factual evidence. General Characteristics of Environm ental Lung Cancers An analysis of the epidemiologic and symptomatic data on environ mental respirator]1 cancers shows that these neoplasms as a group h aw certain general characteristic J'.xposurc l i m e and l.atcnt I 'criod. In tile mapwitv of occuj mth ,nal T am.k XII. Oi cnf'titiannl (j null's ll'ilh an fi.i\ essi-ee l.imi/ Cancer Incidence M\ i"in v, >ihIm ms ji.m-nt fuel w o r k e rs , liiiii.uo n u n , tHiimlry I.ilmrors, rullors, olo. m >1 ( 5 5 ) , liK CC '1 l')52 '\oi;i-li ,ir (onoi.il ( l'i.W) ; M cl .amjlllin (122) l ` S \\ l . l i t r !!' K respirators came:--. dir disease is discovered while the individual is still at w ork; i e. the tx p o -u ro time is identical with the latent period. H ow ever, there exist- reliable evidence gathered from the entile occupational cancer field which prove- that the exposure time mav he much d io rte r than the latent period Therefore, an environmental lung cancer may be come manifest mans' years after exposure to a specific exogenous agent has ceased. An a m h s s <>t the final late of some 150 former chromate w orkerengaged in chromate production for at least six months, and having passed a latent period of more than four years after discontinuation of their e m ployment, demonstrated that of 25 deaths which have so far occurred in this group, five were caused by cancer of the respiratory tract representing 20% of deaths from all causes. In asbestosis lung cancer the exposure-free interval ranged from several months to 20 years in many cases (182). From the information available on the length of latent periods for the different types of environmental respiratory cancers. Tables X III and XIV were prepared which show the interrelations between exposure period and latent period, as well as the years which usually elapse between the onset of exposure and the manifestation of the cancer resulting there from. Attack Rates. The information available on the attack rates of the T Mil K X I I I . .AtC'.l I Jerit>ds' of fin: ironmentoi Res pir atory Cancers Lu: Xares and nasal sinuses A stent Asbestos* Ch romates Nickel T ar fumes Isopropyl oil ionizing' radiation Average latent period 18 15 22 16 -- 25 -.55 Range of latent period 15-48 5- V 6-50 9-25 7--50 Average latent period -- 11 10 25 Range of latent period ___ -- 5-26 -- 6 16 19-52 "Period expressed iri y e a r s. Tmuc XIV. , Agent 7: r/>(ivvre Vd ;cslo-> X K'kcl Average ( T Tile 20.1 7 6 ir mu* e x p r e s s e d in u m h 7 iuu 'r <? !iir< ironmeuta! Lung Range of exposure time nil 40 males 0 -48 rVinab s 1 -aa m ales A`cspu aiorv Xares and Average exposure* time _ - (Ann ers nasal 8iiniMs Range of exposure t line ___ ___ 5- 2<> various environmental respiraium cancels t<>r the populatn 'ii> at risk is detective and inaccurate, with the possible exception at the data on respiratory cancers among chromate matunac; r.rcrs. isopropyl alcohol m a k e r', and radioactive ore miner.'. T he evidence mi ham! on .-.Hack r a t e ' for the various occupational respiratory ctmcer'. moreover, is expressed in terms which cannot readily he brought upon a co m m o n denom inator In evaluating the merits of these estimates, consideration, m oreover, must he given to the fact that the attack rates are subject to various factors, such as the relative potency of a particular carcinogen, the intensity and duration of exposure, and the accuracy and completeness of records kept especially in regard to former workers who left hazardous operations T he attack rates, therefore, may vary with different groups exposed to the same carcinogen. The data given in Table X V , therefore, should he regarded as rough approximations designating the magnitude of trends in cancer frequency for special population groups exposed to several particular occupational carcinogens, rather than exact values of incidence, or frequency of respira tory cancers These attack rates obtained on special worker groups, how ever. are not applicable to any other worker group which might be exposed to the same agents, nor to the general population which has active respira tory contact with some of them in a mitigated form. A ge and .SY.i Distribution. Occupational respiratory cancers often fol low the general pattern of occupational cancers by exhibiting a trend to ward a shift to younger age groups than those characteristic for cryptogenetic cancers of the respiratory organs. It seems that the age at onset of exposure a s well as the intensity and duration of exposure in addition to the potency of the carcinogen account for tin's phenom enon ('Table XVI). A characteristic and significant shift in age distribution of occupational respiratory cancers is demonstrable for lung cancers produced bv chrome pigments, tar fumes, and ionizing radiation. The great majority of occupational respiratory cancers recorded in volved males, because only males were employed in the hazardous occupa tions. The only exception to this observation i' offered bv the asbextosis c a m e ls of tile lung, which attected in a series of 52 cases-- for which sex data are available-- 37 males and 15 females, representing a male-female ratio of 2.5-1 (general ratio 5:1 to 10.1 > h.utilization of <arcinogenic exposure, as represented h\ asbestosis for the two -exes, thus resulted in a trend toward equalization of liability to lung cancer These observations which can he duplicated lor other carcinogens J .jtes also do not favor the concept ot a sex related siisceptibilitv to lung r a n n r. <i i i t / m n r . i f h a t i<*n 1C.mIiu <t i\ o n i r s I amt; i \ \1K( I \ M I \ i \I ! t \' , . \\ \ JO ! r U'.i I \\ ! h \ s ' , v < v ... A^VM ("hromav** L Jironie pigment** Tai iunk*' i< ni/ing r.iui ui'Ti: t 'o n t r u N in 30 \A -> 4 11 cl 4(1 X. i r P 12 11 t c -M _"P \'a 11 21 >> 24 5 1 oO V. Its 2, > 74 3S 0(1 30 1 / 33 12 r / 1 = 6 5 30 27 ps ; g 2 `} 2t, OP 6 2 2 2 12 44-i 24 V IP 44 01 70 X- 14 c l 21 >^ 1 1c ! i) ! , 21 71 ox ( )\ xr rii-. Xu 40 i i` in 21 11.1 p 2 3 1?2 I he marked and growing' predominance of male', among lung cancer victims seems largely to be due to the following factors: 1. Males are more extensively employed than temales in occupations where known or suspected atmospheric carcinogens are produced and used, and work more consistently and over longer periods of their lives in such occupations. 2. Males predominate in outdoor occupations, especially in urban areas, where they become exposed to carcinogenic pollutants contained in the general atmosphere ( effluents of domestic and industrial furnaces, exhaust of gasoline and diesel engines, dust from rubber tire.'., and asphalted and oiled roads). 3. M-ales more often than females perform heavv physical labor requir ing deep anfl frequent respiratory movements facilitating the penetration of carcinogenic air pollutants into the distal portions of the respiratory tract. and thereby increasing the frequent'} and degree of exposure. 4 Mtiles more often than females w ork through the entire span of their occupational life within urban areas with proven carcinogenic a t mospheric pollution, while females to a greater degree than male--, star tor larger portions of their lives in the cleaner suburban dormitor\ communities. 1] isfoloi/ic / ypes of Occupational Respiratory Cancers. Although the information available on the histologic tvpes of occupational respirntor\ cancers are quite detective, it is apparent from the data on hand, that among the respiratory cancers recorded a- of occupational origin, \ a n o u s histologic t\pes occur, and that there does not exist anv relation between a specific etiologic factor and the histologic t \ pc of can momatou- re sponse i A ii. The numerical relations b-tween the various histologic t_\pes oi occupational respirator} la n c e r elicited be difh n nt n u i i o i i mental carcinogens are presented m Table YYM 202 \l l . ! 11 1.1-1 R Q raiiiini.ii o imposed of -everal histologic types u ere repeatedly serveil [Mjuanimi^ cv-H-.ulcn >cai cinonia w hi) asbt-stosis t 114 : six c>-tiibinations of sijuninoii' coll and round cell carcinomas ( Schneeberg orc'cors ) ( 15 4 i j T o n .f X \ 11 / / o - l y r e s at (h -i u/v-,: an! !''pire tory [ en, ci > Anc-nt 'Jar fum o >, Kkrl Chromium A^K'rstO', Radioactive gases and du-t Nickel Kadioactive gases and dust Isopropyl oil t )rcan f ung i -UU^ 1.ung 1.ung Luni; >(|uamouv cel! .aixinoma with or without cormfication 4 -- 1! 14 Kotmd cell or oat cell carciii'ima -- -- 2 > Aiuipl.tviic or I>ol\ niorphic carcinoma A -- 2 7 \ -Un Cal'C i! .> 2 -- -- 6 i X'arcs ar.d naval h r u v 3 -- Vare< a:ul naval >::iu ^ 3 -- X' a res and naval -- -- 0 i -- -- 4 -- It may be mentioned that a multifocal origin of various occupational respiratory cancers (asbestos, ionizing radiation) has bec-n reported In srerai investigators. This observation may be interpreted as reflecting the marked severity of occupational exposures since multicentric carcino genic developments are rather commonly observed under the abnormal and extreme exposure conditions practiced in experimental carcinogenic studies. Causal Mechanisms. Biochemical Reactions of Respiratory Carcino gens. A pa rt from the ra th e r diffuse causal concepts such as hc-reditv. cell misplacement, and chronic irritation, there have been obtained during recent r ears, data on specific chemical intern-actions of respiratorv carcino gens with constituents of the host organism. It seems that all of these reactions are common either to .several or all of the known respiratorscarcinogens and therefore may furnish a sciciitiiicallv sounder basis i,,r future investigations into the nature and different phases of the actual chemical local and systemic, humoral, cytoplasmic, and nuclear changewhich ultimately u-sitlt into Lancerons cellular transformations. Sulfhy dry 1 Inactivation D uring the past two decades \a rioU ' in vestigators- hate T o w n that several carcinogenic substances act upon I. \ \1K< >X M I- \ ! \l. I I X 1> . K 2( IS siilflndryl groups, and thereby cruise an ; .\a ta m it --r.itIn dry 1 a c tu a t e d enz\ me and disturbances m the >.t !!u\." met;.!- .hsiu . tv 81, 146), and that chemical carcinogen-' may he inactivated !>\ combining with or inducing oxidation of stilfhydryl g r o w " i So Mich efteci- have been demonstrated for spin p ro d u c t' m ~-dmk th \ '.minoa/i >bcti/( m t ! 3 9 ) as well as for 3.4-ben/.py renc ! 2/ . ami were- d e m o n stra te d by H ueper i'/ n! i 88 i , f( >r iom/.ing radiaimn ..i ; g upon biologic, grow th promoting material (emlirio extract i \r-cnierds are known to combim with and accumulate in tissues rich in suifhtdrvl groups . epidermis, hairs, nails p There thus exists some evidence that certain exogenous earcinogcn- whicli produce cancers of the respiratory tract inhibit the metab die action of free stdfhydryl groups and or may cause enzymatic and oxidative dis turbances. The extensive industrial use of nickel and chrom ium as cata lysts, and the inhibiting action of beryllium on alkaline phosphatase provide evidence suggesting other action mechanisms of carcinogens upon enzymatic activities. There exists, moreover, the possibility that through a direct chemical action these carcinogens may bring about the production of abnormal endogenous substances, such as for instance steroids bv an oxidative effect of chromates on cholesterol . 53.. Protein Conjugations. Following the successful artificial conjugation of aromatic chemicals and related carcinogen-, with proteins through azo-. or isocyanate-, or carbamido-linkages and the production of carcinogen- hapten specific immune bodies in the serum of animals injected with such synthetic antigenic complexes (34, 54. 80, 102. 144). a tte m p t' w ere made to demonstrate similar hut spontaneously formed carcinogen-protein com plexes in the tissues of animals exposed to carcinogen' Ficser (53 . suggested that carcinogenic polycyclic hydrocarbons might combine with cell proteins by the opening of an S = S linkage. W h ile the- actual e x istence of protein carcinogen combinations was first shown in connection with hepatoma producing aminoazo dves f 125. 126 i. Miller i 1123 j suc ceeded also in demonstrating the formation of grotcin bound derivatives of 3.4-ben/.pyrene in the epidermal fraction of mouse 'kin ft is likdv tliat arsenicals combine with protein bound sulfht drvl groups, and therein form arsenic-protein complexes which mnv gut- ri-e at times to alletgn reactions. The not infm juent occurrence of allergic dermatoses in worker- exposed to two additional respiratory metalln carcinogen-, namely chro mium and nickel. suggests tile formation of corresponding protein com plexes through linkages of these metal- with tie- I'.irbiv,:-. hvdroxvl- or sillily dry 1-groups of the ammo acids In fact, recent investigations 1.oiselcur ( 10N-, as well as llueper. [oh:,-on and ( irogan '<() i on 204 NS l M l I D K animals miected with mixtures of chromium and nickel compounds m protein solution, ::a\c l e - n lu d m the production of moral specific a n ti bodies. Attempts at demonstrating similar antibodies in ihe serum of chro mate mainline! 11<rs. sect ml of whom had keen operated on tor tancer ot lire lime, g a te e- moca! ri u ilp . Of the positive precipitin reactions ob served m these evpcrimenis with human material, antigens prepared with trivalem chromium (chromium acetate i gave, in general, more consistent and stronger reactions than those obtained with antigens containing hexas ulent chromium *potes-nun c hrom ate). Associated studies of Grogan and Oppenheinicr -h2 i ,,n trivalem and hexavalent chroniinni comjxninds dissolved m human plasma and tested for the presence of metal protein complexes hy the- tcchnajues of dialysis, moving boundary, and paper electrophoresis, and light scattering phenomena, provided chemical evi dence supporting the immunochemical observations. Mention also may lie made in this connection of the statement of D eX ardi ct al . i 57 i to the effect that the pulmonary granulomatous r e actions seen in berylliosis are attributable to the formation of beryllium protein complexes eliciting an allergic reaction. These more recent ob servations on the formation of protein complexes hy polycyclic hydro carbons and metals possessing carcinogenic properties lend support to the chemo-allergic mutation theory proposed by hlueper (82) in connection with the development of bladder cancers in dye workers exposed to certain aromatic amines >beta-naphtlnamine, benzidine ( 1 2 1 ) ) . Recent studies of English investigators (65, 70), have furnished a new and intriguing concept as to possible combinations of carcinogens with tissue proteins through the postulated formation of cross linkages between carcinogenic chemicals and the niacromolectilar fibers of chromosomes. This hypothesis was evolved from evidence obtained in the study of carcinogenesis by nitrogen mustards, di-epoxides, polyethylcneimines, and related compounds. In view of the fact that one of the various means bv which these substances may exert their specific action in the cells is through polymerization, it is assumed that polymerized epoxide chains might interreact with proteins or nudeoproteins of chromosomal origin, bv cross linkage with multipoint attachment, and thereby cause mitotic aberra tions. The initial reaction of one of the epoxide groups of monomeric molecules, with the cell component also may start a process of polvmeri / a rion by being follov. td In a seif-condensation of the free epoxide group.into a polyethenoxv structure. These concepts are of interest to respiratory carcinogenesis for several reasons. They may have direct application to the development of pul monary cancers :n connection w uh occupational exposures to silicon ).N \ [KO.\ \! I V I U . 1.1 N o J ( '5 and carl ii in poB m ers. namelv. a-best ns and -.-propyl mi containing nob - proprieties anil nr lsopn >p\ 1 epoxides (45. S i.' > u i a it has lu-cn shown experim entulh that al least one epoxide i i '5 a 4 -ok ><-\\ 1nilanr is c a r cinogenic i 71 i. the observations of Kotin n: u " cinicernui^ tin oresence of carcinogenic tni'aturuted aliphatic i.ii\iiio in the atmosph<.u of Los Angeles gain increased im portance O' to tito naturi of po--ibh carcinogenic air pollmants in uibanized a r e a s Additional potential extensions of cross linking carcinogenic ]>ohnnrs m relation to pulmonary carcinogenesis may a suit from the proposal medicinal use of polyvinyl .alcohol and metlivlnn timer) late balls for tin. extraperiosteal plombnge of the pleural cat in for in -u n n g a ]>erntanent collapse of the lung because of pulm onary tuberv uk>~is .So, lSf>i. M e n tion may also he made of the fact that two large molecular polvmcr'. namely, polyvinyl pyrrolidone and dextnm. which have recentlv been in troduced as ]>liisma extenders, are m part arre ste d in the pulmonary cn]>il!aries and enter the capillary endothelial lining and interstitial peri vascular tissue, thereby creating intimate contact with pulmonary struc tures. These medicinal uses of various natural .are! synthetic polymers are of potential significance because of the demonstration of carcinogenic effects (43. 135, 190) produced in mice and rats following an intra- peritonoal and subcutaneous implantation of a considerable number of chemically closely related polymers, such as cellophane, polyethylene, polyvinyl chloride. A'ylon, acrylic resin, polyamide ( H-caprolactam , Teflon, and Silastic. Although there are no observations indicating w hether or not these findings in animals may apply to man. it appear to he wise to Keep all industrial workers, who may have respiratorv contact with fumes, vapors, and dust of these anil related polymers in the produc tion and processing of synthetic plastics and textile fibers, under close medical surveillance for a possible development of respiratorv cancers These precautions are also indicated because of tN- use of sunn- known or suspected chemical carcinogens (nickel carbonvi. aromatic amines) as catalysts and or antioxidants or curing agents in the manufacture of these polymers (methacrylate plastics, synthetic rubber; epoxv reins i. Because of the similarity of the cytologic alterations, especially chromo somal fragmentation and bridge fi.rmation <it antiphase, produced by the various aliphatic carcinogens studied hv Hendrv t til. i 70, 71 , and H.id- dow t()5i to those elicited by ioni/ing radiation, their ration has been called "radiomimelic." It is interesting to note in this connection th.it ionizing radiation mav stimulate depolymeri/atam of maeroniokvular pop.- 11let's as well as the tormaum, ol cross jmk.sges t u i t u pwlvrthvkne chains W hether -neb e l l u l s are active m the production of j million,u . 20< ) \\ I I l l I- )') K and nil sal mu cancers m worker exposed to radioacm e dust and . however. ;. pi. >.illative ' L'-M. 'I'hc various observation and Inpothcse discussed in relation to the possible biochemical changes underlying environmental respiratory car cinogenesis >uggei that all agents seem to interact hv some mechanism with proteins or nucleoproteiiis and produce, thereby, abnormal proteins. The siginficnnv> <:>f thee proteinic alterations to the cancenzation process, however, : undeterniim d Specific R espiratory Carcinogens and Cancers The respiratory carcinogens so tar recognized differ greatly m their chemical and physical properties as well as in the physicochemical statu in which they come in contact with the respiratory tissue. Some are chemical agents, such as various metals or ineta! compounds (arsenic, chromium, nickel , o r m inerals (asbestos i. or aliphatic organic (isopropyl oil^, or aromatic organic compounds ( chemical carcinogens in coal tar. pitch, soot, petroleum derivatives). Others exert a carcinogenic effect through physical forces lionizing radiation /, such as the various radio active chemical. They enter the respiratory tract in the form of dust, fumes, mists, vapors, and gases. Depending upon the particle size of the dispersed carcinogenic material they may penetrate into different parts of the respiratory tract. If the particles are rather large, they produce mainh cancers in the upper parts ( nasal cavity, la ry n x ) They mav enter, on the other hand, the deeper portions, such as the bronchi and lung or paranasal sinuses, if they are of very mall particle size or take the form of vapors or gases. M e t a l s . Xickel. Xickel, one of the most industrially important metals, and principally mined in the Sudbury district of Ontario, Canada, finds many uses (alloyed with iron, copper, chromium, aluminum, cohalt, and molybdenum ) employed in the manufacture of stainless teel, heat resisting steels, forging, casts, wires, sheets, structural shapes, tubing, rods, bar, trips, etc. i. electroplating, catalysts, ceramic enamels and colors, pigments in paints and ink, storage batteries, etc. Exposure to nickel fumes and nickel dust of metallic nickel and its compounds or to nickel carbonyl vapors is. therefore, frequent for indus trial worker of many types and in many operations. The l'nt report concerning the occurrence of an excessive num ber of cancers of the nasal passages (nasal cavity and paranasal sinuses') and of the lung among workers on the Clydach plant of the Internationa! Xickel Company located a t South Wales. England, was made hv Grenfell i.bl) in 19.12; although the first appearance of these neoplasm among the ! X V ) Kl l X M ! X I \I. I : X ; \ N l 1 K i3ic w! tefmer\ workers \\a- noticed in `'2~i '> :"ubse,mvw 'amoy;- -tea? in," v. nil the -e canct rs were made he Stei ' mis <\<>2< A iim r ( 4 . Coopet M Canizci i d 'A . a n d Merewi liter 124 :ruin l u25 to SMS n-chtsue. thm * w ei e notified with the ( 'hiei Inspector . : Factories .1 total ot 4-f m -e - >i cancer oi the nose and 82 c a se ' of cat!cer ou the lung l o a n the m c k t1 works Bv the end of BM8. 4fi of the na-'d cancer and 72 i >t tin- btng r . w - h-id 'he'! Xnm o i the na-ai ca-es and oniv tw o or the I n n " case' had commenced work in the nickel refinery after l u24. when a reconstruc tion of the plant had keen carried out T he m e ra g e exposure period a li the nasal cancers was 2d years i range. d-2n v u r s i, :,ni! for the lime eancers 25 tears tr a n c e . 1-dd wears,. Xo ca-cs of cancer of the ! a r \ n \ h;i\e occurred, and only one cancer of the nasopharynx was observed at Clydach. Tlte nasal cancers involved the turbinate-, nasal septum, and paranasal .sinuses ( ethinoids ). O f these the majority were of the undifferentiated cell type ( s i x ; , some showed a squamous cell character i three i, while columnar cell carcinomas were uncommon i one's <If the lung cancers, of v hicli histologic studies were available ;n only four case-, th re e were nt the small cell, pleomoiphic type, while one was a squamous cell carci noma. '-miilar observations were recently recorded from a Norwegian nickel refinery, where three cases ol lung cancer were seen i 109. [it one of these cases a squamous cell carcinoma was a'-ociated with sarcoid Ic'ions (boldblatt and W agstaff (f>0) mentioned tha t so far cancers of the respiratory tract have not been noted among the w o rk er' emplovcd at the ( ivrman nickel refinery at T.udu jgshaien. nor has there been ol,served an unusual frequency of respiratory cancers among the workers of the Sudbury nickel ore mines and smelters in Canada Amor ('4 1 pointed out that the majoritv of individuals employed at Chu.u'h. who developed respiratory cancers, sere not exposed to the inhalation of nickel carbonyl, hut to that <.f nickel m atte dust, or diist from the nickel matte roaster (309). More recent data communicated by Morgan ( 127 ) confirmed this observation, although e x p o -u re to nickel carbonyl vapors had occurred more frequently among the affected workers than apparent front the data previously given by Amor. T he relatively Sngli incidence of cancer ot the nasal cavity, indeed, -ugge-ts that a rather roar-e particulate dust readily arrested at dm region of the tu rb in a te - may have been active in the production of , oncers at th t' particular 'in . Ahllc nickel cnntammg t a p e s or a vert -n tall paiti'iilari - mov JKt'i' account mr the cancel-' ol die lung .p i a a-a! -m!!-( \ , 'o the c a n -a b le agent. \a i;o n - theore - ! -. . e peel! *" !' .. nor,! 2 ( >S U l I I I l-.l'l . K favored tlu- concept that the inhalation of mist troni ai'M'mc containing sulfuric acid um'i! in the reluung process was the active carcinogenic agent It is most unlikely that this is correct because the nickel refiner}' workers do not suffer from perforated nasal septa, and o i s p l a y no evidence of chronic arsenicism. such as dermatosis and cutaneous cancers, which almost always have accompanied the occurrence of lung cancer anion; worl rs exposed to arsenical dusts or fumes. Amor (4 I stated that the refined nickel-copper ores are free from radioactive matter. The respiratory cancers observed anion; nickel refin ery workers thus are not identical in etiology with those seen in miners employed in the radioactive mines of Schneebers; and Joachimsthal. Workers employed at the roasters, in the nickel carbonyl operation and at other parts of the plant, on the other hand, become exposed m the inhalation of dust, fumes, or vapors containing nickel. Xickel is the common denominator for all of them. It thus is most probable that the respiratory carcinomas observed anion; nickel refinery workers are re action products to more or less finely dispersed nickel particles or vapors. There is no evidence available, however, which indicates that the in halation of nickel in particulate or vaporized form is accompanied bv pul monary changes of a pneumoconiotic nature. The concept of a nickel etiology of respiratory cancers was tested in animals by Campbell ( 2 8 i , who exposed mice to the inhalation of pow dered nickel matte, and observed that these animals had a lung tumor in cidence significantly higher than that of the unexposed control mice. The recent experiments of H u e p e r 18 5 ) seem to demonstrate more conclu sively the carcinogenic properties of metallic nickel. W hen pure metallic nickel powder was implanted into the femora! and pleural cavities and in the subcutaneous tissue of rats, cancers developed at the site of injec tion within 6 to 24 months in about 4 0 r/r of the surviving rats. Among 49 tumors thus produced among a total of 175 rats, 4^ were sarcomas, and 1 was a squamous cell carcinoma (Figs. .5. 4 ) . Whether or not nickel assumes a carcinogenic role for cancers of other organs and following exposures by other routes is unknown. It may he mentioned, however, that Araki anu Mure f 5 i demonstrated bv spectrotfraphic methods, nickel in human and animal cancers of various types and sites. The nickel content ranged from i>27d mg. kg. of fresh tumor tissue to 0.2 mg. kg. Xo assessment of the degree of occupational nickel cancer hazard can he made from the data available, since the number of workers at ri-k is un known. Likewise, no definite opinion can lie expressed as to the possible existence ami extent of respirator} cancer hazards fur persons having for ! 'S \ ! Rii.N I \ I \1 ! I \ , \\i ! R _>( )< 1 Flo 3. Osteogenic 'a rco m a in the thigh o a rat injected with powdcre' metallic ickel into the femoral \ein. Flo 4 M yoblaste >arconu in the thigh of a r,tr i n j n n d into thi femoral <avitv n h DOvV(jT(`(j TTlrtalhr T1o'k i'lo R o u n d ei! c a m i i o m a of t he lung in a . nroin.it : ! u i m < t m v i F l o O M a - " n \ e (iepiNtimi ot c h r o m i t e o r e '.inntacturc i m - t r i * . e 'n i g ,L . i n o r n a t e 210 \\ . l ! ! ! 1J ' l . l ! other reasons contact \\r.!t <!n-t. tunic.'-, and \apor> com.um.'g nickt 1 or ;> compounds. Chromium. Chromium as a mctttl. allot, or compound is used f a mailt purposes in industry. It is for this reason that a large number and tariety of t\ orkcr.t h a te contact ttitli chromium ami chrom ium com pounds, and that even restricted groups of the general population mat possible heroine reposed To these agents in the form of d u s t , vapor f u m e s , mist, liquid, and solid <22i. W orkers most likelv to be exposed to chro mium and its compounds are acetvlene workers, aniline workers, bleachers, bhieprinters, chrome workers, chromium platers, chromate manufacturers, chromite miners, crayon makers, dye workers, electroplaters, enamel workers, glass and pottery fro'ters. glass colorers, pottery gla/ers, artificial tlower makers, battery makers, linoleum workers, paint makers, ink m ak ers. painters, photographic workers, photoengravers, polishers, printers, rubber workers, steel workers, tannerv workers, vulcanizers. waterproof ers of textiles and paper, welders, users of chromate antirust agents (loco motive attendants and en g in e e rs), bitumen and oil rellnerv workers, plas tic manufacturers, vegetable oil processors. The observation of apparently occupation connected cancers of the res piratory organs, especially the lung, has been limited so far to two t\p e s of operations, the production of chromates from chromite ore and the manufacture of certain chromium pigments (zinc chromate, barium chromate, lead chromate i. in these operations both w ater soluble and insoluble chromium compounds are inhaled by the exposed workers. The chemical nature of the actual carcinogenic agent which is responsible for the excessive liability of chromate and chromium color workers to cancer of the lung is still controversial. Although all investigators believe that some chromium compound or compounds are can sal Iv involved, it has remained uncertain whether the compounds suspected are he.xavalent or trivalcnt. water soluble or insoluble, monochroniates. or diebromates. Water soluble chromium compounds ( monochroniates. dichromates, and zinc chromate) are most often incriminated. Mancuso and Hneper i 11W recently pointed out that it may be more likely that carcinogenic effects are elicited by chromium com pounds which arc cither not soluble in water or onl}- slightlv so, because such chemicals when inhaled as dust would be retained and deposited m the lung and thus exert a prolonged effect upon the pulmonary tissues. Such chromium compounds present in a chromate plant would be represented In chromite ore and its r a r h con version products preceding the formation of monochroniates 1 lu sr little water soluble trivab-nt chromium compounds occur m the man nal present ill mixers and foa-ter-. and are contained in the -lag which u-ualh is stored for hit tire use in the card a n a of the plants I. \ \ IKO\ \ 11 ,\ i M 1 \( . i \ \ U K >1 ^ It b <lef)iiitc;]% surprising that ,m e \ c e " i \ e liability a ang canct r h ~ been established su far on!\ lor c h u rn ,m vankiT,' mi t e w m a m end tm I'n ite d Slates ( 11, ,V>. 'G, 11(>, and in chrome a gmt nt w n r k c a in G e rm a m (A 10, fi.i. 104. 140,. iiid 'tru p i l l ) . found , single case >a lung cama-r upon \ - r a \ examination of the chest of 421 chrom ate m an u facturers e m p k n e d for more than 10 \c a is in Kngh'h plants while no data exist on this point in regard to chromate producing; o r c- 'ism -ang pi,ant' in other countries, such .as Switzerland. Italy, and France Apart from the e \ c e " i \ e frequence of lung cancers .wong chroman workers which according to American observations r a ttle from l a --51 times the normal, an occupational origin of these cancers is stn m g h suggested hv the shift oi the age distribution toward \ o u u g e r age p i n i [ s This is particularly striking for the lung cancers present among German chrome pigment workers, since 50G ot the cancers affected individuals before the age of 40 \ e a r s when lung cancers ot u n k n o w n etiologv am relatively infrequent. W ith the exception of two cases [one cancer of the i i a t i ' i la a i ; one cancer of the maxillary sinus ( 6 0 j] , the lung was the exclusive site if respiratory cancers observed am ong chromate workers. The- total number of these cancers is at present around 140 cases from all sources. X om lias been reported as originating from nasal septum ulcers . Fig. 5 t Chromium pneumoconiosis seems to accontpanv the development of cancer of the lung in chromate and chrome pigment m a n u fa c tu rers It is uncertain, however, whether the pneumoconiotic phi}' an essential or modifying role in the .specific cancerization process or w h e th e r it is merelv a phenomenon of coincidental coexistence (Fig. 6,. W hile the attem pts of G ross and Koel'ch f(>3). and Campbell i 2 8 i to produce lung cancer m mice by their exposure to chrom ate dust wi re w>- siiccessfui, Sihinz (15.G and Vollmann (177). who implanted powdered chromium metal m to the femoral cavin of rabbits. obserw-d, after m-in than 3 vears. one animal with cancer of the lung and om with ca n a r ' the femur In a scries ot pilot experiments recenth cot ducted, guinea pigs, rats ami mice were exposed to the inhalation of chrom ite ore dti'i at a concentration of 155-/, liter of air for 5 -6 hours dav. 4 d a v s /wc< for a total of 18 months, 4 of the o W istar rats showed t u m o r ' i n \ o l \ b g respiratory organs, fine rat had a squamous cell carciimma \ Fig 7 originating in till' paranasal s i n u s c - and invading and u'or ating iF mchall, two additional rats showed, at autopm. s.iriomato g ro w th ' m \olviiig the mediastinal K m ph tiodi s and lungs d h< re - - uau! Mm ' pigment within the thickened nitimtitial ti-siie din- hr-g- f t !r <<- gmm pigs rew aled on hi'tologie exaimnation i m a ile d ;.. oi > i a Ia ai ..f ii" 212 \\ I I I ! l'I' K bronchiolar epithelium which mten occluded the bronchiolar lumina f>\ the formation of cellular plugs consisting of oval and spindle shaped, hvperchromatic epithelial cells. These cellular masses extended in places into the adjacent alveolar lumens form ing polyps, coatings or '.olid cast'. These changes were widely distributed in the lungs which showed, more over, a scattering of dark brown to black amorphous pigment located especially in the suhpleural zone, and within a fibrous and thickened inter stitial tissue ( Fig. W Arsenic. Arsenical' represent a bv-product. or waste product of the smelting of many ores (copper, zinc, silver, cobalt, antimony, iron, bis muth, nickel, tin, and lead*. Arsenicals are present in the smelter fume' and slag heaps. They are extensively produced and used, especially during past decades, as insecticides, fungicides, and vermicides ( sheep and cattle dip, grasshopper bait, rat poison) as well as a herbicide, especially for clearing railroad right' of way. Arsenicals are applied as sprays to or chards and vineyards, and are dusted from airplanes upon cotton, corn, soybean, and potato fields. T hey are employed as wood preservatives, in the manufacture of glass, lead-base alloys, dyestuffs, bronzing, and paint pigments, and medicinal and cosmetic preparations. While the causal role which arsenic plays in the production of cancers of the skin on the basis of chronic arsenicism of occupational, medicinal, o r environmental origin has long since been firmly established, it is of rather recent date that exposure to arsenicals has seriously been con sidered as a principal causal agent of cancers of the mucous membranes, such as those of the bronchi, stomach, and bladder. Indeed, today there exists as yet only highly suggestive hut not conclusive evidence linking cancer of the lung with an occupational exposure to arsenical dust. How ever, in almost all cases of lung cancer for which such claims were made, there existed stigmata of chronic arsenicism in the form of arsenic derma tosis, with or without skin cancers. Since the inhalation of arsenical dust and fumes produces, rather frequently, the development of perforated nasal septa, as well as chronic irritative conditions of the bronchi, thereincreating a symptomatic cancerigenic pattern similar to that seen in chrom ate workers, the existence of a causal relationship between cancer of the dung and chronic arsenicism appears under such circumstances to be a 'reasonable conclusion. Chest and x-rav ''vamination- of worker., em ployed in an arsenic smelter revealed a mild degree of pneumoconiosis (152). Although Saupe himself did riot discover any evidence of lung cancer among the workeis studied-- even though they often were afflicted bv hyperkeratoses of the skm and perforated nasal septa he filed the antnpsv i \\i k<>\\i ]\i \i i Fin. 7. S q u a m o i ^ celi c a r c i n o m a o r i g in a ti m i r t h na-vil -hmi- <f a r a t m lialin g f<>r 18 nioml'A r h r n t i n u o re Orni nt a p a r t a l e >1/ ' b c l o u 4 n. m< 8 ^.,-^<1 l u i \ia--ove p r o n tcra tio n ot th hnnicliio '.ar epiilichuin ni a unnica pii* ck8 montila io < inumile u n du-st. ]!(,. 0 Anaola-'lic c aiunoiiia ni th na-od vii'L' in ari i'Upn mano! itMmjicC'turer F i n 10 N j n . i i n o u - i e l l c a l c i n o l o . i w *j a d u m - ho-ln - r> i l a t< \i i lo u o r k c r lana ot ac a - F u to s 214 \\ I . I I I T I 'K K observations previoush made b\ Sehmorl ( 1c-l i on two arsenic 'inciter workers who died with cancer of the lung ( 1 7 0 1. Four additional cases of lung cancel in sheep dip workers with arsenic dermatosis noted in one of these were reported In .Merewether (12a I, while Hopkins and Van Studdiford I 79 > observed in a fanner living near a cotton field sprayed with insecticides, arsenical dermatosis, epitheliomas, and cancer of the lung. The occurrence of 5 cases of lung cancer (79, 123), among only 24 individuals suffering from occupational arsenical dermatosis and epi theliomas caused X eubatter (132) to wonder whether this is mere co incidence, because onlv two cases of lung cancer were observed am ong 143 cases of medicinal arsenic cancers of the skin (ISO), or under occupational conditions, whether the irritation of the respiratory tract l>_v arsenical dust was responsible for the phenomenon. Henry (72). commenting on the occurrence of skin cancers among' sheep clip w orkers t 1910-1923), recorded the occurrence of two additional cases of lung cancers among ten workers of this group having cutaneous cancers. H e mentioned, moreover, the presence of cancers of the left foot, abdominal wall, and lung in a furnace man of a sodium arsenite factor}'. Analyzing the mortality experience of a sheep dip factory, Hill and Faning (7 4 j found th a t 7, or 31.89c, of the 22 cancers causing death among members of this g ro u p were located in the respiratory organs, while 3, or 13.69'c, were situated in the skin. T here were during the period 1910-1943 a total of 75 deaths from all causes. The proportional excess of cancer deaths was mainly attributable to an excessive frequency of cancers of the lung and skin which were confined to workers in the chemical processes and were absent among members of the general group) who would be unlikely to be exposed to any specific hazard. Perry, Bowler, Buckell, Druett, and Schilling (137 ) concluded from the clinical evidence obtained that after many years of exprosure to arsenicals these sheep dip workers may develop a squamous cell carcinoma in the bronchus. The most recent addition to epidemiologic investigations on arsenic cancer was made by Snegireff and Lombard (161} studying cancer deaths among employees of several metallurgical plants of unidentified type. Of the total of 109 deaths from all causes recorded during the last 25 years. twelve were due to cancer of all sites and ol these, six were located in the -lung. The investigators concluded from this evidence that "there are in dications that biologically the human race made the adjustment to arsenic in the environment and that otilj rarely, when associated with other con tributing endogenous factors such as systemic disease, or possibly factors such as radiation, it may he capable of upsetting the biological equilib rium ;" and further "that the handling of arsenic trioxide in the industry I 1 X \ I IMl.N M I \ I M. I.( ' \ ( . ( ' \ i !'N does nut produce a significant rh,im;i` in tile cancer m m i a h n <>t the plant employees: hence other factor' m addition to arsenic m iw he considered significant in the causal relationship to c an cer" In view of the tact that 50rd of all cancer deaths among iinplo\ees oi .me plant surveyed were caused bv cancer of the lung, the observations n u d e in tact confirm a carcinogenic action of inhaled arsenic trioxidi upon the tissues of the lung of the exposed workers. This interpretation . 1 tin data oi Snegirett and Lombard is supported by die high incidence ot lung cancer among the population of several counties in Montana where copper smelters and mines were operated for many years creating an occupational and environ mental pollution of the atmosphere and soil with arsenicals. Prolonged inhalation of arsenical dust and fumes appears to produce an increased liability to cancer of the lung. However, the existence of such connections should In acknowledged only when there existed at some time, clinical and if possible, histo- and biochemical evidence of chronic arsenicism. Jn view of the absence of any such evidence associated with chronic arsenicism among the nickel refinery w orkers affected by cancers of the nasal cavity, paranasal sinuses and lung, among excessive tobacco smokers with cancer of the iarvnx and lung, it is most unlikely that exposure to arsenic dust, fumes, and vapors plays any role in the production of respiratory cancers in members of these population groups. Beryllium. Beryllium is a metal which has found significant industrial use only since about 1920. It was not until about 1940 that beryllium and its compounds were extensively employed for num erous purposes and products ( beryllium-copper; beryllium-aluminum, and beryllium-nickel alloys: glass: phosphors in fluorescent lamps and. neon tu b e s; atomic energy products; ceramics, refractories; x-rav tube windows; vitreous enamel; radio tubes; textile fibres: gas mantles). Hardy (OS; noted as a conservative estimate that there w m il up to September P H I between 500-400 cases of acute ber\Ilium poisoning and at least 200 cases of the chronic variety in the I 'nited Stales which resulted in the fluorescent lamp industry in a mortality of about 25H among the ill workers, it is remarkable, moreover, that chronic berylliosis has appeared not only among exposed workers. but also among poi sons living in the neighborhood of fluorescent lamp factories and inhaling their beryllium effluents i 40, 50 > 1l is notew orthy that beryllium apparently once inhaled is retained over a long period of time m the human both, -nice ber\Ilium was de tected m the urine up to ten years .after ess.-uion of m-.posine .'>/ and has been dem onstrated ui the lungs u f rats une w a r after the inhalation 210 W . ' ii i l . r i k of b e n lliu m oxide (4(>) as wed as m tlic-ir bones i 13. 165 i where it may replace calcium. (experiments of .Mdridge. Barnes, and Denz ( 2 i, tnoiem cr, have shown that benlhum nuts react rapidly with certain tissue proteins and form complexe- with plasma proteins when introduced into the Mood. These complexes protte t the h e r\Iliu m from being; precipitated by phosphate intis. Gardner (57) in 1646 reported the production of osteogenic sarcomas in rabbits injected ititravenously with insoluble b e n Ilium containing powders (beryllium phosphate, zinc beryllium silicate). Other investi gators subsequently confirmed these results with the same and other beryll ium compounds i beryllium oxide, beryllium silicate, metallic beryllium) introduced into rabbits by the intravenous or respiratory routes (160, 14, 76, 120, 75. 47, 13). T he p re p a ra to ry period for the sarcoma was from 11--24 months. Commenting on the successful production of o s teogenic sarcomas in rabbits after inhalation of beryllium oxide. Dutra, Largcm, and Roth (47) noted the fact .also that the hones of persons dying with berylliosis contained not inconsiderable amounts of beryllium. B arnard (12 ) and D utra ct cl. 14 7 1 suggested tha t osteogenic sarcoma from compounds of beryllium "might possibly be another industrial hazard." In 1943. Hucpcr (87) proposed that the sarcoid pulmonary manifesta tions of berylliosis might be followed by outright malignant lesions in the lungs. 'I'lie recently reported successful production of bronchogenic car cinomas in the lungs of rats which inhaled over periods of more than one rear, dust of soluble and insoluble beryllium compounds (17Si makes the appearance of such delayed malignant sequelae in man a distinct possibility. Comments on Respiratory Metal Cancers. The evidence presented demonstrates that some metal- and metal compounds when inhaled as dusts, fumes, mists, or vapors are capable of producing cancers in various parts of the respiratory tract, I 'neumoconiotic changes precede and ac company such developments when chromium compounds are inhaled, while such lesions have not been reported following the inhalation of nickel com pounds and are apparently of minor nature after the inhalation of arscnicals. Although the respirator} introduction of beryllium compounds - 'leads in animals to the development of progressive granulomatous pneumoconiotic .alterations which may become complicated in rats bv bronchiogenic carcinomatous manifestations, no such malignant sequelae has been reported as \et in human herellio-is. Whether or not respirator} metal cancers ma\ develop after the inhala tion of other metals represent- a problem deserting serious consideration I- X \ I lit I \ M I X 1 \ i I ! N o 1 \ M l i t Cspecia'H where 'itch metal- are wnleh n-ed uv h a t e attained m.tinr in.histnai importance only in r m m years Kr. l . i i o x o r 1 x 1 1 \ l . \ i it i.\ n r S n n o s . \ M> C \ n i m v IiX-lURA HIK'I C\XChR 1'' i .'l' a5r r ^ lii T he -econd group ot respirator\ cavciniigens i- c o m )>-ed ni chemical agent- of r.alter d i\er-e composition. hut -haring she Tun.icterisic lliai thev mac form or occur ax polymer- T he principal r\-d e u c e suggesting the existence of "polvmtT cancer.'" lias come from e c p o m u n t a l oh-en.ation.'. T he >o tar known or suspected carcinogenic poly nit rs are either polymerized carl ion compounds or silicon compounds. (danct f ' of the re.-piraton. n act in man mem to he can-ally related to doth varietie' ot polymer carcinogen- I.'oprupvl ( )il. T hrough the recent discovery of cancers of the p a r a nasal sinuses, larynx. and lung among isopropannl manufacturers, the oc currence of carbon-polymer cancers has probably been extended to man. Isopropcl oil. i.e.. the crude !i(|uid from which isopropyl alcohol is distilled, and which is a slightly turbid., viscous 'liquid, turning, upon standing, slowly into a brownish to blackish tarry material, contains nolypropt lone compounds as well as propylene ether which, may 'be oxidized into p r o p s lene peroxide and propylene epoxide having a tendency to polymerize. Polypropylene, merchandised as Oppono! lx, is used conunerciaih a- an oil for cable idling. W orders employed in isopropanol manufacture have been exposed to the inhalation of \apors, mist, and dust of isopropyl oil. escaping from leak)' pipe connections, defective pumps, and gaskets, or spilled on the floor at the occurrence of breaks in pipelines and during repairs on pipes, pumps, and stills Weil, Smyth, and Xale (IKdi reported that between 192S and 1950. a total of seven neoplasms affecting various parts of the res pirator} tract [nasal sinuses ( four i . l a n n x ( t v o i . and lung ( fine i j came to observation am ong 71 employees o r in S.4T who worked more than live years in the isopropanol plant (Fig. W . Since the occurrence of an excessive number ol respiratory cancers am ong isopropanol m anu facturers has not been limited to one particular plant, it can be concluded that isopropyl oil. and thus possibh polypropylene com pound-, represent a human carcinogen. .\-be-to-is. Asbestos difler- from the ordinary giant molecular cr\stalime silicates, not only in its chemical and pin-teal propeitiex. hut also iti the anatomical aspects ot the pneumoconiosis produced b\ it In (on tra -t to tile tridimensional ]ok nu n u-d sdtc.i c r t - m P A .lei h no oxt gen atom s ate le!1 cat ry mg charges (o attract positive ions, a-b e -io - consists 2 IS \\ . C I l l I ' l T K of giant libroiis lmfi-cuies composed of p<>Kmerizod silico-oxvgen tetrahvdra which arc arranged in chain-, or bands. Canada furnishes about 7557 of the woild production e>f asbestos. Canadian asbestos, because of its long fillers, is especially suitable for textiles. The co-existence of asbestos with cancer of the lung was first reported by Lynch and Smith (115 t in 1935 (one c a se i. who recorded later three additional cases (114. 115). Similar observations have subsequently been recoided from die L'niued States (77. 78, Cl. 166) ; Canada (30, 38, 149) ; England (36, 5T 6*4 124) ; G erm any (9, 20, 21. 81, 106. 184. 184). T o this number must perhaps be added the eight cases of cancer of the lung complicated by asbestosis which Kennaway and Ivennaway (96) dis covered in an analysis of the death certificates of males registered between 1921 and 1938. and the series recorded by W j e r s (1 8 8 ). There were 37 males and 15 females among the 52 cases for which information on sex was available. T he male: female ratio is thus 2.5:1, which represents a marked shift toward the female side when compared with the usual sex ratio of 5:1 to 10:1 for lung cancers of unknow n etiology. Equalization of carcinogenic exposure as represented by as bestosis, for the tw o sexes, thus resulted in a trend toward equalization of liability to lung cancer. Additional support for a causal relation between asbestosis and cancer of the lung is derived from the fact that Merewether (124) found among 266 cases of asbestosis observed from 1924-1946, 31 cases of co-existing ancer of the lung (13.2(7 ), while there were 91 cases of lung cancer with an average age of 59.4 years among 6,884 cases of silicosis (1.32(4), which came to autopsy. W edler (182) noted that asbestosis cancer of the lung occurred in 14 cases or 16(1 of 92 cases of asbestosis on which necropsies were performed, whereas the normal rate of lung cancer in autopsy material was estimated to be 2-6(7. (Table X V III-4 1 a ). The histologic types of lung cancers observed do not essentially deviate in their relative frequency from those seen in cancers of unknow n etiologv. There were 22 squamous carcinomas ( Fig. 10), 7 oat cell carcinomas, 4 anaplastic carcinomas, and 6 adenocarcinomas. The evidence on hand has convinced the West German Government to make asbestosis cancer of the lung a compensable disease (169). Comments on Re-piratory Polymer Cancels. While the fundamental concept of "polymer ca n c e rs'' is a tentative one and needs to be supported by additional evidence, the available data are sufficient Iv important to require serious attention from Isith a scientific and practical viewpoint, 'file rapidly expanding industrial production and industrial and general use of natural and synthetic p o h m e n z e d substances in plastics, films. 1 N V I K O N M l-'N 1 \ L I . r \ l, l \ N O K T \ bik NVI1I L im it's the M o r t a l i t y o i D e a t h . - I m o n a l/,;.',' /ix p e rie u e e a j .lit . ?ob - f l a t l l ' e r h e i s L n u p a r e d >: D r y l a n d r.nr l l ~ l i e s ' 1 it'll XU Ux t aii'C of dtath No <ibscrved K Vfn-cieil m F and \V. rate^ bung cancer'" 11 Other respiratory diseases (included pul monary tuberculosis) and cardiovascular ji".ea>es: with mention of asbestosis 14 without mention of asbestosis 6 0 8 - t 7.6 | T u t at significance or difference betv. veil ohserc ed and expected ( Value of P ) <(1000001 > 0.001 Neoplasms, other than lung cancer 4 All other diseases" 4 .-Ml causes .19 2..! 1 4.7 ( 15.4 <0.1 < 0.000001 "R. Doll ^Including one case with pulmonary tuberculos;ii> `inclu ding two cases (benign stricture of eso; >hagu$ and asbestosis was present, but was not thought to have been a death septicemia) in which contributory cause of rubbers, textiles, synthetic plasma expanders, etc., brings a considerable part of the w orking population in direct contact with chemicals of this type. It seems to be advisable, therefore, to study these population groups during the coming decades for the occurrence of cancers, particularly those affecting the respiratory system. R elation of I n h a l a t io n of C o m bustion a n d D istilla tio n o f C o a l a n d P etrolf.u m to R e sp ir a t o r y - C a n c e r P roducts The third major group of recognized, suspected, or potential occupa tional respiratory carcinogens is composed of substances containing specific carcinogenic aromatic hydrocarbon, and being derived from the incomplete combustion, distillation, catalytic cracking and hydrogenation of coal, petroleum, shale, natural gas, and similar carl>onaceous matter. The carcinogenic hvdrocarltons are especially contained in the higher boiling fractions of coal tar. pitch, creosote oil. anthracene oil. soot, carbon black, fuel oils, lubricating oils, and crude paraffin oils T h e inhalation of dusts and mists of these materials results in their partial retention in the lung and in the production of anthrao si>, b itum inous, or chiunic oil pneumonia (.omhiistion and Distillation Products <>f Coal T h e apparent in- 220 U i l i l I J 'I K niirninKiici-s of coal : ^i<i posM.bh graphite oust as respivatorv carcinogens, is not shared hv the incomplete combustion distilhition and hydrogenation products of coal i pitch, far. soot, creosote oils, anthracene oils, tar oils, and the highlv vi'CHis oi!v and ta rrv tractions obtained hv the direct h\drogenation of coal employed by the B e rlin s p raccsst. Keceitt observa tions made among generator gas oven workers in Japan. Canada and England (35, 41. u 5, (,o i indicate that a n exposure to coal tar fumes produces an excessive liability to limy cancer. The Japanese investigators found within a ('-te a r period, 21 cases of lung cancer among generator oven -workers, v.ho were exposed to the inhalation of hot tar fumes when stoking the coal. An excessive lung cancer rate was absent among workers employed in other parts of the steel mills. T he general incidence of lung cancer among the generator gas workers was 5/1,000 workers employed. Seven of these 21 lung cancers occurred in w orkers 40 years or younger (3 3 0 , against ISC . in crvptogenetic lung cancers i The exposure tune varied from ^ t e a r ' to 23 te a r ', the average being 16.6 years. Similar observations were recently made among Canadian gashouse workers. Of 14 cases of cancer am ong retort house workers, six were due to cancer of the lung, one to cancer of the larvnx and one to cancer of the ethmoid sinuses (57'4 cancers of the upper and lower respiratory tract i. It is likelv that similar lung cancer incidence rates mav exist among American tar workers. Following a visit with a tar distillerv where, among the 300 workers during an 8 -year period, some 25 skin cancers and more than 80 pitch warts had Iteen observed, there was found one case of lung cancer. Subsequent inquiries made by company officials brought the number of lung cancers in this and other tar operations to 6 cases of cancer of the lung. Similar exposures exist for the carbon electrode workers in aluminum production plants, where workers have developed cancers of the skin as the result of contacts with petroleum `'carbon'' tar fumes. Front the evidence available, it appears that the inhalation of tar fumes sustained by workers of certain operations (coke ovens, generator gas plants, gas plants, tar distilleries i seem to have an excessive liability to cancer of the respiratory tract. It is not unlikely that a more thorough ,,'and competent analysis of the death records of other worker groups, which have .->0 tar been found to lack such t e n d e n c ie s , might extend the t\]K-s and number of far and pitch workers having rut abnormally high respiratory cancer rate. Petroleum and Shale Oil. In addition to 'k in contact with 1arcinogenic petroleum derivatives m am workers tire also exposed for occupational reasons to an inhalation of oil m bt or fumes (w orkers in paraffin picssing I \ \ Ii.O\ \ 11 N I \ I ! ; \ ( \ M I U operations. certain groups ut oil r c m ic n ' r i '"!u T \ ' 'eimcrs, metal lathe worker-:. ju;tn(ir\ worker--, nu mllurgica! w orkers. ; milters. etc w In spite of tin.-- established oceti] -:itntnril respiratory exp- '-.tire to petroleum and alitile oil', it wti- oniv u m i t l \ that t\'a> u;- three ca-e s of occtt]>;iti(>n:il oil pnetintonia ,anione -uch worker-: were p n e e d <-ti record, although such conditions h a w rather frequently been observed .alter repeated medicinal instillations of mineral oil cum .nnr g nasal drops toil aspiration pneumonitis, or parainunma -! the lout, it. tact, tw. i c a s ts of o i t i o r of the lima apparently developing on the 'ta-i: of a medicinal mineral od pneumonia have been described ( l r l , I S c o The oeeupalional evidence available or published on this aspect is rather scanty .and in part controversiti!. K ennaw av and K e n n a w a v t ()6 ) found a relatively high ratio of laryngeal, hut not of pulm onary cancer in mule spinners, wiio inhale a spray of carcinogenic shale oil lubricating the spindles. Southam (167) noted that mule spinners occasionally develop multiple primary cancers involving the stomach or the lung in addition to cancers of the skin. Scott (157), on the other hand, stated that he had not observed a single case of lung cancer among shale oil workers. H uguenin, Fauvet, and Bourdin (91 i who analyzed a series of 112 lung cancers for possible etiologic factors, found th at 18 o r 16% were metallurgical workers exposed to the inhalation of nebulized lubricating and cutting oils, eight were chauffeurs, five mechanics, and one was an engineer. They concluded that their observations indicateci an excessively high frequency of lung cancer among workers exposed to vaporized or nebulized lubricating oil. While the study of Gafafer and Sitgreaves (56) on cancer morbidity and mortality am o n g the male employees of an oil refining company did not reveal any abnormal liability of the members of the occupational group to cancer of the lung, this judgm ent may have to be revised at least for certain types of refinery w o rk e rs according to morerecent and scrutinizing observations. Roesch (145) observed three pri mary cancers (skin, stomach, and lungi in a paraffin worker. Touraine and Hour (171) also attributed the development of pulmonary cancer among certain worker groups to lubricating oil mi~ts. Such exposure conditions may account also for the excessive lung cancer mortality among male metal grinders observed by T u r n e r and Grace ( 174 i. In one la rye American oil refinery, the employees of the paraffin pp--ing operation showed not only a highly recessive incidence of scrotal cancer ami tuniished 45 8 '.' of all cancers r m o rd e d am ong all y\ork<-r-, but also 5 b '. of all lung cancers, although -hey represented about 1 2 ' o! the total worker population. Ntia- oil soot as a waste or commere al product has been found in be >? ? \ \ . r. in l-'i'KR carcinogenic ant] to contain known carcinogenic hydrocarbons, a thorough and competent survey of occupational groups particularly exposed to the inhalation of soot (operating railroad personnel, stokers, carbon black manufacturers, rubber, paint and ink makers, painters, soot burners, print ers, diesel engine drivers, electrode manufacturers, smudge pot operators, phonographic record m akers) is an urgent necessity. Comments on Respiratory Aromatic Hydrocarbons. At the present rime, exposure to tar, pitch, asphalt, heavy fuel oils, lubricating and cutting oils, soot from domestic furnaces, incinerators, industrial pow er plants, oil refineries, steel plants, metal smelters, carbon black factories, oil dumps, and smudge pots, as well as to the effluents of diesel and gasoline engines represents the most widespread occupational and environmental contact with carcinogenic material. Since our civilization and economical life has been built around the production and use of the basic carbonaceous substances and their deriva tives, it does not seem feasible to attain complete protection against ex posure to these carcinogenic chemicals with the preventive and prophylactic engineering and sanitary measures practical and economical at the present time. T here is, however, no doubt that a great deal remains to be done in this respect and that we are still rather far removed from having the maximal amount of possible reduction in exposure to the respiratorv cancer producing hydrocarbons contained in the various carbonaceous substances mentioned. R e l a t io n of I n h a l a t i o n of R adioactive A g e n t s to R e spir a t o r y C ancer Up to some ten years ago, occupational exjiosure to radioactive agents was limited to relatively small groups of industrial and professional work ers [miners and refiners of radioactive ores, industrial and medical con sumers of radioactive substances (gas mantle manufacturers, luminous dial painters, radio tube makers, physicists and their assistants, radiologists and their assistants)]. Since the advent of successful atomic fission and the ready production of synthetic radioactive substances, the number and variety of individuals who have occupational contact with radioactive matter have rapidly and greatly increased | uranium and thorium ore minera, smelters and refinery' workers, atomic energy plant employees, military personnel, agricultural, biologic, medical, chemical mtallurgie, oil, pharmaceutical, and other industrial research workers employing radio active isotopes, as well as operators handling directlv or indirectly such materials or technical devices giving off ionizing radiation (radioactive ] ,\ \ ! K( > \ M I N l \ I 1.1 \ ( . l \ \ i 1 K static elim m a tu isi. sew age di-t'-al workers, paper. and Textile* m a n u facturers, etc | The "mala m etallnrum " causing hath at an cariv age <>t tlie m iner- m the ore mountains of S a x o m was first described bv A g n e o la t 1 i <1n r in <4 the earlv part of the sixteenth centurx, and was -uhse<|uenth mentioned by other investgators. H ow ever, it was not until 1879 that its malignant neoplastic character was c o rre c th recognized (661 ( Fig 11 1. This j u d g ment was siihse(|uentlv confirmed id. 8-10, 18. 2d. 25, 40. (>8 . 102, 105, 131. 143. 148. 154, 170. 175, 18] 1 . Although the m iners of the uranium ore mines in Joachinisthal i Czechoslovakia) also were suffering from a fatal lung disease similar to that observed among the cohalt ore miners in Schneeberg. Saxony, it was not until 1926 that the cancerous nature of the pulmonary disease am ong these m iners \va recognized f i l l ). A d d i tional confirming evidence was provided later by lieutel ( 17 1 ; Ziel ( 189 ) ; Sikl (159) : Saupe (152) ; Teller ( 136i : Pirchan and Sikl ( 138) ; Baader ( 10); Behounek and h'ort flfu . F.vidence supporting a radioactive origin r>f the lung cancers am ong these two groups of miners was provided by the observation of lung cancers among employees of radium refineries and radium laboratories. Lowy ( 111 1 reported the occurrence of tw o such cases am o n g the workers employed in the laboratories of the Joachinisthal mines, where the ores are refined and the purified material is tested. One of the cases had chronic radiodermatitis, leukemia, and lung cancer. A similar observation was recorded by Teleky ( 170) and Xeitzel (131 ) in a German technician of a radium laboratory. The cancerous lung was found to be radioactive. Four cases of lung cancer have recently been observed, according to Baader (10 1. am ong the w o rk ers employed m the rad iu m ore processing plant in Belgium, where the occurrence of such complications were pre viously said to be absent (117). Perhaps the development of a bilateral alveolar carcinoma of the King in a woman 10 years after the intravenous injection of 75 cc. of th o ro trast may also supply suggestive evidence bv the medicinal use of radioactive material arrested in the lung. Mention may also be made in this connection of a report relating the occurrence of carcinomas of the paranasal sinuses in three luminous dial painters. The dial painters not only ingested radioactive materia! which became deposited m the bones and produced there the development of osteogenic sarcomas, but they also inhaled this matter (7). The attack rate of lung cancer among the Schnceberg miner-, ha- con sistently been between 75 and 8 0 ', since 1879. while that of the [oachim-thal miners has been stated to range from 40 5 0 although this in cidence rate may he too low considering the recent statement of [kinder 224 w . i n i i i i k (1 0 ) who noted that during the period P H ' 1 l'M-3. a total of 180 cases of lung cancer wine acknowledged as compensable iver,national diseases and that in 1926 there were only 828 miners employ td at Joachimsthal. Con sidering the fact that the exposure andi latent period of lung cancer in joachimsthal miners ranges from 13-23 years, it may justly he assumed that these lung cancer ease' originated in a miner population of approxi mately 300-400 members w orking at these mines hetween 1420 and 1030. T he exposure and latent p .rio d at S ch neeleig is staled to v a n front 15-18 years for the majority of the cases, hut to he occasionallv as short as seven tears (10. 142 i. Measurements of the radioactivity of the Sehnveberg and Joachimsthal mines have demonstrated that in both places, mine air and dust have an excessive degree of radioactivin surpassing many times the maximal tolerance dose [Joachimsthal 30 times (15. 16, 103. 112, 136. 141, 163, 172)]. Similar, if not even more serious exposure conditions exist in most of the mines situated on the Colorado Plateau where uranium ore miners inhale not only radon, hut its solid daughter elements and excrete polonium in the urine (31. 168), K ahlau and Rajcwski d9 4 1 ami Schraub and K ahlau (155) subjected mice to the inha'ation of radon. M any of the animals developed bronchial lesions characterized by an atypical epithelial lining as well as pulmonary adenomas (in 7 of 12 mice of the test series, against one in the control series;. While they concluded from this evidence that the radioactive origin of lung cancers in Schneeberg and Joachimsthal miners was con firmed. it seems to he advisable to consider the evidence obtained by these investigators as highly suggestive but not conclusive because great varia tions in the incidence rate of lung tum ors occur among different groups of mice belonging to nonmbred strains. Similar observations have been reported by Lorenz, Heston, Eschenbrenner. and Deringer ( 110t as well as by flenshaw . Riley, and Stapleton (73 ). These investigators found that mice exposed to ionizing whole boclv radiation revealed m addition to leukemia and ovarian minors an increase in the number of pulmonary neoplasms. Of greater significance in this connection are the findings of Lisco and Finkel (107), who found in rats inhaling an aerosol of radioactive cerium, nirtaplastic, and neo plastic proliferations of the bronchial enithelinm Similar i-em'p were oh tamed with plutonium brought into the lungs of rat'. Since uranium ore miners inhale not only radon and radium dust, but also uranium which may be retained in the lungs, If neper, /fucile. Link, and Johnson (84 i injected metallic uranium powder dispersed in lanolin into the pleural and lemoral cavities of rats and obtained sarcomas at the sites of injec- I \ \ I K< l \ M I \ I \ ! I i M , i \ \ l I k I'].,. 11. A naplastic cariinorna of tin- hint; of .t cobalt ore t i m e r of t!'c r a d io active nmif- a! Sclineeberjr, Sa.xotn. F u , 12. X - r a y picture of a l)onc forming s i r c n i i u of tin- n m u r of a rat follow ing the i n tra fc m o ra l deposition of powdered metallic titanium, v; :b,V it, eiumps in and around the tumor l-'u, 1.1 Hone forming -arcuma of the femur of tin- i.it -1 - o . m Fig. 12 J iie tumor formed lm-tastases in the lung l-io 4. spmdlc tell s.ireoin.itous mctastusi- m tin- lung of ,t rat v.ith a uni.art sarcoma, of the thigh dttelnpmg .fn i tin itui.ifemor.il dip. i- -in, .,f , nui. red metallic uramuni 22n W O. I H T I T K tion in 13 or 24' ; of the (>> r a t ' used ( Figs. 12. 13, 14). Kvidencc thus produced shows that focal accumulations of uranium which is an alpharadiation emitter may exert a caiicerigenic action upon the surrounding tissues, hut it does not discriminate between the influence of metal toxicin per sc and radioactivity in the genesis of these lesions. From a critical evaluation of the epidemiologic, clinical, and experi mental evidence available, it appears that a prolonged inhalation of radio active gases and o r dust may elicit in n u n pulm onary cancers (52, 120 i. In commenting on the production of lung cancer by atmospheric car cinogens, an editorial ( Lancet . 1052) (-k>) remarked, " radioactivity of Joachimsthal mines is stated to he thirty times the tolerance dose. It is scarcely surprising, therefore, that in the past more than half theminers died of lung cancer." It stands to reason that this effect on the lungs of workers will prevail w herever similar conditions of exposure to radio active gases and dust exist. Comments on Respiratory Radioactive Cancer. The rapidly growing production and use of radioactive material, and, thereby, conditioned increased potentiality of inhalation of radioactive gases and dust for certain occupational groups and possibly, also, for parts of the general population determine the scope and significance of respiratory cancer hazards which may result from such exposures. Since the attack rate of lungcancer from this source is very high, according to past experience withminers of radioactive ores, a competent assessment of the degree of exposure to radioactive dust, mist, and gases by worker groups and neighborhood population is essential wherever radioactive material is produced or handled. The available information supports the view that the simul taneous inhalation of siliceous dust, causing the development of a silicosis in individuals mining or processing radioactive ores, does not represent a condition which favors the production of lung cancers, or fundamentally modifies their course once they have become established ( 8 6 ). Summary and Conclusion'. The reported evidence leaves no doubt that there exist an appreciable number of well defined chemical and physical agents which are responsible for the occurrence of cancers of the lung and other parts of the respiratory tract among members of certain occupational groups. The epidemiologic data available on these occupa tional respiratory cancers indicate that some of them pO'se>> a high c a r cinogenic potency. Since environmental contact with these agents also exists for members of other and in part, very large occupational groups as well as for the population in general, especially its urban component, it can justly be assumed that 'licit e x p o su re ' account for an undetermined number of respiratory c a n c e r ' occurring among them. T he validity of I ' N \ I K D N M I ' A I \ l . 11 \ <* l \ N U H this o inclusion is siippoi led bv tile statistical and eonk mining ic data re corded mi the r e la m e frequency of n i n r r r oi the lung am ong different countric'. .'fates, regions, communities, urban and rural area..', a n d large occtn .anonal .group'. The problem of occt.pationu' re'piraiory cancer, therefore, is not of speculative nature but a widely recognized and well estabb'bed reality, which deserves serious consideration not only In members of the medical profession and of public henhh ageneu s, but also b\ the representatives of industrial management and labor d'he genera! evidence as to the recording of occupational cancers as well as the rather recent discovery of most of the respiratory carcinogens make it likely that the scope of the industry related lung cancer problem is much larger than indicated In the number of cases as yet reported and the tvpes of carcinogens so far recognized. Epidemiologic data and medical con siderations. moreover, do not support the view that the causation of lung cancer and its recent phenomenal rise in frequency are attributable to the action of one single environmental factor and its recent entrance into the human environment, respectively. It seems rather that various factors have been responsible for these developments and have contributed to different degrees to these events in different jiopulation groups and at various times. A n effective future containment of the environmental res piratory cancer hazards depends upon the widest dissemination of the existing d a ta as well as on the acquisition of additional inform ation In adequately conducted surveys supported by properly integrated experi mental work. R h K K M .X t f.s 1. A a r i e a , l 'i "H e re m ctalb ca " Ba'el. 1597. 2 A ' d n d a e , \Y. X., lia m c s , J. M., a n d !Jenz, ]'. A. E x p e r im e n ta l beryllium )). n-oning. hrit. J. li.rptl. J'alhol. 30.375-389 (1949.) .1. \ m e r h a n C a n t e r Society C ance r death rates fur each -tate in the U nited M ate- by -ite A m erican Cancer Society, 1949 4. Am. .r. A .1 Xickel, in occupation and health. Im crn a ti uiial l a b o r Office, O'm.ca. Supplement (1938) 5 Arabi. ,M., and Mure, K. Spectronraphic analysis of Us'iic--., on jiiatnnative a n a h s is of nickel m tumor tissue. Gann 40.76-79 t i 9 4 9 1 6 Arn-tein, A. Sozialhygicnischc UntcTsuchungen uber die- Her^Ieute m den M-hnecbc-rKc-r Kobaltgruben, msbesondere uber das Yurkotmnen da-, ,o eenaunten .-chneeberger 1-ungcnkrebses. I I 'nc/i\chr d j t c r r W iu'/ a />a Bei- heft. 1 (1913) 7 tab. J , Irian-., K. 1) , 1i empelmann, i. 11. and Martian-.. 11 S ! be late u K - c . of internally depo-uted radioaetne m aten.d- m nia '29 .1952> 1 / , nn 31 221- 8 'un i-.< ! h r 1.unyenb r> b- m den Mel u n el I per A ra b u 1 4t --- .A - . . . o o h n i 22X U l I ]I l l ' i k 9. Baader. K. W . B e r u f s k r i h ' in 'A'cucre T_u<.`! i n i - e au f deni Gebiet 1er k r o b s - krauU ieiti"!" ( C A'k-.n- uh! H. A u l t r , cfb i. pp. 104-128. S H i r / e l , 1 eipzig, 1937. 10. Ilaader, K. \Y. Our n.K iie w k rbu-rcKdi/.im-^chc ' Problem. 1\'r- liana'/, d m ! 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P a t h o l , u . l l a k t e r i o l . 15.666-671 (1952). Problem s A rising From a Study of T um or H ost Relations P i I ' nrt ah' uf ,>l M r d h \ h ' AY k. w . p u ;<; h, ( ui r .>/ /j'Y ,viY//i (>:!ari>, 1/: i\i>.,:da 'l'o refreshen your memories, and perhaps add something lo clarity I would like to define and discuss tumor-host relations for the purpose of this paper. W e regard tumor-host relations (or. in the older terminology, "systemic effects of tumors" i as those changes produced in tissues, remote from the tum or, in which no evidence of metastatic malignant ceils is found. These effects ma\ he anatomical or biochemical in nature. W e have added more recently that thev should he divorced from the effects of inanition and anemia. As our knowledge of tumor-host relations increases, and some under standing is obtained of the mechanism of their production, we mav be aide to talk about primary and secondary effects. For example, the in volution of the thymus gland seems to be secondary to an increased activ ity of tlte adrenal 19). T hus adrenal hyperactivity would lie classed as a prim ary effect and the thymus involution as secondary, liut it is probable that the hyperfunctional adrenal is due to increased pituitary activitv. The adrenal then becomes secondary and the thymus tertiary. It mav he that the introduction of the terms primary and secondary would be useful in organizing the expanding body of ou r knowledge, but they will be only relative terms, to be discarded as progress is marie. The study of tumor-host relations may be classified into three approaches to the problem : ( a ,i the description of different t \ p e s of effects produced by the tumor, a routine, but necessary catalogue; (b ) attempts to under stand how these effects are produced in the complexities of the mammalian organism ; and f c ) defining the prime cause of the effects. Sufficient is now known of ( a i so that more work and information are needed about (h i and ( cj , particularly about the latter. T here is evidence to support the concept that some material is released into the blond stream from the tu m o r ( 1, 21) , or on the other hand that sonic component necessary for the normal function of tissues is abstracted from the blood by the tum or (30). Xo one has produced a Upical tumor bearing rat bv the chronic administration of a tumor e\lract. A final word about specificitc -;m\<me who works in the field is aware that none of the effects described to dale are specific for cancer; indeed if this were so tin- basis ior a diagnostic test for cancer would be established ! It is probable- that tile Im-rature on diagnostic tests for cancer lias welded more to the tumor-host s; u<11<-s than to cancer diagnosis (7 j. _>v