Abstracts/Lung Cancer 10 (1993) 266-286

It has been observed in various coontries that regional variation in long cancer mortality can baldly be explained by differences in current smoking. This paper addresses the question of whether mortality variation within The Netherleeds in 1980-1984 is due to differences in past instead of current smoking. A first iodicatioo of the role of past smokiog is that. within male birth cohorts, regional mortality patlems have bea very stable for over 30 years. Reliable date oe smokiog in 1972explain40% ofchemortnlityvariationnmongwomen, butonly2% of that among men. A crude indicator on smoking in 1930 explaioed 43 % of the mortality variation among men aged 75 + years (correlalion = 0.66). The lack of a relationship with smoking in 1972 appears to be due to a radical cbenge in regional smoking differences, which caused smoking in 1972 to be unrelated to smoking in 1930; long time lags, so that these chaeges were not yet followed by chaoges in regional mortality differences. It is concluded that the explaoatioo of regional long cancer death r&es sometimes has to go far beck in time. Studying determinants of long cancer by mesas of regional analyses requires a more detailed control for smoking history than has been usual.

Occupation and lung cancer risk in Trieste, Italy Bovenxi M, Santa G, Anoga GL, Pemur, P, Cavallieri F. lstiruro di Medicinn del Lavoro. Uniwrsita di Trieste, c/o Centro Tumori, Via della Piem 19, 34129 Trieste. Med Lav 1992;83:338-48.

To investagate the relationslop between occupatmn and lung cancer, a case-control study was performed in the province of Trieste, Italy, where metallurgical and mechanical industries, dock activities and shtpbudding and ship repainng are predominant. Through the local Cancer Registry, pathology records of 938 men who died of pnmery lungcancer(ICD 162)inafive-yearperiodwereexamined. Residential, smoking end occupational hIstories were obtained from interviews of next of kin of 756 cases and 756 age-matched male controls ( f 2 years). Occupational exposures to lung carcmogens were assessed according to ajob-titlebasedapproach. Ident~fy~ngindustries/occupationswithwell- recognized lung carcinogen exposures (list A) and industries/occupations wth suspected lung carcmogen exposures (list B). Exposure lo asbestos was classified es absent, possible or detimte. After adjustment for cigarette smoking (four levels)andresidence(three levels), asignificant assoc~atmn was found between lung cancer end occupations in list A (RR=2.28.95%CI=1.70-3.07)andinlistB(RR=l.33,95%CI=l.04- 1.71). A significant excess risk was found for workers wth definite exposure to asbestos when compared to those with no exposure to lung carcinogens(RR= 1.99,95% Cl= 1.43-2.76). Avery higbrelntivensk was observed among heavy smokers wth definite exposure to asbestos (RR=42.8). A stratified analysis showed that the combined effect of asbestos and smoking was compatible with that expected under a multiplicatwe model. The overall attributable risk in the population ( ARp) for cigarette smoking was found to be 87.6 I. The ARp fraction for occupations with well-estabhshed exposures to lung carcinogens (hst A) was 16.2%. The ARp fraction increased to 25.5% (85% Cl = I .4-34.6) when occupations wth suspected exposure to lung carcinogens (hst B) were included. The ARp fraction for possible or drfimte exposure to asbestos wa 20. I % (95% CI= 11.6-28.6).

Mutational analysis of a dominant oncogene (c-Ki-m-2) and a tumor suppressor gene (~53) in hamster lung tumorigenesis Oreffo VIC, Lin H-W, Gumerlock PH. Kmegel SA, Wits& H. Inst.

for Toxicol./Environm. Health, Uniwrsiry of California, Davis, CA 95616.8615. Mel Carcinog l992:6: 199-202.

In human lungcancers. alterationsofbotbadominantoncogene(ras) and a tumor suppressor gene @53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki- ras-2 and ~53 gents from Syrian golden hamsters. The PCR products were confirmed by predicted-sizeanalysis, probing with nonradioactive (blotin-labeled) oligonuclwtides, and direct sequencing. Lung tomors were produced in hamsters by repeated injections of 4.(methyl- nltrosamino)-I-(3-pyridyl)-I-butanone(NNK). Ofsix tumorsexamined, three (50%) had mutations in codon I2 of Ki-ras. Examination of the conserved regmns of ~53 revealed no mutatmns. We conclude that NNK-mduced carcinogenesis in the hamster results in charecterist~c alterations of Ki-ras but may not necessarily involve the ~53 qene.

Cytochmme P45OIlEl genetic pcdymwphism, racial variation, and lung cancm risk Kate S. Shields PG, Capons0 NE, Hoover RN, Trump BF, Sugimum H et al. Division of Etiology, Norional Cancer Itwfitute, Building 37. Bethada, MD 20892. Cancer Res 1992;52:6712-5.

CytochmmeP4501IEl isnspollsiblefnIhe~ivetionof~minogenic N- oitmsamines. benxene, urethane, and other low-molecular-weight compounds. Restriction fragnwat Imgtb polymorphisms (PsU and Real restriction enwmee) have hem identified io the cvtochmme P450IIEl . transcription regulatory region tba1 may affect expression. This study describesthePstImdRslIpolymnphismsindifferrntrncillpopul~iws and in P case-control “dy of hmg caecer. The sllelic haquenciee were markedly different ie Japeoese, African-Americans, and Caucasians: the PstI rare allele was present at P frequency of 2 % in Cauusisns, 5 % in African-Americans. nod 24% in Japaoese (P < 0.05). For the Rsel w-e allele, frequencies were 2% in Caucasians, 2% in Africa- Americpns.nnd27%inJ~~(P<O.O5).Thelsssywns~so~lied to 128 individuals enrolled in e case-control study of long cancer. Although limited in statistical power. the date indicate no evidarce for en association in the aggregate bf cytochmm P45011El Pstl [for which the odds ratio was 0.7 (95% confidewe interval (C.I.) = 0.2-2.8)] or RsaI[forwhichtheoddsratiowas0.9(95% C.I. = 0.2-5.4))restrictioo frngmentlengthpolymorphismswithlungcllnccrinthisU.S.populltion. When analyzed by race, the luag cancer odds ratio for the Pstl muteot allele in African- Americ~swasO.19 (95% C.I. = 0.03-1.38). and in Caucasians it was 4. I3 (95% C.I. = 0.3448.8). For the Rsel mutaot allele, tbeoddsra~ioswere0.20(95% C.I. = 0.02-2.43)aed4.28(95% C.I. = 0.35-50.6), respectively. The ethnic differeaccs of these restriction fragment length polymorphisms might be related to genetic suscept~tebt~ee for lung cancer among Caucasians nod for gastric or esophageal caocer among Japaoese.

Incidence of lung cancer by histological type among ssbestes cement worken in Denmark Raffn E, LyngeE. Korsgaard B. Clinicof OccupatioaaIMcdicine, State Universiry Hospital. Copenhagen. Br J Ind Med 1993;50:85-9.

Objective - A sigoiticaet hvofold increased risk of lung cancer was found among 8000 mea employed in the Da&h asbestos cement industry behveen 1928 nod 1984. The histological pattern of 104 lung caocer cases was studied with the aim of evabmting e relation between specific morphological types, duration of employment. nod time since first employment. Methods - Age, sex, nod calendar time specific incidence of morphological subtypes of long cancer (adenocarcinoma, squamous cell carcinoma, aoaplastic carcinoma. nod unspecified maligoaot tomour) for all Da&b men were computed from 1943 to 1984, from dale mutinely collected by the Danish Cancer Registry. Person-years of observation were counted fmm I5 years after the date oftirst employment until deteofdiagaosisofcancer. death, emigration. or the end of follow up on 31 December 1984. Expected numbers of cases were computed by applying persoo-yeam at risk to the appropriate Incidence rates. Observed numbers weredistributed accordingly nod the relative risk calculated. Results - The relative risk for adeoocarcinoma was 3.31 (observed (0) 24, expected (E) 7.26), for squamous cell carcinoma 1.67 (0.37, E, 22.12). foranaplasticcarcinoma 1.58 (0,23, E, 14.53),pndforunspecifiedmplignrrnthlmour1.57(0. l&E, 11.46). An increased risk by duration of employment and time since first employment was most pronwnced for adenocarcinom.4. Conclusion - Tbe link between adenocaminoma sod asbestos was confirmed in this. the first study of risk of long cancer by histological category based on incident caocer cases for P whole population during a 50 year period.

K-ras mutatiom in h- admearcimma of the lung: Asswiation with snaking and eccup&mal exposure to ~gbwos Hus~~el-Rvsi~K.H~P,Ri~M.AoailaS,KjPI~ A, Vainio H St al. Institute Ocaqmtional HeaW. Topeliukwnkat~ 41 A, SF-OO2SO Iielktki. Iot J Cancer 1993;53:250-6.

We investigated poiot mutational activation of the ras genes (K-w codons12,13aod61;N-rascoda1s12,13aod61;H-rascodons12and 6 I) in primpry, resected lung cancer by dot blotting end oligonoclmtide hybridization. K-ras mutations were found ie 14 (29%) of the 48 lung

268 Abstracts/Lung Cancer 10 (1993) 266-286

tumour specitnms exemined, but no N-ras or Has mutations were found. The highest frequency of K-ras mutation was observed in edeaocarcinome: 12 of the 21 samples studied (57%) had a mutation, whichisweoftbehighcst~~~icsreportedforl~ndenocorcinoms. Thecommonesttypeofmutntioniathesslungtumour~lesconsisted of transversions: we observed 11, of which 8 (57 % of ell mutations) were G to T trensversions. Most of the 48 patients studied bed P history of heavy smoking, either with or without evidence of occupetionrd exposure to asbestos. Stetistical analysis revealed - in addition to the highly signiticant association between the adenocarcinome type of lung cancer and K-ras mutation - a clear association of K-ras mutations with heavy life-time smoking (50 pack-years of cigarette smoking: odds ratio (OR) 4.9, 90% CI 1.2-19.5. multivariete analysis). In addition, ~u~tiolulssbestosexpogursshowsdsnelev~. hutnon-significent, OR of 2.2 (90% CI 0.6-8.7) with the presence of K-ms mutation. We conclude thet the occ-ce of K-res mutations in adeuocarcinoma of the lung is frequent, end thet such mutations are associated with heavy life-time exposure to tobacw smoke, possibly in combiiation with occupational expasure to asbestos fibres.

Effet of occtqmtioti.4 air pollutanb on variot~ bist&&al typep of lung cancer: A population based asceontrol study Becher H, Jahychowski W, WahreadorfJ, Basa-Cierpielek 2, Flak E, Gomoh K. Gennrm CanmRcsearch Cetwe. IAsrirurcofEpidemiology/ Biometry, Im Neuenhcimder Feki 2&W, 6900 Heidelberg. Br J hd t&d 1993;50: 136-42

A population based use-control study wan performed in Cracmv, Poland. to determine the effect of ownpationaI air pollutants on various histological types of lnng cancer. Male cases end controls were identified from tbe Cracow Death Register. Information was obteined by mailed qnestionnaire from next of kin on smoking, occuptionel bmoch,occupptionrle~posuns,Mdotberpertinentveriebles. Response rates were 73.5% in casea and 72.0% in controls. For cases that underwent P bronchial biopsy or surgical excision the histological diagnosis of the tunmur was obtained fmm clinical records. The case group contained 343 subjects with squamous cell carcinomes, 15 1 with small cell carcinomes, end 106 with adencarcinomas. Twenty seven cases showed other histologicel types (large cell carcinoma end not classifiable). Analysis was performed separately by histological type for occupational exposure variables adjusted for smoking. Long 1e.m

exposune lo mineral dust end metal dust (20 years or more) wes found to bee significant risk factor for small cell and squamous cell carcinoma. The effect was more pronounced if the analysis was restricted to those agedlessthPn70yeprs.‘Ihehigbestreletiveridc(RR)duetooccupptionel exposures was found for squamous cell carcinoma and exposure to mineral dust for more than 20 years (RR = 2.45995% CI 1.43410). The estimated effect of mineral dust on small cell carcinoma and adenocarcinome was smaller (RR = 2.29,95% CI 1.164.53 and RR = 2.04,95% Cl 0.89-4.64 respectively). The effect of metal dust end fumes seemed about the same for sqoamous and small cell carcinoma. No specific agent could be identified as particulerly important for a specific histological type; it rather seemed that the effects of the substances considered were similar for lung cancers in general.

A prospective study of cigarette tar yield and lung cancer Sidney S, Tekawa IS, Friedman GD. Division of Research, Kaiser PennanenteMed. Care Program. 34Sl Piedmont Avenue. Oakland, CA 9461I. Ceocer Causes Control 1993;4:3-10

We examined the relationship of cigarette tar yield end other cigarette-usage characteristics in current smokers to tbe incidence of lung cancer in P study population of 79,946 Kaiser Pernxmente Medical Care Program members, aged 30-89 years. who completed P detailed, self-administered, smoking-habit qnestionneire during the years 1979 through 1985. Mean length of follow-up was 5.6 years. There were 302 incident lung cancers, ofwhich 89 percent occurred incurrent or former smokers. The tar yield of the current cigarette brand was nnwociated with lung cancer incidence (relative risk [RR] = 1.02 per 1 mg tar-yield in men, 95 percent confidence interval [Cl] = 0.98-1.05; RR = 0.99, CI = 0.96-1.03 in women). However, in long-term (>20 years) smokers, the risk of lung cancer wes dewased in women who had

smoked filtered cigarettes for 20 or more years relative to lifelong smokers of unfiltered cigarettes (RR = 0.36, CI = 0.1 E-0.75), but not in me0 who bad smoked filtered cigarettes for 20 or more years (RR = 1.04. Cl = 0.58-1.87).

Lung cancer: Worldwide variation in oceunence and proportion attributable to tobacco use Par-kin DM, Sasco AJ. Int. AgencyforResearch on Cancer, IS0 Cows Albe1?-l71omar. 69372Lyon Ceder&% Lung Cancer(Ireland) 1993;9: l- 16.

Gut of 660,500 new cases of lung cancer in the world in 1980,76 % (84% of cazes in men, and 46% in women) can be attributed to tobacco smoking. Thus. the frequency of lung cancer in different regions is directly related to the prevalence and duration of smoking in the population. Both the number of cases, end the proportion due to smoking will increase for several decadesat least. Thesmallerperceotage attributable to smoking in women is mainly due to their much lower exposuretotobacco. Innon-smokerslungc~ncer(palticularlysqu~mous cell cancers) also seems to be less frequent in women then men, possibly because of an excess of other causative exposures (particularly occupational) in men. Chinese women have relatively high rates of lung cancer which cannot be explained by tobacco smoking alone.

Migration to towns, occupation, smoking, and lung cancer: Experience fmm the Finnish-Nonve&m lung cancw study Tealwen L. Department ofPublic Healfh, Uniwnity of Tampere. P. 8. 607.33101 Tampere. Cancer Causes Control 1993;4:133-41.

A total of 4,604 men who were interviewed in Finlend in 1962 in C~ionwithrheFionisb-No~egilluag- study were followed- up for lung cancer during 1963-87 to establish why urbanized (via migration) men who smoked had P greeter lung-cancer risk then native urban smokers. Exposure to occupational carcinogens was inferred from the title of the longest job held. A clear dose-response relation behveen occupetional exposure end long cancer was fonnd in the urbanirsd but not among the native urban dwellers. The extre risk associated with migration to towns end smoking was found especially by those urbanized subjects who worked in heavily exposed industries: their long cancer risk was more then hvice thet of native when men in similarjobs. while those urbanized subjects in academic or clerical jobs showed no increased risk when cornpad with native urban men in corresponding work. Cardiorespiratory symptoms bad P prognostic value in every residential group, but especially smong the urbanized. Urbenized men who smoked end worked in heavily exposed industries. end suffered from shortness of breath, had e fourfold risk of long cancer when compared with native urban smokers without this symptom. We conclude the1 although the joint effect of smoking end occupational exposure is the mein explanatory factor for high risk of lung cancer in orb&d males, environmentalendpsychosocial factorsalso may have a contributory effect.

Lung cancer mortality among a cohort of male chromate pigment workers in Japan Krmo K, Horikewa M. Ulstutomiya T, Tati M. Satoh K, t’amaguchi S. Inrriture of Community Medicine, University of Tsukuba. Tsukuba. Inr J Epidemiol 1993;22:16-22

In 1975, tive manufacturers of chromate pigment in Japan were examined in a study of the carcinogenicily of chromates. These companies were producing lead chromate, zinc chromate, molybdate orange and/or strontium chromete. The current study covers B cohort of 666 workers involved in the manufacture of chromete pigment for at least I year behveen 1950 and 1975. The workers were followed up for 15-40 years, until 1989. Many previous reports have found an excess long cancer risk among workers involved in the manufachwe of chromate pigments and chromate chemicals. In the current study, subjectswereclPFsifiedonthebnsisofyeprsworked,yePrsofobservation, characteristics of company, type of work engaged in for the longest period of time, end involvement in the manufacture of zinc chromate. Mortality was compared with that of all Japanese males by means of the person-year method. The route of exposure was primarily inhalation