Document G4Br5Z8M0vG7RV3JdX7KvrQ4

FE13RUARY 1992 VOL <19 No 2 Papers 73 A new high resolution computed tomography scoring system for pulmonary fibrosis, pleural disease, and emphysema in patients with asbestos related disease N Al Jarad, P Wilkinson, M C Pearson, R M Rudd 85 Reproductive and developmental hazards and employment policies J Don Johnston, Geoff G Jamieson, Susan Wright 95 Occupational and other environmental factors and multiple myeloma: a population based case-control study Mikael Eriksson, Maria Kartsson rr04'i Effects of ethanol and phcnobarbital treatments on the pharmacokinetics of f ' - --'toluene in rats Rui-Sheng Wang, Tonic Nakajima ' I .. \> ' '. ' ' --r 113 An examination ofthe time course from human dietary exposure to -'.l.-Vj-.. ; polycyclic aromatic hydrocarbons to urinary elimination of 1- ` . hydroxypyrcnc Timothy J Buckley, Paul J Lioy 125 Prevalence of respiratory disorders among aluminium potroom workers in relation to exposure to fluoride Vidar-Seyseth, Johny Kongerud 131 /The possible haematological effects of glycol monomethyl ether in a frame i - -A factory Francesca Larese, Antonio Fiorito, Renata De Zotti 134 'Exposure to vinyl chloride monomer: results ofa cohort study after a seven - ''year follow up Agnes Laplanche, Franfoise Ctavel-Chopelon, Jr JeaifClattde Contassot, Claudine Lanouziire, and the French VCMgroup (see end) " Short report , rJ'v 138 Are hearing loss and balance dysfunction linked in construction iron workers? Kaye H Kilbum, Raphael H Warshaa, Brad Hanscom f y "> *<' rii tr 142/Haemolytic anaemia in a case ofoccupational asthma due to cmaleic ' * I ^ anhydrido P F G Gannon, P Sherwood Burge, C Hewlett, RR .D Tee Correspondence ~ -i; ' . >. . , 144 An update of cancer mortality among chrysotile asbestos miners in , Balangero, northern Italy , Roberto Calisti, Paolo De Giuli, Gian Luigi Ghione Notices' Ti&ES/Tox. Library' BMJ PUBLISHING GROUP MAR 0 9 1992 Dow Chemical-1803 134 British Journal <*J Industrial Medicine 1992;49:134-137 Exposure to vinyl chloride monomer: results of a cohort study after a seven year follow up Agnes Laplanchc, Fran^oisc Clavcl-Chapclon, Jcan-Claudc Contassot, Claudinc Lanouzicrc, and the French VCM group (see end) Abstract In 1980 a prospective cohort study of exposed and non-exposed subjects was initiated in France by the Institut National dc la Santi et de la Recherche M6dicalc (INSERM U287) in collaboration with occupational physicians from the companies involved. The aim was to evaluate the association between mortality and cancer morbidity and occupational exposure to vinyl chloride monomer (VCM). A total of 1100 subjects exposed to VCM and 1100 nonexposed controls matched for age (to two years)) plant, and physician were followed up for seven years (8299 and 8202 person years for exposed subjects and controls respectively) for vital status and health and occupational state* Forty deaths occurred among exposed and 43 -among non-exposed subjects (relative risk (RR) 1-0; 95% confidence interval (95% Cl) 0*6-1 *5)* Forty eight and 32 eases ofcancer were reported among exposed and non-exposed subjects, respectively (RR = 1*3; 95% Cl 0*82*1). Three cases of angiosarcoma of the liver occurred in the exposed group. Eight cases of lung cancer occurred among exposed subjects and six among non-exposed subjects* Fourteen cases of Raynaud's disease were found among exposed and one among non-exposed subjects and the differencewas significant* One hundred and twenty three and 93 cases of cardio vascular disease (Raynaud's disease excluded) occurred in the exposed and non-exposed Departement de Blostatistiquc et d'Epidmiologie, Institut Gustave Roussy, 94895 Villejuif, France A Laplanchc Unit dc Recherche 287 INSERM, Institut Gustave Roussy, 94805 Villejuif, France F Clavcl-Chapclon Mtdcclne du travail, ATOCHEM, 69191 St-Fons, France J-C Contassot Mtdeclne du travail, Solvay et Cic, 39500 Tavaux, France C Lanouztcrc groups respectively (RR = 1-4; 95% Cl 1 *0-1*8); this difference was mainly due to hypertension. The test for an increasing risk with increased exposure was significant. The percentages of diseases of the respiratory system did not differ between the two groups (RR = 1*1; 95% Cl 0*7-l*8). In 1980, a prospective cohort study of workers exposed to vinyl chloride monomer (VCM) and nonexposed workers was initiated by the Institut National dc la Since ct dc la Recherche Medicate (INSERM U 287) in collaboration with occupational physicians from the different companies involved in France. The main purpose of this study was to evaluate the association between mortality and mor bidity (especially malignant tumours) and occupational exposure to VCM. This paper presents the health characteristics of the cohort after a seven year follow up. Materials and methods The design of the study has been described previously.1 Briefly, the exposed group consisted of 40 to 55 year old employees exposed to VCM at the time of inclusion in 1980-1 or previously. Controls were employees who had never been exposed to VCM. Each control was matched to one exposed subject for age (to two years), plant, and physician. Interviews for initial data collection were conducted by the physician ofeach plant over a one year period. Data collected comprised the following information: identification, employment history (the entire work history was coded), occupational category, dates of exposure to VCM, and medical history as well as smoking and drinking habits. The subjects were followed up yearly for seven years from the time of inclusion until December 1988 for vital status and health and occupational state. Causes ofdeath as well as pathological findings were coded according to the 9th revision of the International Classification of Diseases (ICD-9). Subjects who had terminated R&S150742 r>- --I'-rr- '*"?> <r'VV>r-c Izxpasure to vinyl chloride monomer' results of d cohort study after a seven yearfollow uf> Table / Relation between exposure to vinyl chloride and deaths during the seven yearfollow up Deaths during follow up * Non'exposed Exposed after 1976 Exposed < 10 y before 1976 Exposed ^ 10 y before 1976 Yes (n - 81) 43 4 15 21 No (n - 2il$) 1056 68 405 586 Two subjects were lost to follow up. tAdjusted for initial characteristics defined in Materials and methods. 135 (95% CI) 10 1-04 (0 3-3 2) 094(0 5-1 7) 099(0 6-1 7) Table 2 Causes of death during the seven year follow up Exposed (1099) Controls (1099) years before 1976, or exposed after 1976. The data were verified using the PIGAS system2 and analysed with the GLIM package.1 Alt causes Cancer Circulatory system Suicides Traumas Alcohol Others Unknown 40 20 9 2 2 1 1 5 43 22 10 4 0 3 0 4 their employment (resigned, been transferred, or retired) were followed up by each physician by mail. Relative risks (RRs) among exposed compared with non-exposed subjects, are presented for death (all causes), malignant tumour, cardiovascular dis ease (Raynaud's disease excluded), and pulmonary disease. Subjects with a disease at the beginning of the study were excluded from comparisons concent* ing that disease. Relative risks were adjusted for age (continuous), duration of activity as a blue collar worker (continuous), foreign origin (yes/no), marital state, (married, single, widowed, divorced), place of residence (urban or rural), paternal or maternal history of cancer, cardiovascular, respiratory, or other disease, smoking habits (non-smoker, current or ex-smoker, number ofdaily cigarettes, (< or 20) duration (< or 25 years)), subject considered cthylic by the plant physician (yes/no), and weekly alcohol consumption (<14, 14-56, 57-112, >112 glasses). Relative risks were also expressed according to whether the workers were exposed to VCM for 10 or more years before 1976, exposed for less than 10 Results The study population included 1100 exposed and 1100 controls in 12 plants, and has been described elsewhere.14 The follow up of the two groups was similar. In 1990 die number of person years was 8299 and 8202 and the number ofsubjects lost to follow up were 2% and 1% in the exposed and non-exposed groups respectively. MORTALITY During the seven year follow up, 40 and 43 deaths were reported in the exposed .and non-exposed groups, respectively (RR =* 1-0; 95% Cl 0*6-1 *5). Table 1 gives the RRs according to the different levels of exposure. None of the risks differed significantly from unity. Table 2 presents the main causes of death. MORBIDITY Exposure to VCM increased the risk of malignant tumour H CD-9 140-208) slightly but not sig nificantly (RR * 1-3; 95% CI Q'8-2-1). Table 3 shows the relation between the different categories of exposure to VCM and the occurrence of malignant tumour. Tabic 4 presents the distribution of the 70 sites of malignant tumours. Three cases of angio sarcoma of the liver occurred in the exposed group, but no cases of skin melanoma or malignant brain Table 3 Relation between exposure lo vinyl chloride and occurence ofmalignant tumours (ICD--9 140-208) during the seven yearfollow up Malignant tumours*' Yes (n - 70) No fit - 2119) (95% Cl) Non-exposed Exposed after 1976 Exposed <10 y before 1976 Exposed > tO y before 1976 - 32 3 14 21 1061 69 404 565 1-0 H (0-M *) l-2(0-&-2-) 1-3 (0 7-2 3) Nine subjects had * malignant tumour at entry to the study (three among exposed subject! and six among controls). t$ee footnote to table 1. Laplanche, Clavel-Chapelon, Contassot, Lanouziere Tabic 4 Types and number} of malignant tumours found during the seven year follow up F.xpottd (1099) Commit (1099) AH sues (ICD-9 140-208) Lip mouth pharynx (140-149) Digestive organs (150-159) Oesophagus Stomach Small intestine Colon rectum Liver angiosarcoma Liver Pancreas Digestive non-specific La.ynx < 161) Lung (162) Bone (l 70) Connective tissue (171) Melanoma of skin (172) Other skin (173) Tc*ti* pent* (186-187) Bladder kidney (186-189) Endocrine (194) Lymphohematopoictic (200-208) Secondary (196-198) Primary sue uncertain (199) I Subjects without malignant tumours at initial examination (No of subject! at risk): exposed 1096, controls 1093. `The total exceeds 32 is four subjects exhibited two primary cancers. tumour. Fourteen lung cancer cases were reported, eight in the exposed and six in the non-exposed group. One case of lymphoma was seen in the exposed and two cases in the non-exposed group. The risk associated with the onset ofdiseases of the circulatory system (Raynaud's disease excluded) (ICD-9 390-459) was significantly higher than unity (RR = 1-4; 95% Cl 10-1-8; p < 0-05). Moreover, an increased exposure to VCM was significantly (p _ 0-02) associated with increased incidence of cardiovascular diseases (table 5). One hundred and twenty three and 93 cases of diseases of the cir culatory system were noted in the exposed group and controls respectively. Table 6 presents the types of cardiovascular diseases. Fourteen cases ofRaynaud's disease were seen in the exposed and one in the nonexposed group (p < 0-01). The occurrence of diseases of the respiratory system (ICD-9 460-519) did not differ between the two groups (RR = 1-1; 95% Cl 0-7-1-8). None of Table 6 Type of cardii*vaicular disease (Raynaud's disease excluded) found during the seven year fallow up hxpoted tlOV9) Contrail (1099) No of subjects at risk* Circulatory system (390-459) Hypertension (401--405) Coronary in*un>cicnc)' (4)0--114) Myocardial Infarction (410) Cerebral vascular disorders (430--ijfl) Arteriosclerosis of limbs (4476,4479,4402) Other Circulatory disorders 933 I23t 55 30 21 R 9 27 955 93t 34 28 16 10 11 15 'Subject! without a Circulatory disease al the initial examination. tThc total exceeds 123 and 93 as some subjects exhibited two or more circulatory diseases. the risks significantly differed from unity when dif ferent degrees of exposure were considered (table 7). Discussion In our study, no relation was found for the occurrence of malignant tumour or respiratory dis eases and exposure, whereas an increased risk of cardiovascular diseases was seen in the group exposed to VCM compared with the non-exposed group. With respect to cancer, the risk ofangiosarcoma of the liver has been well documented since 1974. This was confirmed in our study although only three cases were found. During the same period 14 cases of angiosarcoma of the liver were registered in France. This discrepancy can be explained by the limited size ofour cohort as well as the selection ofthe plants and exposed group. Our results showing a lack of relation between exposure to VCM and other cancers agree with others.*"* The IARC study,* which pooled data from Great Britain, Italy, Norway and Sweden totalling 222 746 person years, did not show any positive evidence that a particular malignant disease was a hazard either. Our findings for the control group are in agreement with French statistics of incidence of cancer* in the same age groups, as 32 cases of malignant tumours were observed, corresponding to an annual incidence rate of 390 per 100 000. Table 5 Relation between exposure to vinyl chloride and occurrence of cardiovascular disease (except Raynaud's disease) (ICD-9 390-459) during the seven yearfallow up ____________________________________________________ Cardiovascular rfi'ifirm* Nog-exposed Exposed after 1976 Exposed < 10 y before 1976 Exposed > 10 j before 1976 Yes (n - 216) 93 7 46 70 No (m - 1672) 862 63 327 420 RRf (95% Cl) 10 04(0-4-14) 14 <04-14) 1-5 (1'1-2'i) Three hundred and ten Subject* hid * cardiovascular dUeue at entry in the atvdy (166 among exposed and 144 among Coouedt). fSce footnote to table 1, iv; y. Exposure to vinyl chloride monomer: remits of a cohort study after a seven year follow up 137 Table 7 Relation between exposure to vinyl chloride and occurrence of pulmonary disease (ICD-9 460-519) during the seven yearfollow up pertod Pulmonary diseases* Yes (n - 82) No (h - f9I8f PPt (95% Clf Non-exposed Exposed after 1976 Exposed < 10 y before 1976 Exposed > JO y before 1976 37 952 1 0 8 61 1 3 (0 5-3 5) 18 381 1-2(0 6-2-1) 19 524 l 0(0 6-1 9) One hundred And ninety eight subjects had a pulmonary disease at entry to the study (88 among exposed and 110 among controls) tScc footnote to table I. An increased occurrence of non-malhgnant respiratory disease as a result of exposure to VCM and polyvinyl chloride dust has been cited. In our study, morbidity from non-malignani respiratory disease was not different among the exposed and nonexposed group. Also the incidence ofdeath from nonmalignapt respiratory disease was not affected by exposure to VCM in two other recent studies.47 By analogy with the effect of other halogcnatcd hydrocarbons, an increased risk of myocardial infarction has been suspected4 with, however, little published evidence. One study10 showed a slight increase in mortality due to ischaemic heart disease. In our study, although a linear increase in risk of cardiovascular diseases with increased exposure was noticed, no association with myocardial infarction was apparent. The increase in cardiovascular abnormalities is mainly due to hypertension but also to a variety of other circulatory problems including venous disorders, arythmia, and valvopathy. This lack of precision makes it difficult to provide an explanation forour positive result. The excess hyper tension could be explained by the shift work," but this relation has never been found, not even in a study that included 15 000 workers.12 With lcspect to Raynaud's disease, 14 cases were seen among the exposed workers (0*2%); this rate is lower than that estimated for the general population--namely, 4%.13 The difference can be explained because (1) the disease affects women more than men, (2) a healthy worker effect may exist, and (3)thecases ofRaynaud's phenomenon have perhaps been included in the estimation for the general population. To study the effect of the degree of exposure to VCM* we decided to take into account exposure before and after 1976. This was the year when exposure to VCM was reduced due to the implemen tation of the 1975 French legislation.14 Measurements of exposure on workers, or in the workshops themselves, were not available and doses of exposure before 1976 were extremely high com pared with doses after 1976.15 For these reasons, the duration of exposure to VCM was only considered before this date and periods of less or more than 10 years before 1976 were taken as thresholds of low or high exposure. In conclusion, angiosarcoma of the liver and Raynaud's phenomenon seem to be the major hazards related to the exposure to VCM. Apart from these diseases, the evidence indicates that the risks associated with exposure to VCM, in terms of both mortality and as morbidity, arc probably negligible. French VCM group: Drs Aubrun, Barrat, Baylac, Bellcc, Paris, Quelin, Rambaud, and Richard (Rhonc-Poulcnc); Drs Bennech, Cestin, Favre, Lcvcquc, Lussato, Pucch, Rety, and Ruty (ATOCHEM). Requests for reprints to: Dr Agnes Laplanchc, Department dc Biosiatistiquc ct d'Epidcmiologic, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villcjuif Cedex, France. 1 Laplanchc A, Clavcl F, Omtassot JC, Lanouzierc C, Exposure to vinyl chloride monomer: report on a cohort study, Br J tnd . Med 1987^44:711-5. 2 Warteik M, Kramtr A, Jan P, tt el. PICAS: an interactive statistical database management system. In: Proceeding of the second international toorkshop on statistical database manage* ment. Los Altos, CA:1983;124-32. 3 Baker RJ, Nelder JA. The GLIM systemt release 2.77. Oxford: Numerical Algorithm Croup press, 1985. 4 Clavcl F. LapUnche A, Gontassot JP, Lanouzicre C Exposure to vinyl chloride monomer: Report on a 7~yc*f follow-up cohort study. In: 23rd International Congress on Occupational Health. Montreal, Canada: M Cusson, 22-28 September 1990. (abstract 278.) 5 Simonato L, L'Abbc KA, Andersen A, et al. A collaborative study of cancer incidence and mortality among vinyl chloride workers. Stand J Environ Heat'h 1991;17:159-69. 6 Doll R. Effects of exposure to vinyl chloride. An assessment of evidence. Seand J Work Environ Health 1988;14:61-78. 7 Jones R, Smith D, Thomas P. A mortality study ofvinyl chloride monomer workers employed in the United Kingdom in 1940- 1974. Seand J Work Environ Health 1988;14:153-60. 8 Wu W, Stecnland K, Brown D, Wells V, JonesJ, ScbulieP,*/a). Cohort and case-control analyses of workers exposed to vinyl chloride: an update. J Qccup Med 1989;31:518-23. 9 Benhamou E, Laplanchc A, Warteik M, Faivre J, Gignoux M, Mcnegoz F, RobilUrd J, Schaffer P, Schraub S, Flamant R. Incidence det cancers en France, 1973-1982. Paris: editions INSERM, 1990. (0 Greiser E, Reinl W, Weber H. Vinykhlorid-cxposition und morulitat dcutschcr chemkarbeitcr im vergkich zur mor- ttlitAt nichtexponicrter chemiearbeiter und PVC-verarbetter. Prophytaxe und Ergonomic 1982;32:44-62. 11 Dc Gaudemaris R, Monxie A, BattistcUa P, Siche JP, Mallion JM. Pressionancricllcctactivitcs dc travail pant. Archives da Maladies ProfessionnelUs 1988;49:5-9. 12 Perroud D. Travail petti, tension ertiriclle, corpulence et tobagitme. Lyon: these de Medeeme, 1983. 13 Bayle O, Consoli SM, Baudin M, Vaysaairat M, Ficssinger JN, Housset E. PhcnoiQcnc dc Raynaud idiopathique et secon- dairc. La Press* MidteaU 1990;19:741-5. 14 Reglemcnt d`administraiion publique relatif aux mcsurcs de protection des travailkurs centre les risques presenter par !c chlorurc de vinyle monomcrc. Journal Omeiel, Dccrct n 80-203 du 12 mars 1980. 15 Contassot JC. Chlorurt de vinyle. Paris: Encyclopedic Medico- ChirurjpCale, 9-1990. Accepted 8 July 1991 R&S150745 i\ Mutation Research, 2St (1992) 129-132 O 1992 Elsevier Science Publishers B.V. All rights revived 0165-7992/92/S05.00 il MUTLCT 00620 K--1711 -- (100) 129 The persistence of sister-chromatid exchange frequencies in men occupationally exposed to vinyl chloride monomer Aieksandra Fucic Verica Garaj-Vrhovac l, Boris Dimitrovic 2 and Mladcn Skara 2 Croatia (YuRoslaria) (Received IS September 1991) (Revision received 28 September 1991) (Accepted 30 September 199!) Keywords: Vinyl chloride; Persistence of sister-chromatid exchanges; Human Summary The persistence of sister-chromatid exchange frequencies in a population occupationally exposed to the well known chemical mutagen vinyl chloride monomer was studied. It was shown that increased values of sister-chromatid exchange frequencies were still present in the lymphocytes of workers who had not been exposed for 8-120 days and retired persons for 5-10 years after exposure. The possible ability of vinyl chloride monomer alkylating metabolites to cause long-lasting damage of the DNA molecule is discussed. ... Vinyl chloride monomer (VCM) is a well known carcinogen and mutagen in humans (Anderson et ah, 1980; Purchase et ah, 1976; Crecch and Johnson, 1974; Fui6 et ah, 1990). After metabolic activation by cytochrome P-450dependent monooxygcnascs VCM is transformed into alkylating intermediates which express mutagenic and carcinogenic activity (Bartsch and Montesano, 1975; Zajdela et ah, 1980; Barbin and Bartsch, 1989). These intermediates are potent inducers of increased sister-chromatid exchange frequencies (Perry and Evans, 1975; Fui6 et ah, 1990; Uzyeh, 1988; Simes et ah, 1991). Sister-chromatid exchange is a selective and Correspondence: Dr. A. Futil, Institute for Medical Research and Occupational Health, University of Zagreb, Ksaverska c. 2, Zagreb, Croatia (Yugoslavia). sensitive method for detecting the mutagenic activity of chemicals (Natarajan and Mullcndcrs, 1987) although it has been shown that sistcr-chromatid exchange frequencies arc decreased 4-16 weeks after the end of exposure (Stetka and Wolff, 1976; Uzyeh, 1988). The aim of our study was to draw attention to the persistence of changes in the DNA molecule which lead to expression of increased sister-ehromatid exchange frequencies after occupational exposure to high concentrations of VCM. Material and methods Fifteen plastics industry workers were chosen for the study of sister-chromatid exchange fre quencies. As a control population we chose 10 male subjects from the general population 40-50 R&S 150746 ( 130 years old. In the experimental group the exam ined workers had been employed in a polyvinyl chloride plant for 1.5-35 years. Those with recent X-ray exposure and drug treatment were ex cluded from the study. The VCM concentration in the working environment was 2000 ppm. Due to the technological process the concentration could occasionally reach 2000 ppm for a very short period of time. Sister-chromatid exchange frequencies were measured during and 8, 30 and 120 days after exposure. Retired workers were examined 5-10 years after exposure. Sister-chromatid exchange frequencies were measured on slides from cultures of blood lym phocytes stimulated with phytohcmagglulinin. To 0.5-mI samples of whole biood 8 ml of F-10 medium (Gibco) containing 20% calf scrum and 10 fj.g/ml bromodcoxyuridine was added. The cultures were harvested after 72 h. Smoking habits of the individuals were taken into account. For statistical analysis the r-test was used (Pavlic, 1970). Results Sister-chromatid exchange frequencies in 15 plastics industry workers and 10 control individu als from the general population arc shown in Table 1. The periods during wh>ch workers had not been exposed were 8, 30 and 120 days. Re tired persons had not been exposed for periods of 5-10 years. Two retired persons were examined twice with a 2-year interval. There was no statisti cally significant difference between sister-chro matid exchange frequencies in workers during exposure and 8, 30 and 120 days after exposure. The range of sister-chromatid exchange frequen- TaBLEi COMPARISON OF SISTER-CHROMATID EXCHANGE FREQUENCIES IN SUBJECTS DURING AND AFTER EXPO SURE TO VCM Subject No. Employment (yean) Employed 1 2 3 4 5 6 7 8 9 10 11 12 Retired 1 16 12 1.5 12 3 12 2 10 10 9 15 20 17 Cigarettes/ day 0 20 0 20 0 0 25 0 20 20 30 30 15 SCE frequencies During exposure per cell range 9.8 6-15 10.7 4*17 7.6 4-15 9.7 4-16 8.6 5*14 85 6-12 8.5 4-14 9 4-14 9.7 4-19 12J 5-26 12.7 8-16 11.1 6-19 2 35 2 37 0 Control subjects (mean value, n -10) For all calculations 50 celts per person were counted. After exposure period per cell 8 days 8 days 30 days 30 days 30 days 30 days 30 days 30 days 30 days 30 days 30 days 120 days 11.5 9.1 8.0 11.1 8.6 9.8 8.5 8.3 9.7 10.4 n 10.9 8 years 10 years 5 years 7 yean 9 years 10.4 8.6 95 10.1 7.5 5.9 range 7-17 5-16 4-14 6-23 5-15 4-13 4-14 4-14 4-18 4-19 5-23 6-18 6-20 4-13 5-19 5-18 5-13 0- 7 B & S 150747 i' cics during exposure was 4-26, and after expo sure it was 4-23. Even 10 years after chronic exposure to high concentrations of VCM retired persons showed significantly increased values of sister-chromatid exchange frequencies ranging from 4 to 20. The value of sister-chromatid ex change frequencies for control individuals was 5.9, with a range of 3-7. Discussion Sister-chromatid exchange frequencies provide useful information about exposure to chemical mutagens. Although the mechanism of sisterchromatid exchange induction is still a matter for speculation this method is very sensitive and very frequently used in biomonitoring of people occu pationally exposed to a wide range of chemicals. It is generally believed that in contrast to severe morphological changes in chromosomes which may persist for a long time, sister-chromatid ex change frequencies in lymphocytes may maintain a high level for 4-16 weeks after exposure (Stetka and Wolff, 1976; Uzyeh, 1988). The transient nature of increased sister-chromatid exchange frequencies raises the question of the mode of action of the substances that cause them. The question is whether the decrease in sister-chro matid exchange frequencies is due to the disap pearance of the chemical agent or its active metabolite from the organism or to the repair process. Sister-chromatid exchange is a result of a mechanism independent from that which causes chromosome breakage (Wolff and Bodycotc, 1975; Lin and Wcrtelecki, 1982). However, fragile sites are hot spots for DNA recombination as mea sured by sister-chromatid exchange (Glover and Stein, 1987). This is also confirmed by the obser vation that chemicals that do not induce gross chromosome aberrations significantly increase sister-chromatid exchange frequencies (Latte, 1974; Perry and Evans, 1975). Vinyl chloride monomer is a mutagen which increases the frequencies of sister-chromatid ex change in people exposed to high concentrations of it. In contrast to the general opinion today we were able to show increased values of sistcr-chro- 131 niaiid exchange in humans exposed to high con centrations of VCM as long as 10 years after the exposure. Our findings, which demonstrate that there was no significant decrease in sister-chro matid exchange levels from 8 days to 10 years after exposure, present a new aspect of the mech anism of sister-chromatid exchange and the ac tion of VCM. The primary adducts isolated from DNA after exposure to VCM were 3,^cthcnodcoxycylosinc and 7-(2-oxocthy!)guaninc along with smaller quantities of l,N'*-cthcnodcoxyadcninc (Green and flathway, 197S; Barbin ct ah, 1981). The aromatic character of the sus pected persistent monoadduct cthcnodcoxyeytosinc ensures its easy formation and stability. The presence of such etheno derivates in synthetic nucleic acids has been associated with misincorporation of bases during DNA synthesis (Barbin ct al., 1981; Hall ct ah, 1981). The carcinogenic potency of VCM may be related to the persis tence of such potentially miscoding lesions. It is suggested that the mode of action of chemicals such as VCM is a multistcp mechanism which also includes the formation of interstrand cross links with either its complementary base or an adjacent base on the complementary strand (Con ner and Cheng, 1983). Such cross-links may pre sent yet unknown highly persistent sister-chro matid exchange-inducing lesions. The levels of sister-chromatid exchange even 120 days after exposure to VCM were not decreased regardless of smoking habit. The most interesting subjects were retired persons who, even 10 years after exposure, still carried high levels of sister-chro matid exchanges. The range of their sister-chro matid exchange frequencies did not differ statisti cally significantly from that in still working sub jects. Consequently it may be assumed that even bone marrow stem cells are affected and that these lesions are not being repaired during the S-phasc of the mitotic cycle as described in some hypotheses on the origin of sister-chromatid ex change (Schofeld and Lajtha, 1973). Further investigation is necessary to prove the persistence of alkylated sites in the DNA molecule caused by VCM and detectable by the sisterchromatid exchange method after long exposure to high concentrations of it. At the same time it is ` R&S 150748 132 necessary to consider this population as having permanent damage o the genetic pool. Acknowledgement The authors acknowledge the excellent techni cal assistance of Mrs. Jasminka Kapetan. References Anderson* D., C.R. Richardson, T.M. Wci&hl, I.F.lt. Purchase and W.G.F. Adams (1980) Chromosomal analysis in vinyl chloride exposed workers, results from analysis IK and 42 months after initial sampling, Mutation Res., 79, 151-162. Barbin. A. und H. Bartsch (1989) Nucleophilic selectivity as a determinant of carcinogenic potency (TD*,) in rodents: a comparison of mono- and bi-functional alkylating agents and vinyl chloride metabolites, Mutation Res.. 215,95-106. Barbin, A., J. Bartsch, P. Leconte and M. Radman <19Kl) Studies on the miscoding properties of l,NA-ethcnoadeitinc and 3,N4-ethenocytosine DNA reaction products of vinyl chloride metabolites during in vitro synthesis. Nucleic Acids Res,, 9. 375-387, Bartsch, H-, and R. Montesano (1975) Mutagenic and carcino genic effects of vinyl chloride. Mutation Res,, 32, 93-114. Conner, M.IG, and M. Cheng (1983) Persistence of ethyl carbamate induced DNA damage in vivo as indicated by SCE analysis, Cancer Res,, 43,965-971. Creech, J,L., and M,N. Johnson (2974) Angiosarcoma of the liver in the manufacture of polyvinyl chloride, J. Occup, Med., 16, 150-151. Fufid, A., D. Horvat and B, Dimilrovid (1990) Mutagenicity of vinyl chloride in man: comparison of chromosome aberra tions with micronucicus and sister-chromatid exchange frequencies, Mutation Res., 242, 265-270. Glover, T.W., and GK. Stein (1987) Induclk>n of sister chro matid exchanges at common fragile sites. Am. J. Hum. Genet., 41, 8S2-890. Green, T., and D.E. Hathway (1978) Interactions of vinyl chloride with rat liver DNA in vivo, Chem.-Biol Interact., 22, 211-224. Hall, J.A.. R. Saffhill, T. Greerf and D.E, Hathway (1981) The induction of errors during in vitro DNA synthesis follow ing ehloroacculdehyde treatment of polyWA-dD and pofyfdC-dG) templates. Carcinogenesis, 2,141-146. Kuderova, Z. Polrvkova and J. Baton (1979) Comparative evaluation of the frequency of chromosomal aberrations and the SCE numbers in peripheral lymphocytes of work ers occupationally exposed to vinyl chloride monomer. Mutation Res,. 67, 97-100. 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Bartsch (1980) Carcinogenicity of chlorocthylene oxide, an ultimate reactive metabolite of vinyl chloride and bisfchloromethyl) ether after subcutaneous administration and in initiation promotion experiments in mice. Cancer Res., 40, 352-356. Communicated by M. Alaccvic 33 f~ i Ui { i r\ Tit tC_X . (,f o\ aflaioxins z-z"n 4-aminobtphcnyl (analgesics containing^ l.'iL';w . phcnacctm . Mf> t* azathioprinc Vi-2C,CpV . 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