Document 6RN461K7BkkekYGq1kMaMq0JR

British Journal of Industrial Medicine 1989;46:826830 a.wssment of leukaemia u Risk assessment of leukaemia and occupational exposure to benzene G M H SWAEN, J M M MEIJERS From the Department of Occupational Health and Toxicology. University of Limburg. 6200 MD Maastricht, The Netherlands benzene, several r ing the available epidemi, sessment proposed by t etherlands will be describ ABSTRACT Experimental toxicological studies have offered clear evidence that benzene indurn haematopoietic neoplasms, and it is generally accepted that exposure t o benzene is a risk factor for toxkological data leukaemia, in particular for acute non-lymphatic leukaemia. Quantitative aspects of b e r ::.: risk assessment are still a matter of controversy, however. In several risk assessments a n estimated 50 belled benzene ha deaths from leukaemia per 1000 deaths would arise from exposures t o benzene of 10 ppm during a nt0 nucleic acids working life of 30 years. The assessment presented in this paper leads to lower estimates, which are more in agreement with the weak toxicological data. Furthermore, an approach is presented to incorporate the results of low exposure epidemiological studies into the process of quantitative risk publications have e metabolites tc assessment. In the past decades a substantial body of knowledge has accumulated regarding the long term health effects qf occupational exposure to benzene. In addition to experimental data, this consists of epidemiological data mainly from retrospective cohort studies of workers occupationally exposed to benzene. Except for the ability of benzene to cause non-malignant blood anomalies, the main chronic health effect of concern is the increased mortality due to leukaemia and, in particular, acute non-lymphatic leukaemia: several investigators have stated that this is the only increased risk a h exposure to benzene. Nevertheless, other investigators have pointed out that benzene EFollowing a request from the Minister 8 Jfam, Public Health and Culture, a Committee of the Health Council ofThe Netherlands has drawn UP a somewhat differentrisk assessment for the risk ofleukaemiaaftm exposure to benzene in ambient air. It is the PurpooC of isolated bone 6arroL relevance for in vivo gen onable. Investigations of t: A repair and the occurr: -synthesis in mammalian cC `a" have so far not yielded a tion. Despite extensive ons that benzene is capat ons in bacteria, yeasts, c of this article to apply this risk assessment to cells if tests not caDabil occupational exposures to benzene. Several weaknesses of epidemiological data can be .'` Benzene has been she, identified that may form a source of controversy.'h chromosome aberratio first weakness is the lack of accurate and reliable dam and somatic mammali; regarding the exposure levels that exisre; i ' ~ pcart Phocytes. Chromoson and have been experienced by the stud]-i coho- h as translocations have This is not a particular problem in the course of 8 induces a variety of malignant neoplasms, including qualitative risk assessment: in other words to assessif lymphatic leukaemia and lymphomas.'" The relation exposure to high concentrations of a certain chemid between exposun to high concentrations of benzene is a risk factor for a particular neoplasm. In the COW and the risk of leukaemia is well documented and of a quantitative risk assessment, however, the es- generally accepted. Case reports and epidemiological confirmations have led to regulatory legislation throughout the world in the field of occupational exposure, and exposures experienced by the general population.+" Several risk assessments have been conducted for occupational exposures."-" In a recent review the authors presented a risk assessment based on the results ofa retrospective cohort study of 1006 exposed workers, applying a linear dose-response relation." Accepted 13 Fcbnmy 1989 tion of past exposure will have substantial impad OQ the outcome of the assessment. A second weakness d epidemiological data is the lack of information regard- ing the mechanisms, leading to the inc:::~,:d observed. Insight into the mechanism th:. 5 *of great importance in the determinauon of tbC extrapolation model to be applied to assess the related to low exposure levels. The choice of extrapolation model may also have a great impad '? the outcome of the risk assessment. A major *ssW whether or not the chemical should be considered@ genotoxic or not. In the case o f a non-genotoxica@ it is customary to take a no-effect level approach ad r neoplastic transfor s. Only in Syrian h2 n the .incidence of trans Benzene is also capat, tumours in Zymbaj': an for tumour form: the basis of the mL mals, benzene may lnogen in animals anc ld in principle be viev 826 assessment of leukaemia and occupational exposure to benzene Epidemiological data 827 assessment proposed by the Health Council of Netherlands will be described. rimental toxicological data ne has been reported to be acids in the liver, spleen, cell of mice and have made covalent bind- occurrence of unscheduled alian cell cultures'' and in ielded any evidenceof DNA nsive efforts there are no n gene mutations and recombinations are ,d." Benzene has been shown to be capable of :. chromosome aberrations in yeast, fungi, and somatic mammalian cells, including lymphocytes. Chromosome breakage phenouch as translocations have been found in vitro ations were observed with benzene concenlower than 10 ppm. Several in vivo experindicate that the sensitivity of laboratory icate that the sensi- ted for neoplastic transformation in a variety ystems. Only in Syrian hamster cells was an .29 On the basis of the multiple site carcinoin animals, benzene may be considered as a carcinogen in animals and the carcinogenic should in principle be viewed as a stochastic After case reports were published indicating a possible relation between exposure to benzene and the occurrence of leukaemia, many epidemiological studies in this field were started and an extensive review has recently been published." The findings of these studies leave no doubt that workers exposed in the past to high concentrations of benzene have experienced an increased mortality from leukaemia. Both case-control studies and retrospective cohort studies have confirmed this relation. Several studies, however, in low exposure groups have reported con- tradictory results. For instance, in a retrospective cohort study of about 13 500 workers in the rubber industry an excess mortality risk for lymphatic leukaemia was observed9 and not for non-lymphatic leukaemia as has been reported by other epidemiologists. In several other large studies of workers exposed to low concentrations of benzene no indications were found that these cohorts had experienced increased mortality for leukaemia. In a study of 38 800 workers employed in the petrochemical industry 18 cases of leukaemia were observed compared with an expected number of 23.m In a study of similar size (34781 workers) in the oil industry 30 deaths from leukaemia were observed, compared with an expected number of 32." In this study, however, a dose response relation appeared to exist, which was shown by means of a nested case-control study design.I2 Again this casecontrol study confirmed the existence of a risk of leukaemia after exposure to high concentrations of benzene. A third study of workers exposed to benzene that should also be regarded as negative is the study conducted by Parkes et a1 in the British rubber industry." In this study of 33 8I5 workers, 31 cases of leukaemia were observed compared with an expected number of 28. As has been pointed out by Hernberg, the inter- pretation of negative results of epidemiologicalstudies is complicated.Y With a negative outcome, it is not always clear whether the finding is an effect of methodological deficiencies or if there actually is no increased risk present in the cohort and exposure level under investigation. The greatest weaknesses of the three large studies of low exposures are the lack of quantitative exposure data and the possibility that a proportion of the "exposed cohort" had not been exposed to benzene at all. Despite these weaknesses, the committee of the Health Council of The Netherlands decided not to disregard these findings in establishing a risk assessment. Thus the committee was left with the task of incorporating positive results of high exposure studies and negative results of low exposure studies in a risk assessment, low exposures being defined as lower than I 828 a time weighted average exposure of 10 ppm which is the current threshold unit value in many countries. This contradictory conception has also been supported by the European Chemical Industry Ecology and Toxicology Centre." As a consequence it was decided not to estimate an overall relative risk for leukaemia after exposure to benzene, as has been done in the evaluation of vinyl chloride.I6 Two separate risk assessments were made, both based on the findings of epidemiological studies. The first departed from the findings in high exposure studies, the second from the findings in low exposure studies. Although the risk assessment conducted by the committee was intended for risks experienced by the general population, it may also be applied to the occupational environment. RlSK ASSESSMENT BASED O N STUDIES OF HIGHLY EXPOSED WORKERS Before embarking on a risk assessment several assumptions must be made. The first deals with the magnitude of risk after a particular exposure dose. The second is concerned with the extrapolation model. The first assumption may be derived from several cohort studies. A reasonable estimate of this risk, based on Rinsky's risk assessment, is that workers exposed on average to 40 ppm over a period of 10 years have experienced a fivefold increase in the risk of dying from acute non-lymphatic leukaemia (SMR = 500)." Assuming a stochastic working mechanism, if a doubling of the dose also implies a doubling of the risk, a linear extrapolation model is suitable. Such a model may be formulated as: SMR = 100 + b x d where SMR is the standardised mortality ratio (observediexpected x loo), b is the tangent of the angle between the straight line and the horizontal axis (dose), and d is the benzene dose in ppm-years. By means of this model the number of additional deaths from leukaemia per 1000deaths which may arise from a benzene dose of 300ppm-years may be calculated, as done by Austin et alls: 500=100+bx400-b=1 if d = 300 ppm-years then SMR = 100 + 1 x 300 = 400 Thus workers having received a total benzene dose of 300 ppm-years may experience a SMR of 400. In a western country such as The Netherlands the age adjusted death rate for acute non-lymphatic leukaemia in men is 1.6 per 100 0003' and the total mortality is 923.2 per 100 000. This implies that about 1.7 deaths per 1000 deaths are due to acute nonlymphatic leukaemia. In a population in which an SMR of 400 exists 4 x 1.7 = 6.8 deaths due to acute non-lymphatic leukaemia may occur per 1000deaths, which is an excess of about five deaths. This estimate differs from that proposed by Austin" which is in range of about 50 excess deaths per 1000 deaths. RISK ASSESSMENT BASED ON THE RESULTS OF L O W EXPOSURE STUDIES ''benzene,"'" Thorpe conduc workers in petroleum refineries.'0 Alt has several methodological weakn could have detected a risk if there uous service in the There was no excess of leu of workers potentially expose leukaemia were observed. A 95% two sided fidence interval may be calculated around combined finding, which is: . ,[ln(SMR) f 1.96 ,h/obsJ = J4.605 f 0.1125) = 89 This upper limit can serve as a point of ? the risk assessment. Again no accurate 0;1tii on exposures to benzene are available. Since 10 the threshold limit value in the early 197Os,i reasonable to use 5 ppm during a period of ten an estimate of the exposure. Subsequently it is to calculate b in the linear model. SMR = 100 + b x d 112 = 100 + b x 50 b = 12/50 = 0.24 which may be used to calculate the S M k Slven a t dose of 300 ppm-years. SMR = 100 + 0.24 x 300 SMR = 172 Since the confidence limits were based on leukaemia mortality, it seems app extrapolate for total leukaemia mortality, 100000. The total mortality is 932 - - ! which implies that 8.2 deaths per 1000 deaths due to leukaemia if no exposure to benzene may occur, of which 8.7 "natural" background incidence of leukaem By analogy, a risk assessment may be mad essmeni of leukaemir as the SMR resui years. Next b mal SMR = IOC he linear model as SMR = 100 + 1.2. s no doubt that relative trations of benzene inc cute non-lymphatic lev s frequently been confi e risk assessment to lower results t h Austin et Bot assessment of leukaemia and occupational exposure to benzene 829 tential risk to acute non-lymphatic leukaemia. erspective is probably more realistic given the itions cited earlier in this article. to the three low exposure studies, an estimated %) of the 79 deaths from leukaemia observed in studies may have been of the acute non- ving a two sided 95% confidence what level of risk would be regarded as acceptable in an occupational setting. This is more a matter ofethics than of science.Nevertheless, it should be remembered that benzene is not the only chemical to which workers can be exposed. and that the interindividual susceptibility for the haematapoietic effects of benzene can differ widely. Perhaps one additional death per 1000 deaths after a working life of exposure can serve as a guideline. Requests for reprints to: G M H Swaen, Department of Occupational and Environmental Health and Toxicology, University of Limburg, PO Box 616,6200 MD Maastricht. The Netherlands. SMR = 100 + b x d 161 = 100 f b x 50 b 61/50 1.22 ose of 300 ppm-years is experienced an SMR for non-lymphatic leukaemia may be estimated by +SMR = 100 1.21 x 300 =: 466 ,,nplies that instead of the 1.7 deaths from acute lymphatic leukaemia an estimated eight deaths occur per 1000 deaths, of which 1.7 are attributto the "natural" background incidence of acute lymphatic leukaemia. e ISno doubt that relatively long exposure to high . In studies of workers exposed to low trations, however, this relauon has been absent confined to those workers who had been to high concentrations in the past. It did not ments have been conducted, giving risks in the s dkaths from leukaemia per 1000 among workers exposed to 300 ppm-years of e. The nsk assessment presented in this article leads to lower results than, for instance, the one ssible, to verify. Thus it remains of great rtance to conduct updates of cohorts already trfied as having been exposed to benzene. References I Maltoni C, Conti 8, Cotti G. Benzcne: a multi-potential carcinogen. Results of long-term bioassays performed at the Bologna Institute ofOncology. Am J Ind Med 1983;4:589-630. 2 Cronlute EP. Bullis JE, Inouc T, D m RT. Bnucne inhalation produrn leukaemia in mice. Toxicol Appl Pharmacal 1984;75:358-61. 3 Maltoni C. Scarnato C. First experimental demonstration of Ibe carcinoeenic efTats of benzene: lon8-tcrm bioassays on Sp&&Dawley rats by oral administration. Med Lov 1979:70353-7. 4 Aksoy M, Dincol K.Erdcm S. Dincol G. Acute leukemia due to chronic exposure to benzene.Am J Med 1972;52160-6. S Infante PF. Wagoner JK Rinslri RA. Youog R. Leukemia in benzeneworkers. Lawet 1977;i:7&8. 6 Ott MG, Townrnd JC, Firbeck WA, Laagnu RA. Mortality among individuals occupationally exposed to benrcne. Arch Environ Heaffh1978:33:3-10. 7 Rinsky RA,Smith AB. Hornung R, er al. B e m e a n d leukaemia. N Engl J Med 1987;3161044-50. 8 Paganini-Hill A. Glazer E. Henderson BE. Cause specific mortality among newspaper web prrss men. J Ocetrp Med 1980:22:5424. 9 Monson RR, Fing JL. Cancer mortality and morbidity among rubber workers.J Nail Cancer Insi 1978;61:1947-53. IO Yin SN, Li GL,Tain FD. ef 01. Leukaemia in benzene workers: a retrospective cohort study. Br J Ind Med 1987:44: 124-8. 1 1 White AC, Infante PF, Chu KC. A quantitative e s h t e of leukaemia mortality associated with occupational exposure to bmzene. Risk Anal-vsk 19822191-204. 12 Alkn RE. Carcinogen awessmenf group'sfinol report on pop&lion risk ro ambient benzene exposures. ResearchTriangle Park NC:EPA, 1979. (EPA 4SO/S-aoocle.) 13 Rinsky RA, Smith AB, Hornung R. etd`Bcnzene and leukaemia: an epidemiologic risk assessment. N Engl J Med 1987;316 1044-50. 14 C W Q KS. Allen BC. Qwnritarive esfimatesof risk of leukemia from occupational exposure 10 benzene. Cinannau: OccupationalSafety and Health Administration, 1984. I5 AustinH,Dellzell E, Cole P. Benzene and leukemia: a review ofthe literature and a risk assessment. Am J Epidemiol 1988;lZl: 419-39. 16 Luu WK,Schlattcr CH. Mechanism of the carcinogenicactionof benzene: irreversible binding to rat liver DNA. Chrm Biol Interact 1977;18241-5. 17 Gill DP,.Ahmed AE. Covalent binding of carbon 14-labekd benzene to cellular organelles and marrow nucleic acids. Biochem Pharmacal 1981;30:1127-32. 18 Arfellinr G.Grilli S, C o l d A, Marrullo M, Prodi G. In vivo and in vitro binding of benzene to nucleic acids and proteins of 830 various rat and mouse organs. Cancer Lett 1985;fl).15w8. 19 Rushmore TH.Snyder R, Kalf GF.Covalent binding ofbmzcne and its metabolites to DNA in rabbit bone marrow mitochondria in vitro. Chem Biol interact 1984;49:133--54. 20 Kalf GF. Snyder R. Rushmorc TH. Inhibition of DNA synthais by benzene metabolites and their covalent binding to DNA in rabbit bone marrow mitochondria in vitro. Am J id Med 1985;1485-92. 21 Robst GS,McMahon RE, Holl LE, Thompson CZ, Epp JK.Neal SB. Chemically-induced DNA synthesis in primary rat hepatocyte cultures: a comparison with bacterial mutagenicity using 218 compounds. Environ Mutagen 1981311-32. 22 Bamt RH. Assays for unscheduled DNA synthesis in Hela 53 cells. In: Ashby J. Scms FJ de, Draper M,et al, &. Evahiarion of short-term tests for carcinogens: report of the international programme on chemical safety collaborative study on m vitro m a y s . Amsterdam: Elscvier, 198537-52. 23 Rijksinstituut v w r Volksgaondheid en Milicuhygihe. (National Institute of Public Health and Environmental Hygiene.) Ontw r p hir-dokument benzeen. Bilthoven: RVM, 1986.(Rapport No 840760002.) 24 Ashby J, Scrrcs FJ de. Drapcr M. et al, eds. Evaluation of shortterm testsfor carcinogens:report on the internationalprogramon chemical safety collaborative srudy on in vitro cusoys. Amsterdam: Elsevier. 1985. 25 Tice RR, Sawey MJ,Drew RT, Cronkite EP.Benzcncinduced micronuclei in the peripheral blood of mice; a retrospective analysis. Environ Mutagen 1984;64214. 26 Dean BJ. Racnt findings on the genetic toxicology of benzene, toluene, xylenesand phenols. Mutat Res 1985;154:153-81. 27 Amacher DE,Zelljadt J. The morphological transformation of Syrian hamster embryo cclls by chemicals reported non- Swam, Meijers mutagenic to Salmonella typhimurium. Carcinogenui, 1983;4291-5. 28 McGrcgor D, Ashby 1. Summary report on the performance cell transformation assays. In: Ashby J, Scrrcsde FJ.7 I.urM. eds. Evaluation of short-term testsfor carcinogens: , ,- drhZ internotionalprogramme on chemical safety c ~ l h b o ~sr,+a ~ , ~ ~ -on in vitro assays. Amsterdam: Elsevier, 1985103-15. 29 Maltoni C, Conti B. Cotti G. et d. Experimental studia oo benzene carcinogenicity at the Bologna Institute of~ c o i o g : current results and ongoing rcscarch. Am J Ind Med 19853: 441-6. 30 Thorpc JJ. Epidemiological S W q of leukaemia in potentially exposed to bcnzcnc. I Occup Med 1974;16:375.8~ 31 Rushton L, Alderson M.The influence of occupation on h d a SomercsultsfromastudyintheUKoilindustry.CarcinogmcJit 1980;1:73W3. 32 Rushton L.A l d m o n MR.A asccontrol study to invccrizae & d a t i o n bctwccn e x p u r e 10 bmzene and .;...,, fmm leukaemia in oil refinery workers. Br J Cancer 1961;.(3.;i-84. 33 P a r k a HC, Vcys CA, Waterhouse IAH. Pel& A. mortality in the British rubber industry. Br I Ind ~d l982;39:2O!L20. 34 Hernbcrg S.Negative results in cohort studies-howto recog& fallacies. S c d J Work Environ Health 1981;71214. 35 European Chemical Industry Ecology and Toxicology Centre A review of recent literature on thetoxicology of benzene.B N ~ & ECETOC, 1984.flesh report No 16.) 36 Swam GMH, Hollander de AEM, Kroes R, et al. A scientificbui, for the risk assessment of vinyl chloride. R e p / Toxicd pharmacol 1987:7120-7. 37 Central Bureau of Statistics. Atlas of cmcer mr' .. m 7k Netherla&, The Hague: Staatsuitpverij. 1980. Coronel Luboraror; 15% whereas ti o predict the indiv: al, human exposur 9 December 1988 ,'t :,.t I'+ British Jomal of Industrial Medicine I987;M:12zI28 i -. 0- ;..e z - 0- ! > 5 ' 4HC'F .> Leukaemia in benzene workers: a retrospective cohort study S-N YIN,' G-L LI,' F-D TAIN,' Z-I FU,' C JIN,' Y-J CHEN,' S-J L U 0 , 3 P-Z YE,4 J-Z ZHANG,' G-C WANG,6 X-C ZHANG,7 H-N WU,* Q-C ZHONG9 From the hstitvte of Health.' Chinese Academy of Preventive Medicine, Beijing, Stations for Health and Preventionof Infection of Shanghai.' Sichuan,3 Tianjin.6and Nanchang,s and Institutes for Prevention and Treatmentof Occupational Disease in Heilongiiang,' Shenyang,' Helan. and G u a n g z h ~ uC, ~hina ABSTRACT A retrospective cohort study was conducted in 233 benzene factories and 83 control factories m 12 cities in China. The benzene cohort and the control cohort consisted of 28460 benzene aposed workers (178 556 person-years in 1972-8 1) and 28 257 control workers (199 201 person-years). Thirty cases of leukaemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukaemia mortality rate was 14/100000 person-years in the benzenecohort and 2/100000 person-years in the control cohort; the standardized mortality ratio was 5-74 (p c 0-01by U test). The average latency of benzene leukaemia was 11.4 years. Most (7606%)mses of benzene leukaemia were of the acute type. The mortality due to benzene leukaemia was high in organic synthesis plants followed by painting and rubber synthesis industries. !e concentration of benzene to which patients with a leukaemia were exposed ranged from 1 ~ 1.0 IOOOmgjh' (mostly from 50 to 500mg/m3). Of the 25 cases of leukaemia, seven had a history of chronic benzene poisoning before the leukaemia developed. In additia to its presence in the general environment as a pollutant benzene is still used in various industries and hChina some 500 000 workers are exposed to benzerr or a benzene containing mixture (SN Yin e f a l , repated at scientific committee on maximum permissibic limits meeting, London, 1983). The aetiologid relation between exposure to benzene and leukaemia has been reported by several authors including Vigliani and Saita,' Ishimaru et al,' A k ~ o y r, e~d Rinsky et al.' Whereas the leukaemo- genic p r o p t y of benzene in man has been well established,' tk epidemiological data are still considered insufficiel and, especially, there has been no epid e m i o l o d report on benzene leukaemia in China. To study the causal relation between benzene and Ieukaemk a further retrospective cohort study was undertalcen in 1982-3. The present paper reports the major fidings of the study. The relation of other malignandcs to exposure to benzene will be described in a sepante report.6 Tianjin, Chengdu, Chongqing, Haerbin, Shenyang, Jinzhou, Zhengzhou, Luoyang, Guangzhou, Nan- chang, and Kaifeng, China, in 1982-3. The members of the benzene group were selected from 233 painting, shoe-making, rubber synthesis, leather, and adi .ve and organic synthesis factories in the 12 cities ciied. The subjects had worked in those factories for at least half a year between 1 January 1972 and 31 December 1981. Those in the control cohort were from 83 machine production, textile, and cloth factories in which there were no known exposures to benzene or other occupational carcinogens. The sex and age distribution in the control group were similar to that of the benzene group. The controls had also worked in the same cities for at least half a year during thp- .me period. The drop out rate was 0.8% in the b. :ne cohort and 1.3% in the control cohort. Thus the henzene cohort consisted of 28 460 workers ( 1 5 643 men 12 817 women) and the control cohort of 28 157 subjects (16 621 men, 12 336 women). Both cohorts we* Materials md methods followed up from 1972 to 1981 so that 178556 person-years were obtained for the benzene cohofl The stu& was conducted in the cities of Shanghai, and 199 201 the control cohort. Items investigated included the occupational hi* Accepted 13 May I986 tory of the individuals, a history of benzene poiGnnin8 124 e concentrati Leukaemia in benzene workers 1 Mortality and relative risk of leukaemia c Benzene Controls Sex Person-years Death Mortality Person-years Death Men Women 100025 78531 17 a 7.00 10.19 122268.5 77932.5 3 I Total 178 556 25 14.00 , 199201.0 4 * R R = Relative nsk defined as the ratio of mortality B to mortality C. -~ 1 :'3' 1 Standardired morrality ratio (observed/e.rpected)for benzene leukaemia - 125 Mortality 2.47 1.28 2.0I RR* 6.88 7.24 6.97 p <0.0I <0.05 <0.0I Sex Men Women Total Observed 1a7 25 Expected 3.392 0.964 4.356 Table 3 Mortality rate of leukaemia in various industries In'. Workers Painting Paint producing Rubber Glueing Shoemaking Leather Organic synthesis Miscellaneous I3604 4533 2208 1512 381 I 323 I976 493 Total 28460 'Mn-.:Iity nte: unit, 1/100OOO person-years. Person-years 87935.5 26859 I3544 I I082 231 I7 I795 I2037 2685.5 178556 SMR 5.0 I 8.30 5.74 Leukaemia 14 2 2 I -1 -5 25 UP 3.30 <0.0I 2.49 C0.05 4.13 CO.01 Mortality* 15.9 7.4 14.8 9.0 -4,3 4-1.5 14.0 and other specific disease, death certificates (for all the benzene cohort, of whom 25 had died and five known deaths), working conditions, and atmospheric were alive in 1972-81; four cases of leukaemia were benzene concentrations in the workplace; this infor- found in the control cohort (all dead). The mortality mation was collected from factory records. Benzene rate of leukaemia was 14/100000 person-years in the concentrations were determined by means of grab benzene cohort and 2~01/100000person-years in the samples followed in the main by gas chromatographic control cohort. The relative risk of leukaemia for the analyses. The cases of leukaemia, aplastic. anaemia. benzene workers was 6-97 and was significantly high and benzene poisoning were obtained from hospital both in men and women (table 1). re( . is; the diagnosis of benzene poisoning was As 25 cases of benzene leukaemia (excluding five es1.toiished based on China national criteria for diag- live cases) were observed compared with 4.3 expected, nosis of benzene poisoning' including occupational the SMR was 5.01 for men, 8.30 for women, or 5.74 history, a peripheral leukocytecount of less than 4000 for both (table 2). When the mortality due to benzene Cdlslmm', and symptoms or signs in the central ner- leukaemia was compared in the various industries, the VOus system. The vital status was followed UP until 31 rate was highest in organic synthesis factories fol- &ember 1981. The standardized mortality ratio lowed by the painting and rubber synthesis industries (SMR) was calculated with reference to the deaths in (table 3). - -the control cohort. ' ---.__.. -- 7Rc!tIts AGE A N D LATENCY I N CASES OF LEUKAEMIA :. The ages of the patients with leukaemia in the ben- /zene cohort ranged from 24 to 62 with a mean of 39.7 'OR.rALITY A N D RELATIVE RISK O F LEUKAEMIA years (38.1 for men, 36.0 for Women). The mean age In total, 30 cases of benzene leukaemia were found in of the patients with leukaemia was lower in the ben- 126 1CrJ Yin. Li,Tain. Fu.Jin. Chen, Luo, Y e , Zhang. Wang, Zhang, Wu,Zhong 1X NE CONCENT PLACES WHE OBSERVED able 4 shows the orkplaces where the orked. The mean c nge of IO to 1000 50 0510620253035 W i n ofexpasurc (yeorr1 KAEMIA MORTA. NE POISONIN( Apc (P-1 Fig 1 Leukaemia mortality rate in male workers at variour ages. Solid line indicatesmortality rate among workers in benzene cohort. Broken lme indicates values among male adults in big cities in China (dota obtainedfrom the National Control Ofice of the Ministry of Health. 1979). Fig 3 Relation of cumulative mortality of leukaemia with duration of exposure. Crosses indicate cumulativemortalit,; of leukaemia observed. Open circles indicate valuepstimatru by an orthogonal pol.vnomica1 curve of +y = 55.56 4.4471 x - 0.09248~' where y is cumulativemortality (1/105persons) and x is duration of benzene exposure (years). zene cohort (38.1 years when both sexes combined) was well described by an orthogonal polynominal than in the control cohort (46.7 years). The mortality for leukaemia increased in the age range 35-45 in the benzene cohort (fig 1). The average age of the workers when exposure began was 27-8 years. Figure 2 shows the relation between the start of exposure and the curve of the form: y = 55.56 + 44471 x - 0.09248 x2 where y is the cumulative mortality (1/105perso. I and x is the duration of benzene exposure (years). time of diagnosis (the latency period). Among the 30 Table 4 Benzene concentration in workplaces where cases cases of leukaemia in the benzene cohort the average of leukaemia were observed latency was 11-4years (minimum 0.8, maximum 49-5 years, respectively). The cumulative mortality of leukaemia was in proportion to the duration of No of cases Industry Lknzene concentralion (mglm' I exposure up to 20 years and then levelled off (fig 3), as I Laboratory in rubber factory 136.2(99.3-173.1) 2 Chemical reagent 253.9i20-440.2) 3 Paint 50.2(0-220) 4 Glue 100(30-1 50) 5 Paint 190.6(5-I2dO) 6 Paint 26.5 (0-250) i 7 Paint 15.5 (3-39.4) 8 Paint I5(10-20) 9 Paint 203.1 (25-500) IO Paint 239.3(0-4736) I I Paint 30.2(0-341.3) 12 Benzene refined 474.2(0-4024) 13 Chemical analysis 87.8(5.3-170.2) 14 Paint 1104.7(3.5-3826). 15 Cleaning 6.5f 1 + I 1.4) 16 Organic synthesis I5.4(l-4-50.0) 17. Paint 243.6(0-618) 18 Shoemaking 13.3. 19 Paint 19043(42-453) 20 Paint 468.1 f13.7-55b 21 Paint 301 (250-352) 22 Paint I18.9(31.3-206.4) 23 Paint 575.2(2.2-6102) 1 0 6 P 2 5 3 0 3 5 ~ 4 5 5 0 5 5 6 0 24 Paint producing 21.4(0.7-80.1) c -.-._. . . .Age ( y e a r s ) 25 Paint 26 Paint 96.8 68.2(54.7-138.8) Fig 2 Age at start of exposure, of diagnosis of leukaemia, 27 Organic synthesis 8.3(6.5-10). and latency of 30 cases of leukaemia. 0 indicates ages of the 20 initiation of the exposure and y ages at which diagnosisof 29 30 Paint Rubber Paint produang 37.1 (2.1-94'1) 86.4(4.9-I 16.2) 159.5 (10-733) leukaemia was established. Connectinglmes show period of latency. 'Single measurement. d were acute an Leukaemia in benzene workers 'ENE C O N C E N T R A T I O N IN THE $\ .ICPLACES W H E R E CASES O F L E U K A E M I A WERE OBSERVED Table 4 shows the benzene concentrations in the workplaces where the 30 patients with leukaemia had worked. The mean concentrations varied in a wide range of 10 to 1000mg/m3 but were mostly in the range 50-500mg/m3. LEUKAEMIA MORTALITY AMONG CASES OF BF -NE POISONING Ir. .< benzene cohort 196 cases of chronic benzene poisoning and aplastic anaemia were found; seven of the 25 patients with leukaemia had a history of chronic benzene poisoning (for criteria of the diagnosis, see materials and methods) or aplastic anaemia, or both, before being diagnosed as having a leukaemia. The leukaemia mortality among benzene poisoning cases was 700*70/100OOO person-years, and was 49 times higher than that in the benzene workers (14/100000). TYPES OF BENZENE LEUKAEMIA Among the 30 cases of benzene leukaemia, 23 (76.7%) were acute and seven (23.3%) chronic. The cases of acute leukaemia comprised 13 myelogenous, four monocytic, two myelocytic-monocytic. one erythromyelocytic, and three lymphocytic leukaemia. Chronic leukaemia included five with myelogenous leukaemia. one lymphosarcomatous leukaemia, and one unidentified case. Discussion Benzene is a well established human ~arcinogen.I~n addition, Goldstein et a1 and Maltoni etal have presented data suggesting that benzene may cause leukaemia in rodents.* About 289 benzene exposure related cases of leukaemia have been reported in Italy, China, France. Japan, the Soviet Union, Turkey, and the United States:" In the past 20 years several epide- logical studies have shown that long term Wi-,:ational exposure to benzene at high concen- ''tration is associated with the occurrence of various blood dyscasias including leukaemia. For example, Aksoy reported 34 cases of leukaemia among shoemakers in Istanbul in 1967-753; the incidence of leukaemia was 13/100000 in shoemakers by contrast !Qth 6/100000 in the general population. Rinksy etal Investigated two pliofilm manufacturing plants and found that the SMR for benzene leukaemia was 560.4 In I' -:cent study of a chemical plant where benzene .cn used as a material for organic synthesis DeLuuHe eta1 observed four deaths due to lymphoreticular cancers (2 leukaemia, 1 leukaemia multiple 127 myeloma, 1 multiple myeloma) in a 30 year follow up study of 259 male workers by contrast with 1.1 expected deathsL2; no quantitative data on benzene exposure were available, however. Arp et a1 reviewed the history of solvent use, raw materials specification, and the job description of 15 cases of lymphatic leukaemia in a rubber industry and comparing them with 30 matched controls found that patients with leukaemia had spent more time in jobs with potential exposure to coal tar based benzene and xylene.'3 Tsai etal by contrast found no deaths from leukaemia in a study of 454 workers who had been employed in a refinery from 1952 to 1978 and exposed to benzene either at 0.14ppm (median; refinery workers) or 0.53ppm (median; workers in benzene related ~ n i t s ) . 'I~n the present retrospective cohort study of workers exposed to benzene the mortality from leu- +kaemia was higher than that in the control cohort (SMR 574 for men women; 501 for men, 830 for women) being in line with the findings by Rinsky et ai. The mean latency period of benzene leukaemia was 11.4 years (range 0.8to 49.5) (fig 2). It is similar to the ''observation by Vigiiani and Saita of 1-46 years,' Goguel et al of 1-20 years, and Infante et 01 of 2-21 years.16 The average age of initial exposure to benzene among the cases of leukaemia was 27.8 years. When 11.4 years of latency is added the sum is about 39 years, which falls in the age range (35-45) of peak leukaemia mortality (fig 1). This may explain why the leukaemia mortality was highest in those aged 31-45. With regard to the benzene concentration to which patients with leukaemia were exposed, some authors have estimated that it ranged from 200 to 600ppm without exact detai1s.I' Recently, Rinsky etal reported that their patients were exposed to benzene at 16-100ppm, only slightly over the current OSHA standard of 1 0 ~ p mIn. ~the present study the benzene concentrations in the workplaces where the patients had worked were reported to be 10-100mg/m3 (about 3-300pprn) and mostly in the range 50-500 mg/m3 (about 16-160 ppm), the levels being similar to the observation by Rinsky et aL4 There remains a possibility that leukaemia may develop among the less heavily exposed workers. In fact in the present study three cases of leukaemia were associated with a benzene concentration of 10mg/m3in the workplace air even though the occupational hygiene data were not adequate for quantitative estimation of exposure intensity. In this connection Infante et alzo cited the fact that Kligerman et a1 (paper presented at the international symposium on sister chromatid exchange, Brookhaven, 1984) had detected a significant increase in sister chromatid exchanges (SCE) in peripheral lymphocytes and in the micronuclei in bone marrow erythrocytes of mice exposed 128 Yin, Li,Tain.Fu. Jin. Chen. Luo. Ye, Zhang, Wang, Zhang. Wu, Zhong to benzene at lOppm for only 10 hours. By contrast, Sarto er a1 found no significant increase in SCE in the blood of the workers exposed to benzene in the range of 0.2 to 12.4pm, although changes in chromosomal aberration were significant." Thus this possibility apparently deserves further attention. It should be noted that seven of the 25 patients had had a history of chronic benzene poisoning such as leukopaenia or aplastic anaemia, or both, before the leukaemia developed. The leukaemia mortality was as high as 700-70/100000 person-years in cases of chronic benzene poisoning. Aksoy also observed the development of 13 cases of leukaemia in 51 pancytopaenic patients with benzene exposure." Thus a close relation between leukaemia and benzene poisoning should be considered. Accordingly, it may be deduced that the prevention of benzene poisoning, is the best way to prevent benzene leukaemia. The way to monitor preleukaemic changes in benzene poisoning, however, remains to be established. This investigation was supported and organised by the Ministry of Public Health of the Government of China. We are grateful to Professor M Ikeda, Department of Environmental Health. Tohoku University School of Medicine, Sendai, Japan, for his interest in this work and his critical review of the manuscript. We thank S-X Yand, Y-Z Wang, W-Y Zhang, T-R Dai, X-J Chao, F-Y Jie, Y-H Huan, D-Y Ding, Z-L Jiang, C-Q Wu,J-S Zhou, and J-F Mu for participating in this study. Requests for reprints to: Dr Songnian Yin, Institute of Health, Chinese Academy of Preventive Medicine, 29 Nan Wei Road, Beijing, China. References 1 Vigliani EC, Saita G. Benzene and leukaemia. N Engl J M e d 1964,271372-6. 2 Ishimaru T, Okada H. Tomiyasu T. Tsuchimoto T, Hoshino T. Tchimaru M. Occupational factors in the epidemiology of leukaemia in Hiroshima and Nagasaki. Am J Epiderniol 1971;93157-65. 3 Aksoy M. Different types of malignancies due to occupational exposure to benzene. A review of recent observation in Turkey Environ Res 198023:I81-90, 4 Rinsky RA. Young RJ. Smith AB. Leukaemia in benzene workers. Am J Ind M e d 1981:2:217-45. 5 International Agency for Research on Cancer. Monographs mi evaluotion of the carcinogenic risk of chemicals to hum. Vol 29. Ben:ene. Lyon: IARC, 1982:9>148. 6 Yin S-N. Li G-L. Tain F-D. etal. Epidemiological study on relationship between benzene and leukaemia and other cancer. Chinese Journal of Industry Hygiene Ocrupational Disease (in press). 7 China national crireriafor diagnosis of beniene poisoning. Beijing: Ministry of Public Health of the Government of China, 1974. (In Chinex.) 8 Goldstein BD, Snyder CA, Laskin S, Bromberg 1, Albert RE, Nelson N. Myelogenous leukaemia in rodents inhaling benzene. Toxic01 Lett 1982:13:169-73. 9 Maltoni C, Conti B. Cotti G. etal. Experimental studie, 3 benzene carcinogenicity at the Bologna Inslitute of Onco. Am J Ind Med 1985;7:415-46. I O Yin S-N, Li G-L. Advance of studies on benzede leukaemia. Communication OfMedical Researrh 1981;11:5-7. (In Chinese.) I I Van Raalte HGS, Grasso P. Hematological, myelotoxic. clastoxic. carcinogenic and leukemogenic efTccts of benzene. Regulatory Toxicology and Pharmacalogy 1982;2 153-76. I2 Decoufle P. Blattner WA, Blair A. Mortality among chemical workers exposed to benzene and other agents. Environ Res 1983:30:16-25. 13 Arp EW, Wolf PW. Chcckoway H. Lymphocytic leukaemia and exposures to benzene and other solvents in the rubber industry J Ocrup M e d 1983;25:598-602. 14 Tsai SP. Wen CP, Weiss NS. Wong 0, McClellan WA. C in RL. Retrospective surveillance studies of workers in beii-ac areas of refineries. J Oecup. M e d 1983;25:685-92. I5 Goguel A. Gavigneaux A. Bernard J. La leucemics benzeniqua de la region Parisienne entre 1950 et 1965 (etude de 50 observations). Nouv Rev Fr Hemarol 1967;746>80. 16 Infante PF, Rinsky PA. Wagoner JK, Young W.Leukemia in benzene workers. h c e t 1977;ii:76-8. 17 Aksoy M. Dincol K. Erdem S, Dincol G. Acute leukemia due to chronic exposure lo benzene. Am J M c d 1972:5216&6. 18 Vigliani EC. Leukaemia associated with benzene exposure. Ann NY Acad Sri 1976:271:143-51. 19 Infante PF, White MC. Projections of leukaemia risk assc 'red with occupational exposure to benzene. Am J h i :ed l98s;7:403- 13. 20 Sarto F. Cominato 1. Pinton AM, era/. A cytogenetic study on workers exposed to low concentrations of benzene. Corcinb genesis 1984:5827-32. -. 21 Aksoy M. Malignancies due to occupational exposure 10 benzene. Am J Ind M e d 1985;7395-402. Does atop: animal alle om Fisons Occupatrc I