Document KRbbk57pgbbGYrBEBk7EvM5ow

COMMENTARY i Occupational Exposure to Benzene: A Review of Carcinogenic and Related Health Effects Following the U.S. Supreme Court Decision Mary C. White, YPH, Peter F. Infante, om,DR PH, and Ballur Walker, Jr., P ~ D , M?H The recent US Supreme Court decision (fndustdal Union Depastment v American Petroleum Institute, 48 USLW 5022,decided July 2, 1980) on the Occu- pational Safety and Health Administration's (OSHA)proposed standard for low- ering exposure to benzene in the occupational setting has been a topic of recent discussion in both the lay [Doninger, 1980: Fishbein, 1980: The New York Times, 1%0] and scientific media [Smith, 1%0].As a result a f t h i s decision, there appears to be some confusion about the actual toxicity and carcinogenicity of benzene. A plurality ofjustices in a 5 to 4 decision stated that OSHA had neither made nor rejected any factual determinations demonstrating "significant risks," to be defined by the Agency, at the current standard of loparts per million (pprn);nor had OSHA made or rejected any factual determinations of significant benefits from lowering the standard to 1 ppm. decision, however, s h u be taken to imply that adverse h benzene below the current 10D D ~ .In light of a possible misinterpretation Gf health effect data related to benzene exposure. we present here both a historical perspective on the current US standard and an updated review of the pemnent literature addressing the carcinogenic. mutagenic. and related toxic effect5 of benzene. PERSPECTIVE ON THE CURRENT STANDARD The current OSHA \tandard for occupational expowre to benzene, adopted in 1971 . is an &hour bme-weighted average ( T W A ) of IO part5 per million (ppm), with a n acceptable ceiling concentration of 25 ppm 129 CFR 1910.1OOO. Table 2-2). Excursions above the ceiling are allowed to a maximum peak concentration not to exceed 50 ppm Evidence for re& more th bv a)n IO minutes in an.y &. hour work period. W e n e S r e -ea sed risk of dev- inn leukemiq, In addition. benzene Office of Carcinogen Identification and Classification. Occupational Safety and Health Administration, U.S.Department of Labor. Washington. DC (M.C.W.. P.F.I.). Health Standards Programs.OccupationalSafety and Health Administration, U .S. Department of Labor, Washington. DC (B.W.Jr.). .Addre\\ rrpnnt requeyt\ to Mary C White. Occupational Safety and Health Administntion, US Department o f Labor. Washington, DC 202IU. Accepted for pubhca~ionDecember 2 . 1980. 0271-55&j6/80/0102-OU3sO3.50`F 19&0 Alan R. Lis, Inc. previously had been linked to other serious adverse health effects. including aplas- tic anemia, pancytopenia, other hematological disorders, and chromosomal aberrations. The primary route of exposure is thougftt to be through the inhalation of benzene vapor [IARC. 19741. although little information is available which adequately addresses the potential for benzene to be absorbed through the skin [NIOSH.19741. Consequently. in February 1978. OSHA promulgated a revised standard for occupational exposure to benzene [OSHA. 19781. This standard allowed for an &hour ume weighted average (TWA)of 1 ppm with a ceiling limit of 5 ppm. It was estimated that more than 35.000 workers were exposed to benzene at TWA concentrations greater than I .O ppm. The standard was based on a determination by OSHA that the availabkescientificevidence established that employ& exposed to benzene were at an elevated risk of developing leukemia, nonmal;gnant blood disorders and chromosomal damage. A lower court vacated the revised ( 1 ppm) standard, and the Supreme Court recently upheld the tower court's decision. As a result, the standard adopted in 1971 is currently in effect. BENZENE CARCINOGENICITY Epidemiologic Evld.nC0 J'he evidence in the 1977 OSHA benzene record celar- benzene is a human Ieukemppl;p, In making this determination, OSHA relied upon an evaluahon ot all the evidence and not on any oneparticular study. partic.ip.ants in the rulemaking for the most part did not~challLppeben y ~'seleuke- and -sneither did the d Court of Appeals for the Fift.h C.ircuit when it vacated the standard. Wit ' scientific communitv. there IS *-r bw instance, the International Agency for Research on Cancer [ 19791has classified benzene as a chemical for which there is sufficient evidence to support a causal association between exposure and cancer in humans. Numerous other scientific reports concur with this conclusion ICEQ. 1980:Cole and Goldman. 1Y7S; NIOSH. 1977: NTP. I%mO]. Two cohort studies have demonstrated an increased incidence of Ihkemia in workers exposed to benzene. The first is a study by Infante et a1 [ 1977ajof workers exposed tobenzenein theproduction of Pliofi1m.a rubberfilmmaterial.in twoOhio industrial facilities. There wa\ a paucity of information regarding atmospheric levels of benzene to which workers may have been exposed. bst the available data indicated that average benzene levels generally ranged from am. All white males who had been directly exposed to benzene at any time between I940 to 1949and who were alive on January 1, 1950 were included in the cohort. The vital status of these workers was determined through June 30. 1975. Causes of death were determined from death certificates. Medical records were also reviewed. Those benzene-exposed workers with unknown vital status. com- prising 25% of the total cohort, were assumed to be alive so that the relative risk of developing leukemia would be biased toward an underestimate. Observed deaths among the benzene-exposed cohort were compared with expected numbers of deaths calculated from both the general US white male population death rates. adjusted for age and calendar time period. and from the death rates of a comparison group of fibrous-glass workers employed in Ohioduring the same period of time. ~ ~ ~ E . r t p a a r e 23ts 0 ~ The investigatorsidentified a significantexcess of deaths from leukemia when compared to either the general US white male population (SMR = 507.7 observed deaths vs 1.38 expected, p less than 0.002). or to the fibrous-glass workers 3 (SMR = 473. 7 observed vs 1.48 expected, p less than 0.002). Subsequent to this initial report, the benzene-exposed population was fol- lowed further [Infante et al. 1977bl. As the vital status of workers previously assumed to be alive changed with the identificationoftheir deaths, the number of person-years of observation they could contribute to the cohort inevitably de- -creased. As a consequence, this reduction in the number of person-years of obser- vation necessarily resulted in a reduction in the number of expected deaths due to leukemia. Because acute myelogeno&&ukemiaand irs acute variants are the cell tmes of leukemia mosttxmuent~vassociaream6enzene5ex-posure, lntante~eat l I19771 - r r data 10 or- r to take into account me mtribution of .meeifiCEeu types of leukemia. Of the se\r e n e r v e d leukemia deaths. one w a s classified as chronic m y e n o u s leukemia and six as acute myelogenous or monocytic leukemia. The number of expected deaths from acute and monocytic leukemia was estimated on the basis of National Cancer lnstitute mortality rates for these cell types of leukemia [Burbank, 197 11. The total expected number of deaths from acute and monocytic- 1 * was calculated to be O.%. When compared to the SIX %served cases of acute myelogenous and m n ~ t i ~ l e u k e m itahi,s yielded an s % ! U m .mus 3- consiaerca to be conservanve IWrwb reasons. Pirst, me arates used for determiningthe expected number included cell types other than acute myelogenous and monocytic leukemias, such as acute lymphatic leukemia. ond. a 29 year-old cohort member, whose cause of death was listed as chronic iears of his initial exposure to benzene. Since there was s u d i X fr- acute myelogenous leukemia. A second cohort study ot -6mdles exposed to benzene in three chemical producuon areas ofa Michigan plant was c o n d u c t e d m t and his colleaguesat the Chemical Company IOtt et al, 19771. All individuals who began employment at any time b e t w x l W O and 1970 were included in the cohort The vital status of these workers was deterrmned throug-h 1973. Three leukemia case4 were observed arppne the cohort members; all were myelocyuc and two were classiried as acute myelocytic leukemia. Because one of these leukemia cases was coded on the death certificatTas having- died from bronchopneumonia. leukemia cases was generated on the basis of .th.e expected number of trom VIe i n u b ffational Cancer Survey rather than mortality data. Using this analysis. the three myelocytic leukemia cases were reported to be significantly in excess of the expected number, 0.8(p less than 0.047)I. All three leukemia cases were exposed to a t m o w beNene concentrations averacginn less than . In addition to the three leukemia cases. two deaths due to anemia. one aplastic and one pernicious. were also observed among members of this cohort.* A&w SUtC-A-t 4- iants are more likely than other types of leukemia to occur in r e b n to benzene exposure I w t ein. 19771. However. the benzene-exposed populations have been 'On the hasir of the\e rewlt\. the D o w Chemical Companv 119771 initiated d global p o l ~ c yof reducing benzene expowre in I I \ oper,ition\ tu il ceiling 6 ~ I u to' f IO ppm 236 WLllr, Irfurc, 8Dd wlllrcr ofinsufficient sample size, and thereby ofinadequate sensitivity, todetect excesses in other types of leukemia that may not demonstrate a relative risk as high as myelomonocytic leukemias. When the expected numba of a specific%ell type of leukemia is less than one. as it was in the Infante et al[1977b] and Ott et al [ 19771 studies, only relative nsks that are of considerable magnitude will be recognized as significant. Nevertheless. several studies and case reports have linked various types of leukema to benzene exposure. Browning [ 1%51 searched the literature and found 61 reported cases of leukema among persons who had been exposed to benzene. The classifications of these leukemia cases were as follows: 6 acute myeloid. 1 subacute myeloid. 21 chronic myeloid, 7 lymphatic, 14 aleukemic. and 12 eryth- roleukemic. Inaddition. Vigliani and Forni I19761 stated that in Paris fro 1965.43 cases of leukemia had been identified in subjects with chronic benzene exposure; 23 were classified as acute leukemia, 13 were classified as chronic myeloid leukemia, and 8 were classified as chronic lymphocytic leukemia. Aksoy [ 19801recently described cases of various types of malignanciesamong 47 shoe workers chronically exposed to benzene and 16 persons employed in other industries where benzene had been used in Turkey. Of the 42 cases of leukemia, only 16 (38%) were acute myeloblastic leukemia. The other types of leukemia in descending order of frequency were: acute erythroleukemia, preleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, chronic myeloid leukemia, acute myelocytic leukemia and acute undifferentiated leukemia. In addition, malig- nancies other than leukemia were found among persons chronically exposed to benzene, including nine cases of malignant lymphoma, three cases of multiple myeloma and five cases of lung cancer. Ishimaru et al [ 19711conducted a study of 303 leukemia cases and 303 matched controls among adult survivors of the atomic bomb explosions in Hiroshima and Nagasaki. Japan. The risk of leukemia was found to be significantly higher among those employed in occupations where various solvents. including benzene. or medical x-ray were used as compared to tho\e without such exposure. The relative risk was 1.8 times higher for chronic leukemia and 2.9 urnes highefifor acute leukemia. -A t the OSHA benzene hearing i n 1977. some witnesses epidemiologic e;rs exposed to \tudies which failed benzene However. to in adlel toefctthaenseexsctuedsiseivs emceatnhcoedronlosikicamd ong. wo1r.kw- made it apparent that they could not be relied w o n for an ev of Dotential a d v e t s e s from occuDationa1 exposure to benzene. Specifically, the authors could not specify the proportions of workers in their study populations that ever had been exposed to benzene. Further, for those who may have been exposed, there was no knowledge of when their exposure took place. making an assessment of the adequacy of latency period difficult. if not impossible. to determine. In one such study, Thorpe [ 19741 analyzed deaths due to leukema among ] 38.000 employees of eight European affiliates of a major petroleum corporation. 1 Eighteen cases of leukemia between 1962 and 1971 were reported by company physicians in response to a questionnare. The author compared the 18 reported leukemia deaths wth a n expected number of ??.l3eukemia deaths. generated u4ing W H O age-\pecific mortality rate4 Prewmdbly because of inadequate I records, the author applied W H O mortality rates to the age distribution of the U K G--- I affiliate. Workers in the other European affiliates were assumed by the author to have the same age distribution as those in the UK.Thorpe concluded that no excess in leukemia mortality could be damonstrated among these employees. However, it is unknown exactly how many of these workers had a history of exposure to benzene. The number of persons potentially exposed to benzene was estimated on the basis ofjob assignments, but the author acknowledged that it was often difficult to distinguish exposed from nonexposed workers. Industrial hygiene measurements of worker exposure were generally not available. For a large number 4-of individualsknown to have died, the cause of Punnertnore. for thoseindividualswhose causes ofdeath were reported, there was no verification of cause of death. This is an important consideration because an individual with leukemia I& die from an&ther immediate causiS&ch as -an acute infectious disease, and the fact that the individual had leukemia may be overlooked when the cause of death is coded. These deficiencies preclude any judgment on the relationship of benzene exposure and leukemia from this study of Europeanaffiliatesaa major petroleum corporation. Nevertheless, some individuals[American Petroleum Institute, 19801 continue to cite this study as evidence of a threshold level for the induction of leukemia among workers exposed to benzene. Studios In Animals At the time of the lW7 OSHA benzene rulemaking, the evidence was not sufficient to demonstrate cancer induction in laboratory animals following expo- sure to benzene. A study by Lignac I19321 showed that 8 out of33 mice developed leukemia or Kundrat's lymphosarcoma 4 to 11 months after the first subcutaneous injection of benzene. Because no control animals were included in the study, no conclusions could be drawn from its results. Other attempts to induce cancer in benzene-exposed animals had been unsuccessful up until 1979. m c e the close of the record in the 1977 OSHA benzene rulemaking. two &independent laboratories have reported henzene-induced cancers in rodents. ioni and Scarnato [ 1979Jobserved a signiticant excess in Lymbal glahd tumors female Sprague-Dawley rats who were administered daily doses of 2$ mg/kg body weight benzene hy stomach tube (8132 exposed vs 0130 control, p less than 0.05).In C37BL mice exposed by inhalation to300pp 6 hours,day, 1; days/weekfor up to 16 months. Snyder et a1I19801 increase (p less than 0.005) in hematopoietic phomas. Thus. a statistically significant increase in tumors has been demonstrated in twodifferent species of laboratory animals. Sprague-Dawley rats and C57BL mice. following exposure to benzene. NONMALIGNANT BLOOD DISORDERS The most commonly reported, but not necessarily the most frequently occurring, adverse health effects associated with chronic exposure to benzene is an alteration in the levels of erythrocytes. leukocytes. or thrombocytes in the circulating blood IOSH.4. 19781. Pancytopenia is a term used to refer to a decrease in all three of these hematologic components. and the term i s frequently used inter- 238 WYte, Imfmte, ud WllLcr changeably with aplastic anemia. The relatively more frequent reporting in the literature ofcases of aplastic anemia than ofleukemia in association with benzene expasure may be a reflection of the shorter biological lag time associated with the clinical appearance of aplastic anemia as compared to the eventual clinical manifestation of leukemia. T h e incidence of these toxic manifestations of benzene exposure presumably is further underreported in more recent times as physicians are less likely to report blood abnormalities already known to be associated with benzene exposure. Numerous studies were included in the 1977 OSHA benzene record which showed Mood disorders among occupationally exposed workers and laboratory animals exposed to benzene. However. several issues remained unresolved at the close of the record. i benzene exposure. such as pancytopenia, may be seriously underestimated be- cause the possible importance of exposure to benzene may be overlooked [19771. OSHA concluded that the data available did not permit an accurate quantitative assessment of the morbidity or mortality from benzene-induced nonmalignant blood disorders. Second, the evidence in the record demonstrated no consensus of opinion as to whether benzene-induced nonmalignant blood disorders persist after cessation of benzene exposure. However, it is well recognized that a large number of patients with aplastic anemia die as a result ofthis disease. In 1977, 1,153 recog- nized deaths due to aplastic anemia (ICD no 284, 8th revision) occurred in the United States (US Department of Health and Human Services. unpublished). OSHA stated that i t was not appropnate to conclude that nonmalignant blood disorders would revert to the tndividual's normal value5 in all caw4 followng the cessation of exposure to benzene. b Finally, some hearing participants argued that a no-effect level for nonmalig- nant blood disorders could be established at an atmosphenc benzene concentration greater than 10 ppm. hecause they believed it was unclear what health effects occur below 20 ppm. After reviewing the evidence in the 1977 benzene record, OSHA I 19781stated that there was n o a l i g n a n t bone marrow toxicity can result from exposure to benzene above 25-40 ppm. Further, OSHA recognized thar Teveral studies repbrted blood abnormalities associated with benzene exoosurg IeTels below 75 ~ mat l,evels perhaps as low as 1OEm. Reasoning that a relatively higher dose would result in an increased nsk. that a lower dose would result in a reduced nsk. a nonmalignant blood disorders. CHROMOSOMAL ABERRATIONS The record for the 1977 OSHA benzene rulemaking included several report\ of chromosomal damdge in henzene-expoied Norken. both with and Nithout clinical symptom\. For example. Forni et al [ 1971bl performed chromosome ~ p . t k r l ~ t o B t B w a e239 studies on 34 workers in a rotogravure plant and 34 controls matched by w e and sex. Ten of the rotogravure workers had been exposed to benzene and tduene and the remaining 24 had been exposed to toluene only. The investigators reported a statistically significant increase in both stable and unstable chromosomal aberrations in the benzene-exposed group compared with either the controls or the toluene-exposed group. In another investigation by Forni et al [ 1971aI. 25 workers who had been diagnosed 1 to 18 years earlier as having chronic benzene poisoning were studied for chromosomal aberrations. At the time ofthe chromosome study, most subjects showed practically normal blood counts. Compared with matched controls, the former benzene-hemopathy cases had a signifEantly increased frequency of unsfable and stable chromosomal aberrations. Follow-up studies rew e d ageneraldecreaseia unstable chrqmosome aberrationsand a-pusistenceor increase i n stable aberrations over time. In addition, after theclosing of the 1977 OSHA benzene hearing record, Kiian and Daniel of the Dow Chemical Company's Bio-Medikal Research Laboratory released the results of a cytqenetic study of Dow employees exposed to benzene damage at low levels. S i m d et al IlWplpcrfOrrned a cytogenetic S exposed in a Fr c &posure&-nts w c r w . Atmospheric UD to 14 ppol.of 50 workers examined, 21 were considered tohave an increase in the number of chromosome fractures and 4 were considered to have a large number of various anomalies, although no control workers were examined. Hartwich and Schwanitz w2]studied 9workers who were exposed to ben6ze-nSe i stated L that the maximum worK. p.iace -0 n or ~3 ppm was never reached. ev Ut me 100 cells examined per worker, tre s no i t a ; p ranged from 8% to 12%. and averaged 10.4%. Concurrent controls were not examned. but the authors stated that the average aberration rate from studies by other investigators of blood donors was 5.1% Interpreting the evidence on chromosomal damage in both human and ex- penmental studies. QSHA stated that chromosomal damage represented an ad- verse biological event which may pose or reflect a potential health risk and as such, -must be considered in the larger realm of adverse health effects associated with benzene. OSHA did not actually link chromosomal aberrations with demonstrable adverse health effects. However, a large body of scientific data suggests that an increased rate of chromosomal aberrations is of serious concern since chromosomal abnormalities have been associated with at least one-half of all spontaneously aborted fetuses [Stein et al. 19751 and with several congenital syn- dromes that also show an increased risk ofmalignancy [Mulvihill, 19751. In addi- tion. chromosomal breakage. whether of genetic or environmental origin, has been search Laboratory r &entable .[Mulvihill. 19751. The ecen EPA t 11197913Haesal.t.h7Effects Re- and their occurrence IS^ often associated with cancer." HEALTH EFFECTS AT LOW-LEVEL EXPOSURE TO BENZENE In ruling on the evidence in the 1977 OSHA record demonstrating health effects at low-level exposure to benzene, the Supreme Court did not attempt to substitute its scientific judgment for that of the agency's. instead, the Supreme Court based its decision on legal issues involving the intepretation of the Occupa- tional Safety and Health Act of 1970(29USC 651et seq).-A cia- re s the evidg-e 1977 OSHA benzene record, as well as the .n_ewevi- t$- close o:teffecozd, reveals that there are data which demonstrate s e y a k e r s e h a e ects resilting from low-le-e to b- In the Ott et W d v FIR71, discussed in the secrion on epidemiologic *;- evidence of carcinogenicity,all threeindividuals diagnosed ashaving leukemia and the individual with the diagnosis d aplastic anemiahad worked i n jobs where benzene exposure was characterize I- increase in chromosomal aberrations among workers who had-been exposed to average benzene concentrationsof less than 10ppm[Holder, 19781. These findings were released shortly after the 1977 OSHA benzene record was closed, and there- fore could not be cited by OSHA in support of the recommended 1.O ppm standard. The results of this study were later published by Picciano [1979]. Data from cytogenetic studies on 52 benzene-exposed workers were compared with data from 44 pre-employment controls. The results showed that the percentage of workers who had cells with chromosome breaks was significantly greater for the benzene- exposed group (Chi-square = 10.24, df = 1, p less than 0.005). In addition, the percentage of workers who had both chromosome breaks and marker chromo- somes was ten-times higher among the benzene-exposed workers (Chisquare = 8.96. df = 1 , p less than 0.005). Plcciano later presented an analysis of the cytogenetic results by level of 3 4 r nonexposed penons. 2 1 q forpersonsexposedtolevelsup to l.Oppm.257 forpersonsexposedfrom 1.Oto2.5 ppm. and ??"rfor worker5 exposed to level\ from 3 5 ppm u p to 10 ppm Thus. data currently available demonstrate the induction of leukemia and C U F B t l e conUce W below 10ppm. THRESHOLDS FOR CARClNOGEMlClTY During the 1977 OSHA benzene rulemaking, the major dispute was whether or not a threshold level existed for benzene exposure in relation to leukemia. Some participants argued that in workplaces where an excess in leukemia was demonstrated among benzene-exposed workers. the atmospheric levels of benzene were several times higher than the current TWA of 10ppm. Furthermore. it was claimed that no excess in leukemia incidence had been definitely established among worker\ exposed to levels of benzene below 10 ppm. .- of a OSHA resDondcd suistancc has been to thaes-eoc established j. . t once the c a r c i .n. w dcd by an in The epidemiologicstudies y c n e w =re! ucited in s stated, were charac- tenred by a number ef flaws in both design and methodology. OSHA concluded that it was not possible to demonstrate a threshdd or to establish a safe level for exposure to benzene. As a result, OSHA stated that it was its belief that occupa- tional exposure to benzene at low levels poses a carcinogemc risk to workers. Whether or not safe or no-effect levels can be set for exposure to carcinogens was one of many important issuesdiscussed during OSHA's recent rulemaking on the identification, classification, and regulation of potential occupational carcine gens, referred to as the OSH-ACancer Policy L19801. During the lengthy rulemaking proceedings, a numbeF d witnesses expressed strong support for OSHA's pro- posed position that threshold, safe, OF neeffect levels cannot be established for carcinogens. The followingcomments summarize the opinions expressed by most of the witnesses who participated in the proceedings. Dr.Marvin Schneiderman of the National Cancer lnstitute stated, 'There is as yet no evide-ver that thresholds exist for the irreversible process of carcinogenesis. . . . Unless some new, compelling information appears, the con: cept of threshold serves no useful purpose in regulatory decisions.'= Matthew After reviewing all bf the evidence in the record for the Cancer Policy, OSHA concluded that no threshold levels could be established for carcinogeps. Specifi- cally. OSHA concluded that there was substantial evidence in the record which demonstrated that. 1) carcinogenic procesces differ from other typec of toxic effect\ in being irrever3ihle and onginatinp from minute foci or even from single cells. so that there is no theoretical reason to expect a threshold even for an ~ndividual2. ) the vanous defense mechanisms advanced as theoretical bases for thresholds, such as DNA repair, detoxification. and immunosuppression. are unlikely to be efficient enough to ensure a threshold: 3) even if thresholds do exist for individual humans, it would not be expected that such thresholds exist for populabons of exposed persons due to individual human variatlons in susceptibility, and the potential additive and synergistlc effects wth other carcinogens. intrinsic. and extrinsic factors: 4) the evidence presented for the existence of thresholds for specific carcinogens was inconclusive or erroneous: and finally. 5 ) no reliable method is known today for establishing a threshold that could apply to an exposed group of workers. Thus. OSHA's earlier conclucion could be established fpr &ne exposure i s wpported by the consensus of the scientific community. ar d- by rne-vp -ve OSH A record for the 242 WUte, I m f ~ t eu, d W a n CancerPolicy. Furthermore,the earlierpositionOSHA took concerning benzene is consistent with the conclusions drawn by the Agency after consideration of all 4 evidence in the record for the Cancer Policy. - REFERENCES Aksoy. M ( 1980) Dtfferent types of malignancies due to occupational exposure to benz- Review of recent observations in Turkey Env Res 23 181-190 Amencan Petroleum Institute ( 1980) Oral testimony before the Environmental Protection Agency. August 2 I . Docket no OAQPS7SL3. Exhibit no IV-F-9 Washington DC US Environmental h o t e m o n Agency Qiowning. E (1%5) 'Toxicity and metabolism of mdustnal solvents '' New York Elsevier Scientrfic -4: Publishing Co p 3-6.5 Bwbank. F (19771) N a n Cancer lnst Mogogr (no 33) Washington DC. US Department of Health, T J3ucatmn and Welfare p 523 Cale. P and Goldman. M B ( 19751. Occupation. In Fraumni JF ted) "Persons N hi& nsk of cancer An approach to Cancer diology and control '* New Yo&. Academic Press Inc. pp 167-184 Councll on Environmental Qualily ( 1980). "Toxic chemicals and public protection." Washington. DC. US Government Printing OPTice. p 157 Dorungcr. D ( 1%0) Defeat in benzene exposure case Nodeath knell to OSHA standard. National Law h m a l 326-27 Dow Chemcal Company ( 19771. Benzene ceiling level lowered to ten ppm. Midland, Michigan: D o w Today, No 41. Fishban. G (1980 The Supreme Court's benzene decision strikes at basic public health prinicples. Occup Health Saf Letter IO 1-3. Forni, AM: Cappelli~A: Pacifico, EandVigliam, EC(19718).Chromosomechangesandtheirevolution in subpcts wth past exposure to benzene. Arch Environ Health 23:38S391. Forni,AM. Pacifico. E and Limonca. A (1971b). Chromosome studres in workers exposed tobenzene or toluene or both. Arch Environ Health 22:373-378 Girard. R: Mallein, ML. Be~tholonJ.: Coeur, Pand Evreux. J-CI(1970).Study ofleukocytlc alkaline phosphatase and of the karyotype in workers exposed to benzene. (French) Arch Maladies Rofess 3I 31-38 Goldstein. BO(19771 Hematoxicity in man In Laskin Sand Goldstein BDfeds) A critical evaluatlon of benzene toxicity Subnutted on behalf of the Amencan Petroleurn Institute Docket no H-059. Exhibit no 4 3 B CIS Depi of I-dhor Occupationdl Safety d n d Health 4dministration Wdshingron DC pp 1 1 2 - 3 4 Hartwick. G dnd Schwaniu. CJ ( 1972) Chromosome studies after chronic exposure to bewol (German) Dtsch Med Wochcnschr 97 45149 Holder BB ( 1978) Cyrogenetic \ t u & of workers expmed to benzene in the Texa< division of Dow Chemical 1 7 4 bk DJ Kilidn and R1. Daniel Letter (M'irch 1 ) to PF lnfdntc. NlOSH Infante PF R i n k \ \ R 4 U'igonrr J K m d Young RJ f IQTa) Leukderniciin hen7ene worken I-dncet I9 J u l y ) pp 76-7X Infanre.Pf-. Rinsky.KA. Wdponer.JKand Young. RJ(I977b) Letrertotheeditor Lancet(22Octoberi pp 868-869 International Agency for Re\earch on Cancer 19741 Monographs on the evaluation ofthe carcinogenic nsks of chemicals to man (no 7) Lyon. pp 203-221 International Agency for Research on Cancer f 1979) Monographs on the evaluation ofthe carcinogenic nsks of chemicals to man ~cuppl I ) Lyon. p 24 ishimdru. T. Okada. H Tomiyasu. T. Tsuchimoto. T Hmhino. T and lchimaru. M ( 197 I ) Occupational factors in the epidemiology of leukemia in Hiroshima and Nagdsaki Amer J Epidem 93 157- 165 Jandl JH 1977) A proposal for d program for medical surveillance to detect earlv and reversible change\ cawed by occupational exposure to benzene Submtted on behalf of Organization Resources Counselors. Inc Docket no H-059.Exhibit no 217-34. US Dept of Labor. Occupa- tional Safety and Health Adminiwation. Washington. 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