Document RJvYjnq8DELQ46Z5GEx2Z6yKa

BENZENE IN FLORIDA GROUNDWATER - AN ASSESSMENT OF THE SIGNIFICANCE TO HUMAN HEALTH by John E. Davies, M.D., M.P.H., M.R.C.P. Professor ana Chairman of the Department of Epidemiology and PudIic Hea1tn University of Miami School of Medicine Miami, Florida and RoDert S. Levine, M.D. Associate Professor Department of Epidemiology and Pud 1ic Hea1th University of Miami School of Medicine Miami, Florida Prepared for American Petroleum Institute Wasnington, D.C. June 10, 1986 SAL 000002666 HUMAN HEALTH EFFECTS OF BENZENE Introduction Benzene has long been identified as a hazardous toxic agent. Both acute and chronic effects from nigh exposure may be severe, but there is consid erable debate about the minimum level of safe exposure. The present report is a review of literature concerning reported human health effects of ben zene. Both acute and chronic toxicity are covered. With respect to the latter, hematologic, cytogenetic and other potential hazards are identi fied. Whenever possible, the group of persons included in the study are described as well as the documented exposure assessment. Acute Toxicity Acute accidental benzene poisoning has occurred both at work and in the home. Aaditionally, intentional benzene poisoning has been reported as a result of "glue-sniffing" among adolescents. Early symptoms of benzene toxicity include irritation of the conjunctiva and respiratory tract, malaise, nausea, vomiting, headache, and the feeling of exhilaration (Drozd and Bockowski, 1967). Benzene is lipid soluble. It is pharmacologically classed as an anesthetic although it is no longer used because of its tnerapeutic index (Winek and Collom, 1971). If exposure is severe, a deep anesthesia may be produced with resultant narcosis, coma and death from respiratory arrest. It has also been suggested (Von Oettinger, 1952) that severe, acute benzene poisoning may result in direct myocardial damage. Gerarde (1960) sought to estimate the levels of exposure associated with particular benzene effects. It was noted that 19,000 to 20,000 parts per million (ppm) for 5 to 10 minutes would be fatal; 7500 ppm for 30 minutes would be dangerous to life; 1500 ppm for 60 minutes would produce serious symptoms; 500 ppm for 60 minutes would produce symptoms of acute poisoning; 50-150 ppm for 5 hours would produce headacne, malaise and weakness; 25 ppm for 8 hours would have no effect. The National Academy of Science (1976) indicated that exposure at the level of 25,000 ppm would be rapidly fatal. Snyder (1984) emphasized that mild central nervous system effects appear to be rapidly reversible following cessation of exposure, that there is no evidence that these effects result in chronic brain damage, and that the effects appear to be concentration dependent since lower levels of benzene do not seem to elicit severe responses no matter how long the individual is exposed. SAL 000002667 Chronic Toxicity -2 A. Hematotoxici ty Nearly ninety years have passed since Santesson reported, in 1897, that 9 persons using benzene in the production of bicycle tires devel oped aplastic anemia. The first report associating leukemia with ben zene exposure occurred in 1928 (Delore and Borgomano). As noted by Goldstein (1977) a major problem in understanding human hematotoxicity to benzene is that exposure has usually occurred to a mixture of vola tile compounds, rather than to benzene alone. On the other hand, the association between hematopoietic disorders and benzene exposure has been relatively strong, there has been an apparent lack of similar as sociation with other known volatile agents in comparable occupational settings, outbreaks of hematotoxicity seem to nave been abated in in dustries where benzene has been replaced, the association has been re produced in many occupational and non-occupational exposures through out the world, and toxicity in animal studies has been shown to produce bone marrow effects when benzene has been the sole experimen tal agent. Today, the primary questions concerning hematotoxicity concern the smallest amount of benzene which is required to produce an adverse effect. Aplastic Anemia/Pancytopenia. Pancytopenia may be defined as a decrease in circulating erythrocytes, granulocytes, and platelets. In very severe cases, the decrease in these three blood cell counts is accompanied by a corresponding de crease or absence of their precursors within the bone marrow, and a diagnosis of'aplastic anemia is made. Just as aplastic anemia may represent a highly severe portion of continuum of changes which may affect the bone narrow due to benzene toxicity, unicellular cytopenias may represent less severe forms of a pancytopenic effect. Table 1 presents a review of 72 reports, dating from 1897 to the pres ent, which deal with benzene associated pancytopenia and aplastic anemia. The table outlines the number of cases involved, whether or not an occupational association was found, the nature of the occupa tional and/or non-occupational exposure, and the exposure assessment technique which was used. Nearly all of the reports deal with occupational exposures. Among those reports for which exposure assessment methods are available, qualitative associations or a general indication of the number of years of exposure dominate, particularly prior to 1965. Among the in vestigations in which a case of aplastic anemia or pancytopenia was detected, the lowest absolute level of benzene reported is 15 ppm (Kliche, 1969). Workers in this study, however, were on the job for an average of 17 years. A somewhat lower minimum level of exposure, 11 ppm, was found by Goldwater and his colleagues (Goldwater, 1941; Goldwater and Tewksbury, 1941; and Greenberg, e_t al_., 1939), in their evaluation of over 300 rotogravure printers in New York. There, a change in the printing process had led to the exposure of workers at levels of benzene ranging from 11 to 1060 ppm for periods ranging from six months to three years. Significant cytopenias were found among 23 of the workers, and six required hospitalization. SAL 000002668 -3 As noted by Snyder (1984), these studies are particularly convincing with respect to a causal relationship between benzene and pancytopenia due to tne many different work settings and different countries invol ved where the only common thread appears to nave been benzene. Addi tionally, the studies of Aksoy, et aK in Tjrkey (1971, 1972, and 1976), temporal relationship between the use of benzene and the out break of hematologic toxicity in leather workers was established. Specifically, in 1971, 51 of 217 apparently healthy workers were found have hematologic problems, including six workers with pancytopenia. The exposure in these cases was estimated to have been from 30 to 210 ppm of benzene, for three months to 17 years. In 1972, Aksoy's group cited 32 cases of significant aplastic anemia in workers exposed to benzene for four months to 15 years at exposure levels ranging from 150 to 650 ppm. While tending to support the causal nature of an association between benzene and pancytopenia, however, neitner the positive reports dis cussed above nor the negative ones (notably those of Shima, 1975; Townsend, 1978; and Pagnatto, 1979) have been able to establish a low er level of exposure below which cytopenic effects are not observed. A more direct approach to this question has been taken by Doskin (1971) and Chang (1972). These studies were described in detail by the Environmental Protection Agency (1978), and were summarized by Snyder (1984). In Snyder's summary, it is noted that many details as to exposure are not given in either of these two studies. Specifical ly, Doskin (1971), working in the Soviet Union, studied 365 workers who had three years of exposure in a new chemical factory. Serial hematologic studies were done on exposed workers as well as a control group. 3enzene exposure levels are expressed in terms of the maximum allowable concentration, 5 ppm. Benzene exposure exceeded this level by two to eight fold in 64? of tne measurements during the first year of the factory's operation, 37? in the second year, and 3? in the third year. The decrease in benzene levels was paralleled by the decline in the number of workers with hematologic abnormalities. It was concluded that exposure of workers to concentrations of 10 to 40 ppm of benzene for less than one year may produce mild cytopenic effects. Detailed information concerning the benzene monitoring system which was used and the actual levels of benzene recorded, however, were not documented in the report. Chang (1972) studied 119 workers exposed to benzene in an unspecified Korean worksite. Twenty-eight of these workers experienced hematologic problems, including 21 with anemia, 2 with leukopenia, and 5 with both. A graph was presented whicn plotted each of the affected individuals in terms of duration of work (on the abscissa) and level of benzene exposure (on the ordinate). Based on this plot, an exponential function was obtained which implied a "threshhold" of 10.0 ppm for cytopenic effects. However, among the 18 workers exposed to 10 to 20 ppm of benzene in the study, no hematologic toxicity was observed. As noted by Snyder (1984) a major problem in understanding this study is the lack of information about the definition of work exposure confidence concentrations for individual employees. SAL 000002669 Leukemia As is true for pancytopenia, tne association of benzene with leukemia has a long history. Summarization of this history has been complicat ed by the fact that hematologists differ in how they define leukemia subtypes. There are differences not only in terms of the evolution of criteria over time, but also because standards differ in different countries. Nosology is particularly important in leukemia because there are major differences between the various subtypes in terms of the frequency of occurrence, the clinical course, the prognosis, and possibly the etiologic mechanism. In summarizing the literature for tne present report, the classification as developed by Goldstein (1977) is used. Leukemia is defined as a neoplastic disease with increased numbers of white cell or white cell precursors in the blood or bone marrow. Leukemias are usually subdivided depending on whether they are acute or chronic and in terms of the cell type involved. Acute myologenous leukemia is the commonest form of adult leukemia, and is the form of this disease that has been most frequently related to benzene. In this disease, there is a proliferation of cells which are morphologically related to the normal myeloblast, which is the precursor of granulocytic blood cells. There are several variants of acute myeloblast leukemia, the one most frequently reported in association with benzene being erythroleukemia. Acute myelomonocytic leukemia, in which the precursor is a myeloblast which has the morphological appearance of a monocyte, and acute promyelocytic leukemia, morphologically a somewhat more mature leukemic cell, have also been associated with benzene, but to a lesser extent. True monocytic leukemias are rare, but have also been associated with benzene exposure. Another uncommon form of acute leukemia, usually called stem cell leukemia, is defined by proliferation of very immature bone marrow precursor cells. Chronic myelogenous leukemia and possibly related diseases, including essential thrombocytnemia, myelofibrosis with myeloid metaplasia are often lumped together unaer the heading of myeloproliferative syn drome. This reflects their presumed origin in the same precursor cell. Controversy persists, however, concerning the relationship of these disorders to each other. Lymphocytic leukemias are also classified as acute and chronic. Acute lymphoblastic leukemias is the commonest form of childhood leukemia. Chronic lymphocytic leukemia usually occurs in late adult life where it is often slowly progressive and not a cause of death. Studies relating benzene exposure to leukemia are summarized in Table II. As noted by Snyder (1984), tne support that these case reports give to the idea of a causal relationship between benzene and leukemia is only partly due to the number of cases involved. With respect to acute myeloblastic leukemia, the relatively common finding of a worker with aplastic anemia associated with benzene exposure who passes through a preleukemic phase into frank acute leukemia (Aksoy, et al., 1972; 1976; Girard and Ravol , 1970; Mallein, el al., 1971; ancfTareef, et al., 1963) is especially impressive. It is also of note (Snyder, T?3TF that tnere is a relatively high frequency of association between SAL 000002670 -5 ery tnroleukemia and benzene exposure since tnis is a relatively rare variant of acute myelogenous leukemia. As was true with respect to pancytopenia and aplastic anemia, further support for the association between benzene and leukemia is provided by the diverse occupational and geographical settings from which these reports originate. Despite the diversity, benzene seems to be the common thread. As regards chronic myelogenous leukemia and its possibly related dis orders including essential thrombocythemia and myelofibrosis with mye loid metaplasia, there are scattered case reports in the literature, but they form a less impressive body of evidence than the group of studies relating benzene exposure to acute myelogenous leukemia. There are only a few scattered reports relating acute lymphoblastic leukemia to benzene. The same is generally true for chronic lymphocytic leukemia. The strongest support for an association between benzene and chronic myelogenous and/or chronic lymphoid leukemia comes from France. Specifically, Goguel, et al., (1966, 1967) reported 50 cases of leukemia in benzene workers near Paris between 1960 and 1965. Among the 44 new cases in this group there were 13 with chronic myelogenous leukemia, 8 with chronic lymphoid leukemia. The relatively high proportion of these types of leukemia, however, have not been replicated in other case series. While case reports and case series' can provide circumstantial evi dence of an association between an exposure of interest (in this case benzene) and a particular disease, such investigations cannot provide a scientific test of the nypothesis that the exposure of interest is associated with increased risk of the disease. Such hypothesis test ing is in the realm of analytic epidemiology. Such studies have been done among shoemakers in Istanbul, in the rubber industry, in the printing industry and in the petroleum and petro-chemical industry. Additionally, a case control study has been done among patients with blood diseases in a hospital in Lyon, France. In general, while these studies tended to support the idea that exposure to benzene is causal ly related to the occurrence of leukemia, many of the investigations have been severely criticized. Controversy has been particularly strong regarding the low limits of benzene exposure which may be asso ciated with the development of leukemia. A specific discussion of these studies follows. Aksoy and coworkers reported on leukemia among workers in small shoemakeing shops in Istanbul. Between 1955 and 1960, a solvent with high levels of benzene was introduced into the Turkish shoe industry. The first cases of aplastic anemia were observed in these workers in 1961, and leukemia appeared in 1967 (Snyder, 1984). Between 1967 and 1975 among 28,500 shoemakers in Istanbul, the estimated incidence of leukemia was estimated to be 13 per 100,000 per year in contrast to the incidence in the general population which was estimated to be 6 per 100,000. The concentration of benzene in the air of the workrooms of the shoemakers was estimated to be 150 ppm, and the exposure had lasted from four months to 17 years (Aksoy and Erdem, 1969). Benzene was banned as a solvent in 1969, and tne incidence of SAL 000002671 -6 leukemia, after peaking in 1973 decreased in 1974 and 1975. No cases were reported in 1976, 1977, or 1978 (van Raalte and Grasso, 1982). Snyder (1984) noted several methodologic shortcomings in Aksoy's work. Specifically, Snyder pointed out that the definition of occupation used for workers with leukemia differed from that used for the offi cial records. It was possible that a worker with leukemia was called a shoe worker whereas the same person appeared on the official record as having anotner occupation. Additionally, there was no follow-up of the 28,500 workers exposed to benzene, and it was possible that some cases of leukemia were missed. Further, the stated incidence rate of 6 per 100,000 per year for the general population was for an unknown location and an unknown time, and no age standardization was done in making the comparison between the incidence rate for the general popu lation and that for the shoe workers. Finally, the exposure levels reported by Aksoy and co-workers represented occasional random mea surements taken in what was in essence a cottage industry. Several cohorts of rubber workers have been studied including investi gations Pagnotto a_h ( 1961, 1979); McMichael et al. (1974, 1975, 1976); Andjelkovic et aj_. (1976, 1978); Monson and flakano (1976.); and Infante et al_. (1977T. These investigations have been summarized and critically" reviewed by van Raalte and Grasso (1982). In their review van Raalte and Grasso note that Pagnotto et aU (1961) performed a survey in a rubber coating industry where a benzene worker had died from panmyelophthisis. In a follow-up study 18 years later (Pagnotto e_t aK 1979), 38 workers who were exposed for one to 24 years at a level of 10 to 50 ppm (PWA) with snort term peaks which were higher, tnere was no occurrence of either blood dyscrasia or leukemia. In the study by McMichael et al. (1974) a three-fold excess mortality from leukemia was found. Though the workers exposed to solvent had a seven-fold excess of death from lymphatic leukemia with six of eight deaths resulting from chronic lymphatic leukemia. In contrast, only a two-fold excess mortality was detected for myeloid leukemia. Subse quent studies by this group confirmed the excess risk of leukemia among solvent exposed workers. An historic-prospective study in a co hort of ruober workers over the period 1964 througn 1973 was done by Andjelkovic et a]_. (1976). While increased risks for neoplasms of the hematicpoietic and lymphatic systems were found for white males, white females did not experience excess mortality. Wolf et al. (1981) were noted to have performed a case control study involvmg"T2 workers with leukemia which had occurred between 1964 and 1973 in four rubber and tire companies with moderate levels of benzene exposure. While in creased risk for lymphatic leukemia was identified, no increased risk was detected for myelogenous leukemia. Monson and colleagues (1976, 1981) reported on mortality among 29,087 men and women who had worked in a rubber plant at least two years within the periods from 1940 through 1974 and 1974 tnrough 1978 respectively. In both instances an excess mortality from leukemia was found. Van Raalte and Grasso were particularly critical of the studies per formed by Infante and co-workers in the rubber industry. In 1977, SAL 000002672 -7 Infante et a_K reported a five-fold increase of all leukemia and a ten-fold in the combined incidence of myeloid and monocytic leukemias. It was stated that 'the benzene levels themselves were generally below the limits recommended at the time of their measurements,' (referring to threshold limit values in force at the time exposure 100 ppm in 1941 to 10 ppm in 1971) and that exposure levels from 1969 onward were, 'in most instances ranging from 0 to 10 or 15 ppm' (van Raalte and Grasso, 1982). This statement appeared to be contradicted by Infante (1977) during OSHA benzene hearings in November and December of 1977. Specifically, at the hearings it was indicated that the leukemia cases were more probably related to unknown but apparently quite high levels (in excess of 100 ppm) of benzene exposure. In 1981, Rinsky et al^. published a followup to Infante's 1977 report. The identical cohort was used in the followup study but it was based upon 98$ vital status identification of the study group versus 75$ in the 1977 report. There were seven deaths due to leukemia among 748 workers who had at least one day of exposure to benzene between 1940 and 1950. The leukemia cell types involved were myelocytic or monocytic. In contrast, to the seven cases identified in the followup study comparable United States death rates standardized for age, sex, and calendar time period were expected to yield only 1.25 leukemia deaths. This Standardized Mortality Ratio (SMR) is equal to 560, p < 0.001. The mean duration of benzene exposure in the cohort was less than one year. For workers exposed to benzene for five or more years leukemia deaths produced and SMR of 2,100. Four additional cases were excluded from the analyses. These included a 67 year old ran with a latency for acute myelogenous leukemia of 37 years, an individual who was among salaried employees not in the original cohort, an individual with acute lymphocytic or aleukemic leukemia and an individual who was diagnosed by a hematologist as having acute myelocytic leukemia but whose death certificate listed the cause as aplastic anemia. While Snyder (1984) felt that Rinsky's investigation indicated that benzene is a human carcinogen at levels not greatly above the current legal standard, van Raalte and Grasso (1982) advanced an argument which reached the opposite conclusion. Specifically, van Raalte and Grasso noted that one of the cases in Rinsky's group of seven was a worker with chronic myelogenous leukemia which had developed after only one month of exposure to benzene. This is at variance witn most clinical experience and suggested that other factors besides benzene may have been involved. Additionally, all cases included in Rinsky's group of seven occurred between 1950 and 1961, and the only exception among the total of 12 cases identified was that worker for whom the period of latency was 37 years. Further, van Raalte and Grasso pointed out tnat there were no new cases at all in employees who were first exposed after 1951. On the contrary, the period of exposure for all cases started in the first 13 years since the plants opened, that is from 1937 through 1950. Moreover, with the exception of the aforementioned unusual case of chronic leukemia with only one month of exposure, the two cases witn the most recent onset had the shortest latency period, three and one-half and four years respectively. In other words, patients exposed to higher concentrations of benzene have SAL 000002673 -8 a longer latency. This, they argue is inconsistent with both general clinical experience and experimental precedent. Finally, all of the cases in Rinsky's primary set of seven had a latency period of less than 22 years. Since the plant closed in 1976, there were only two possible (or suspect) cases noted in 26 years of employee exposure be tween 1950 and 1976 plus five subsequent years of followup, through 1981. Even granting these two cases, van Raalte and Grasso feel that Rinsky's data shows a decline in the incidence of leukemia which parallels the decline in benzene exposure at the factory's in ques tion. Far from indicating an association between leukemia and low level exposure to benzene, van Raalte and Grasso suggest that Rinsky's data is more consistent with the interpretation that low levels of benzene exposure show no excess in leukemia mortality. Turning to studies in the printing industry, Lloyd, et al. (1977) found an increase in the number of deaths from leukemia among printing pressmen, eight observed versus 5.1 expected. Green, et al. (1979) performed a cancer mortality among male U.S. Government Printing Office employees who had worked during tne period January 1948 through April 1977. A significantly higher proportion of deaths were related to multiple myeloma, leukemia, and Hodgkin's disease. Although the excess leukemia deaths occurred primarily in binder's whose benzene exposure was ended in the early 1960$, there was little or no change in leukemia mortality after the discontinuance of benzene. As such, the low level exposures to benzene may not have been associated with an excess incidence of leukemia (van Raalte and Grasso, 1982). Paganini, et aK (1980) performed a mortality study in Los Angeles of 1,361 web pressmen with one or more years of exposure during the period 1949 tnrough 1965. Seven cases of leukemia were observed versus 2.8 expected in a comparable U.S. white male population. Six of the seven cases were of the myelomonocytic type. Additionally, myelogenous leukemia was mentioned in a secondary role in one case and another man had myelofibrosis (van Raalte and Grasso, 1982). As regards the petrochemical industry, Ott, e a_K (1978) and Town send, et_ aU (1978) performed a mortality study of 594 workers invol ved in three production areas on or after January 1, 1940 through Jan uary 1, 1974. Because of limited information available regarding the work place exposure assessment was limited to data collected between 1953 and 1972. During this time the time weighted average exposure to benzene was estimated to be generally less than 10 ppm although some exposures in excess of 30 ppm occurred including occasional higher values with a peak of 937 ppm. Among all workers studied, there were 102 deaths versus 128.2 expected on the basis of age-time specific rates for white males in the United States. There were two deaths from leukemia while 1.0 was expected. A tnird death occurred and was attributed to pneumonia altnough the individual had acute myeloblastic leukemia. Both van Raalte and Grasso (1982) ana Snyder (1984) point to the relatively small size of this study population in suggesting that the data are insufficient to provide a reliable and independent estimate of the relationship between benzene and tne risk of develop ing leukemia. SAL 000002674 -9 In addition to the mortality studies, Townsend, e_t al_. (1978) perform ed a health examination study among 282 workers from this cohort. There was no indication of adverse benzene effects in this group. Another investigation, by Thorpe (1974), involved a much larger population, 38,000 persons employed or on pension from a large oil company during the period from 1962 tnrough 1974. Over a ten year period, 18 cases of leukemia were recorded versus an expected value of 23.2. Precise statements of exposure levels to benzene were unavailable. Several other investigations in the petrochemical industry include studies by Theniant and Goulet (1979), Hanis, et al. (1979), Thomas, et aj_. (1980) and Rushton and Alderson (1980, lWlTT In only one case was an excess of deaths associated with leukemia demonstrated. Theniant and Goulet (1979) studied the mortality of 1,205 men employed for more than five years in a Canadian oil refinery in East Montreal between 1928 and 1976. Three deaths from leukemia and lymphoma were identified from death certificates versus 2.36 expected. Hanis, e_t aj_. (1979 ) studied employees of Imperial Oil Company exposed to petroleum products during 1964 to 1973. The mortality of the exposed group was compared with that of a non-exposed group concerning cancer of the lymphatic and hematopoietic systems seven deaths were identified in the exposed group and 15 in the non-exposed group. Thomas, et al_. (1980) studied 3,105 union members in Texas who worked from 1947-through 1977. Although the study was small, an increased relative frequency of leukemia and multiple myeloma was demonstrated among white males with more than ten years of membership. Rushton and Alderson (1980, 1981) studied 35,000 workers with more than one year of service at eight oil refineries in the United Kingdom between January 1950 and October 1975. There were 30 cases of leukemia identified, but this was relatively less than would have been expected in comparison with national rates. Additionally, these authors formed a case control study on the same population using two sets of refinery controls per case. One set of controls was matched for refinery and year of birth while the other was also matched for length of service. Industrial hygienists classified exposure as low, medium or high. In no case was a statistically significant association demonstrated between benzene exposure and leukemia, althougn the risk of medium plus high exposure workers taken together relative to the risk of those with low exposure approached statistical significance at the level of p - 0.05 (van Raalte and Grasso, 1982). SAL 000002675 -10 C. Otner Hematologic Diseases, In addition to pancytopenia/aplastic anemia and leukemia, several other hematologic problems have been associated with benzene. At present, however, the associations have been noted only at the level of case reports and case series. Aksoy (1975) reported a case of paroxysmal nocturnal hemaglobinuria in a 74 year old male witn a ten year of benzene exposure in a dye factory. An additional case is noted in this paper but the details are not given. Croizat, et al. (1943) also has reported a case of paroxysmal nocturnal hemagTobinuria associated with benzene poisoning. This disorder is of interest despite the fact that the case reports relating the problem of benzene exposure are relatively few. Patients with paroxysmal nocturnal hemaglobinuria often develop acute leukemia, and during the course of leukemic disorders red cell characteristics consistent with paroxysmal nocturnal hemaglobinuria may occur. This suggests tnat paroxysmal nocturnal hemaglobinuria is a paraneoplastic disorder (Goldstein, 1977). Several investigations have linked benzene exposure to the occurrence of lymphomas, including Hodgkin's disease. The largest series was reported by Aksoy in 1974. Among 94 patients admitted with Hodgkin's disease to their clinic in approximately five years, six had a history of occupational exposure to benzene. The results of this study, how ever, are difficult to interpret. For example, as pointed by the authors themselves, the incidence of Hodgkin's disease in the general population was unknown as was the population at risk to benzene expo sure. As such, it was impossible to estimate the relative incidence rates for Hodgkin's disease among people with and without benzene exposure. SAL 000002676 -11 CYCTOLOGIC AND CYTOGENIC EFFECTS Investigations concerned with the effects of benzene on replication at the cellular level have focused on changes in cell nuclei, DNA metab olism, cell division and chromosome alterations; these all constitute direct measures of changes in the quantity, structure, organization, or function of cellular DNA, and the changes are both heritable and in many instances, imply continuing and/or progressive changes of the genome (Wolman, 1977). As is true with respect to hematologic ef fects, investigations as to the cytologic and cytogenic effects of benzene comprise both case reports and epidemiologic studies. Several of the case reports have described additional chromosomes. In two instances this chromosome was identified as a member of tne C group. However, in both instances the patients involved were experiencing acute leukemia, and an additional C group chromosome is frequently found in this disease whether or not benzene is associated. Addition al abnormalities noted in the case reports include tetraploidy and polyploidy (Wolman, 1977). With respect to epidemiologic studies, several of the more recent investigations have been critically summarized by Snyder and laskin (1985). These investigators note that Tough and Court-Brown (1965) " reported on chromosome aberrations in peripheral blood lymphocytes from 20 workers having from one to 20 years benzene exposure. While exposed workers showed an increase in lymphocytes with both unstable and stable chromosome aberrations the difference was not statistically significant in terms of controls. This paper, however, was but a preliminary communication for a followup study which appeared in 1969. The second report deals again with the 20 subjects in the 1965 paper whose exposure consisted of leaks from a closed distilling operation. An additional 12 workers, whose exposure was from open vats of ben zene, were also included in this report. Durations of exposure ranged from one to 25 years. At tne time the cytogenic analyses were done, between two and six years had elapsed since cessation of exposure due to tne substitution of toluene in the vat operation. In the distillation operation, however, exposures were ongoing. In this study, peripheral lymphocytes with unstable aberrations were significantly increased among the first group of 20 subjects. This was true in comparison with both onsite and general population controls. Tne second group of 12 subjects snowed increased unstable aberrations when compared with the general population but not when compared with controls from the benzene free areas of the factory. 5nyder and Laskin (1985) note several problems of interpretation with this investigation. There is, tney state, an apparent failure to consider tne potential confounding factor of age. There was a significant correlation between age and the number of aberrant cells but no correlation between years of exposure to benzene and numbers of unstable chromosome aberations. Moreover, the data were not consider ed to be adequate to assess the nature of the relationship between benzene exposures and the number of unstable chromosome aberations. Additionally, hematological data were not presented. Finally, in addition to age, other potential confounding factors were excluded from consideration by the authors, the single exception being exposure to ionizing radiation. SAL 000002677 Form' et al. (1971a) studied 32 workers with a history of benzene re lated cTimcal disease and from 1 to 18 years benzene exposure. When compared with age-sex matched controls, the exposed workers had a sta tistically significant increase in the proportion of peripheral lymph ocytes with both stable and unstable lymphocytes. Potential confound ing due to exposure from other cytotoxic agents (e.g. smoking, drugs) was not addressed in these analyses, however, (Snyder and Laskin, 1985). In a separate study reviewed by Snyder and Laskin (1985), Forni et al. (1971b) were noted to have investigated workers who, prior to 19TTT, experienced benzene hemopathy while working in a rotogravure plant in which measured airborne concentration ranged from 131 to 532 parts per million. Toluene was substituted for benzene in 1953, and subsequent toluene exposure were about 200 parts per million. In 1967-68, 34 workers, including 10 with the pre-1953 benzene exposure, had cytoge netic studies on 100 cultured lymphocyte metaphases. Healthy, unex posed age-sex matched controls were also studied. Exclusion criteria removed persons with recent viral illness or vaccinations from study entry. Two persons exposed to therapeutic irradiation and three with other chemical exposures were not included in the analyses. Benzene exposed workers (eight of whom had experienced hemopathy including two with severe disease) had significantly more unstable chromosome changes (1.66% versus 0.6%), p <0.01), significantly more calculated breaks (1.8% versus 0.67%) and significantly more stable changes (0.62% versus 0.09%) than controls. Exclusion from the analysis of the two workers with severe hemopatny did not substantially alter the conclusions. Benzene exposed workers also had significantly more aberrations than workers exposed only to toluene. No correlation was observed between frequency of chromosomal change and either age or length of benzene exposure. Notably, three workers, each having three years of benzene exposure and a history of mild anemia and/or leucopenia, were cytogenetically normal. Additionally, two otner workers, one with seven and one with 22 years of benzene exposure, had no his tory of hemopatny but did have 2 to 4 % abnormal cells. In summary, this is an important study which lends substance to the circumstantial evidence, provided by case reports, that hign-level benzene exposure is causally associated witn cytogenetic damage on a population basis. So far as individuals are concerned, however, the study also demon strates present inability to ascribe a particular adverse effect to a particular level of exposure. Factors accounting for individual vari ability remain to be delineated. Picciano (1979) compared 52 workers having one month to 26 years of benzene exposure witn 44 pre-employment controls whose average age was 12.7 years less than the exposed group (Snyder and Laskin, 1985). The TVIA exposure per workers was 2.1 parts per million over the four year period prior to study, but the documentation is not clear regarding duration of individual exposure, peak exposure, or potentially con founding factors such as smoking, recent illness, or the presence of otner environmental clastogens (Snyder and Laskin, 1985). Overall, benzene exposed workers had a ten-fold excess in the proportion of SAL 000002678 -13 individuals with either chromosome breaks or markers. Snyder and Laskin (1985) also note a comment by Dabney (1981) as to the unusually low frequency of aberrations in controls for the Picciano (1977) study, a factor which may have affected the apparent significance of the results. Van Raalte and Grasso (1982) have also criticized the Picciano study. Like Snyder and Laskin (1935) they criticize the exposure assessment. They also point out a large difference in age between exposed workers and controls (mean of 39 and 27 years respectively). Additionally, they note that while there were statistically significant differences in the frequencies of some chromosomal aberrations, the overall frequencies were low enough to nave been considered normal in both groups. Finally, Snyder and Laskin (1985) comment on a 1984 report by Sarto, et al. (1984) in which blood lymphocytes from 22 healtn, benzene, tol uene and xylene exposed workers were compared with lymphocytes from a metallurgic factory. The benzene exposed group experienced levels of 0.2 to 12.4 ppm TWA in 1980-81, but pre-1971 exposures were irarkedly higher. The average duration of benzene exposure (_+ standard devia tion) was 11.4 + 7.0 years. The study groups were matched for absence of other genotoxic exposure, medical history, smoking and eating habits, recent viral infection, number of x-rays in the preceding five years, drug consumption, and incidence of familiarl spontaneous abor tions and malformations. Chromosomal aberrations were signficantly higher in benzene exposed (1.1%) than in control subjects (0.5S0, even when gaps were eliminated from consideration. Sister chromatid ex changes were detected with similar frequencies in both study groups. D. OTHER POTENTIAL EFFECTS While human benzene toxicity has been most often investigated in terms of adverse hematologic, carcinogenic and cytogenic effects, there are many suggestions in tne literature as to other potential hazards. These are summarized in Table III and include adverse reproductive outcome; cardiovascular, renal, neurological, psychological, immuno logic, opnthalmologic, and gastro-intestinal effects; injection injury; and Goodpasture syndrome. As is true for the more heavily in vestigated problems, these observations have generally been made in occupational settings. Evidence concerning these potential problems, however, is not so well developed as it is for hematologic and cyto genic effects. Much of the work remains to be replicated and hypothe sis testing investigations are not always available. sal 00OO02S7,, -14 SUMMARY Based on human studies Benzene may have both acute and chronic effects on health. Acute Benzene exposures below 25 ppm for 8 hours do not seem to produce symptoms. Concentrations of 50 - 150 ppm for five hours may produce acute headache, malaise, and weakness. Very high concentrations (in the range of 25,000 ppm) may be fatal. Of greater concern are chronic effects. These have been reported almost exclusively among the occupationally exposed. Hazards include cytogenetic damage, hematologic cytopenias and leukemia. The effects of occupational exposure, however, are not uniform across individuals, and as shown in a key study of cytotoxicity (Form*, et aK, 1971b), factors mediating individual response are not well delineated. The minimum level which may produce adverse effects among the occupational ly exposed is controversial. For example, one of the strongest pieces of evidence cited concerning danger from low levels comes from the investiga tion of leukemia in rubber workers (Rinsky, et al_., 1981). The identical data, however, was interpreted by Van Raalte and Grasso (1982) to indicate that low levels of benzene are not associated with excess risk. Additional potential hazards are currently being investigated. These include other cancer, adverse reproductive effects, electroencephalographic changes, cardiovascular effects, immunologic and psychological effects, and Goodpasture syndroms. Some of these effects are noted only in case reports. Others reflect initial hypothesis testing efforts. SAL 000002660 TABLE !. PANCYTOPENIA / APLASTIC ANEMIA first vear reference author number of cases type of manufacture non-occupationa! exposure exposure assessment 1897 69 1910 71 1934 11 1938 30 1938 77 939 19 u b5 1939 55 1939 39 !941 37 1942 23 !942 28 1942 78 1943 25 1944 1*1 1946 b2 1965 16 1946 16 1946 29 1947 128 1948 58 1950 18 1951 12 1954 68 1956 21 1956 70 1957 13 1959 3b 1959 38 I960 56 1561 lb 1961 127 Santesson Sel1ing Arderson 9 3 I Emile-HeiI 27 Undritz Bowditch Hunter Hal lory 1 40 14 Greenborg GoIdwater Cheva1ier Duvoir Wilson 0" 3 2 23 bicycle tires tire/rubber cameras, shoes cartriges chemical cartons varied amateur photography; home repairs, inc. paint removal 4 children affected rubber,leather telephone printing painter's son developed leukemia perfume raincoats, cars rubber Davidson 1 Hamilton- 50 Patterson (neutropenia) 44 (leucopenia) Helaer 60 Binet 1 Bernard 212 Duvoir 2 Hutchings 87 Oldfelt 37 Blaney 2 Andre 1 Saita 17 Cassan 18 Salvilahti 107 Appuhn Gadrat 6 Gor in i 5 NcLean 6 3arre 1et 3 bookbinder rubber rubber synthetic leather aeronautics aeronautics printing, rubber plastics hunting clothes - - electrical appliances shoes t - petrol(101 Benzene) siphoned by mouth (3) walked through area with pools of petrol (11 benzene)!!) washed car carts( ) accidentally swallowed ii) varied Dubois 3 watch dial qua!itative qua 1itative 5 years <2 to >5 yrs. 5 years 100 to 350 ppm 6 months12 years 11 to 1,060 ppm 6 mo. to 3 yrs. 15 to 26 yrs. qualitative Avg.=100 ppm; max=53Gppr 6 yrs.(leukemia) 137 to > 21Bppm blood benxene ogr 4 to 3 gr 2pe' 0 ogr 2 per *g of marrow 50 to 530 ppm/day qua 1itative qua!itative qua 1 itayive qualitative qua!itative 10 yrs., 400 ppm t 8 qua! itative 3 times/week for B weeks 4 months, 7 months 12 months 2 yearsi occasion case 1: 3 yrs. case 3: 13 years 75-4CG ppr -15 SAL 000002681 -16 TABLE 1. continued first year reference author number of cases 1962 2h Curtetto 3 1962 53 1963 26 1963 35 Ludwig Degowin Gallinel! i 2 t 3 1963 52 1964 62 1965 20 1965 63 1965 ^7 1966 7 1966 h3 1967 75 Lob Po 11in i Browning 6 14 1 Powars I Jindrichova 1 Aksoy 3 Hernberg Stewart 58 10 1969 ^9 1969 50 1961+ 111 1969 6k 1970 36 1970 67 1971 8 1971 27 Kliche Koslova Pol 1 ini Ralyevic Girard Roth* Aksoy Ooskin 13 t 5 1 - 6 152 type of manufacture non-occupationa! exposure raincoats, leather chemical housepainter worked with a glue diluted in benzene m\) chromatographic testing of coal gas - . - " glue sniffing cobbler - various saal1 shops and factories shoes chemicals " - roof tilers leatherette 1 1 varied shoes shoes chemicals - - 1971 33 1971 1+0 1971 5^ 1972 9 1972 22 1973 31 1973 17 1973 1+8 1973 51 1973 66 1973 73 1973 71+ 1974 57 Forni Guberan Mai 1e in Askoy 17 5 2 32 varied watchmaking chemicals varied - Chang 0 among 119 workers Erdogen 8isea Idi Kahn* Lange Roth Snolik 13 1 0 10 19 34 shoes furniture finishing * painters - - SobC2yk 80 HcHichael * 0 plastics rubber - exposure assessment IB months, 3 yrs., 16 yrs. 14 and 19 yrs. 13 years 3, 12 and 16 yrs. "35 ppm qua 1 itative 3 years 46 yrs worked with 20-261 benzene paste 6 months to 11 yrs. Salvilahti (1956) chronic=<25ppra 8cute*85 to 115 ppm for 3 months averages 17 yrs. 15 ppm 1 1 10 to 25 ppm 30 to 210 ppm 3 months to 1? years benzene exceeded mpe by 2-8 times in 641 of samples in yr. 1, 371 in yr. 2, 31 in yr. 3 qualitative qualitative 150 to 650 ppm 4 months to 15 yrs. about 21 ppm; as low as 10.1 ppm 8 yrs. 1.6-15.5 pp" 1 to 15 yrs 0.011 to 0.022 mg/liter 0.25 to 18 yrs. 0.5 to 10 yrs. general(25 ppm SAL OOOOO u^6S2 -17 TABLE !. continued laximum 125ppm fr r 5t vear reference author number of cases type of manufacture non-occupationa1 exposure exposure assessment 1975 72 Shirca 0 varied smal1 factories - 25,013 person yrs. 1970-74 1976 10 1978 k6 1978 76 1978 32 1979 59 1980 65 1980 kk Aksoy Iwata Townsend ftshbeck Pagnotto Roodman Hisanga 8 1 0 among 282 workers shoes chemical 0 among 10 workers{subset of Townsend, 1978 immediately above] 0 among 37 workers rubber coating I 2 overglaze decoration * marathon runner using rubber cement to attach adhesieve to foot blisters. - 210 to 650 ppm ! to 15 years t <2 ppm twa to 25=ppm twa. mean cancer exposure range of 256-1605 grams exposure of>24 ppm. 2 yr$. 6 months to 22 yrs, 11 months 1 to 24 yrs, 5 to 140 ppm 2-3 hours daily for 12 months 1 notes to table 1; Greenberg (1939): Clinically significant cytopenias were found among 23 workers, and statistically significant declines in hemoglobin hematocrit and wbc were also reported. Gadrat (1959): All reports were of leucopenia only. Roth (1970): Altered lymphocytes and monocytes were found among 231 of 155 workers studied. Kahn (1773): Increased -aminolevulinic acid was found. All cell counts were normal. PIcHichae! (1974): An increased incidence of lymphoma and leukemia was suggested, see also Pagnotto et a! (1961). An asterisk () has been placed in the table when documents or translations were unavailable. These citations were included, nonetheless, for purposes of competeness. Blank spaces without an asterisk indicate the information was not documented in the report cited. dash(-) indicates that no inusual non-occupational (or occupational) exposure was found by the authors. 00002683 SAL 0 Table II Leukemia A. Acute Iflyelogenous Leukemia year 1932 1937 1937 1939 1941 1942 reference 90 116 122 91 123 106 first number of author cases Emile-Weil 1 Sabrazes 1 Tzanck 1 Erf 1 VanRavenstyn 1 Loeper 1 type of non--occupational manufacture * exposure - mirrors - rubber - rubber - rubber - raincoats 19 ^5 19^8 1959 1959 117 58 98 100 1962 1962 1962 1962 24 53 118 26 Salta Oldfelt Guasch Justin- Besancon Curletto Ludvig Salta Degovin 1 1 1 1 1 2 4 1 printing * dyes * chemical varied painter _ - _ - 1963 120 1964 1964 1967 1971 1971 1972 1972 1976 1977 1981 111 125 126 112 119 80 115 10 99 114 Tareeff Pollini Vigliani Zini Pugni Sellyei Aksoy Robustelli DellaCuna Aksoy Infante Binsky 5 1 6 1 1 1 4 1 14 printing and unspecified shoes,leather * varied * shoemaker * shoemakers shoemakers _ - -- - -- -18 exposure assessment * qualitative 13 years 1 year 3 years 5 years (ended 5 yrs. before onset) 5 years * * 13 years (ended 27 Yrs. before onset) * l4 & 19 years * 13 years (15 yrs. after recover from aplastic anemia 13,17,22 years 3 to 19 years 14 years 40 years 18 month, 200-l640mg, m3 210ppm 6,8,10,14 years 6 years 2-15 years, mean 10 years 4 months SAL 000002684- Table II (continued) B. Erythroleukemia year 1950 1952 1957 1958 1958 1959 1963 1967 1969 1976 reference 93 107 13 87 88 104 119 103 92 10 first number of author cases Galavotti 1 Nissen 1 Appuhn 1 DiGuglielmo 1 DiGuglielmo 1 Kuhlmann 1 Tsreeff 2 Kohli 1 Forni 1 Aksoy 6 C. Acute Monocytic Leukemia 1972 1976 90 9 Aksoy Aksoy 1 2 D. Chronic Myelogenous Leukemia 19^9 1951 1961 1963 1967 1973 1976 124 84 101 120 96 105 10 VanS choonoven Bousser fCahler Tareeff Goguel Liaudet Aksoy 1 5 1 5 13 1 1 E. Acute Lymphoblastic Leukemia 1928 1966 1967 1976 86 43 97 10 Delore Hernburg Goguel Aksoy 1 1 2 4 F. Chronic Lymphocytic Leukemia 1947 89 Drouet 1 1951 1963 1965 1965 1966 1967 1972 110 119 102 79 95 97 80 Poinso Tareeff Kiec Bogetti Girard Goguel Aksoy 1 3 1 1 1 8 0 -19 type of manufacture shoemaker * * non--occupational exposure -- * * exposure assessment 19 years * * Rotograuure - 4 years * ** * ** varied # 20-22 years Shoemaker -- 19 years - 7 years Exposure details in Acute Myelogenous Leukemia Shoemaker - lo years Exposure details in Acute Myelogenous Leukemia * ** * _* * varied * * 7 years - 4 to 27 years _ Petroleum Chemist - 17 years Exposure details in Acute Myelogenous Leukemia * - 5 years * # varied * * Esposure details in Acute Myelogeneous Leukemia fabriaue de chausseurs(Fr) # * 13 years ft varied Paints & Laequers falegname(Je) * varied - - 10 to 22 years 40 years 14 years 12 years * Exposure details in Acute Myelogenous Leukemia 000002685 SAU -20 Table II (continued) G. Lymphoma/Soft Tissue Cancer year 1939 1948 1963 reference 55 83 119 1965 1969 1970 1971* 108 85 120 81 first author Mallory Bousser Tareeff Patemi Casirol Torres Aksoy number of type of non-occupational exposure cases manufacture exposure______ assessment Impossible Hodgkins - Occupational exposure l(Lymphosarcoma) - Occupational exposure 2(Atypical Reticulosis and Plasmagtosis) - Occupational exposure 8 & 22 years l(Reticulum Cell Sarcoma) - Printing Industry l( Lymphoma) 2(Multiple Myeloma) - Occupational exposure for 6 & 11 years 6(Hodgkin's) - Exposure details in Acute Myelogenous Leukemia) H. I^yelofibrosis and Myeloid Metaplasia 1938 1941 9^ 112 Gall Rawson I960 1975 56 82 McLean Aksoy I. Thromboeythemia 1- 3 Shoe, Painting -- Machine Cleaning 1 Occupational 1* - - 4 years 5,16 8s "many" years 1 year * 1972 80 Aksoy 1 Shoemaker - 10 years Additional Occupational Investigations Rubber Workers: Pagnotto et al. (1961, 1969); McMichael et al. (1974, 1975); Andjelkovic et al. (1976, 1978); Manson and Nakano (1976); Infante et al.(l977); Rinsky fet al. (1981) Printing Industry: Hoyd et al. (1977); Green et al. (1980). Petrochemical Industry: Thorpe (1974); Theniant and Goulet (1979); Hanis et al. (1979); Thomas et al. (1980); Tushtar and Alderson (i960, 198l). An asterisk (*) has been placed in the table when documents or translations were unabailable. These citations were included, nonetheless, for purposes of competeness. Blank spaces without an asterisk indicate the information was not documented in the report cited. A dash (-) indicates that no unusual non-occupational (or occupationsl) exposure was found by the authors. 000002686 SAL TABLE III. OTHER POTENTIAL HAZARDS - 21 a. Adverse Reproductive Effects (Barlow and Sullivan, 1982). Year First Author Effects Study Design 1965 Mi chon Prolonged/Heavy Menses 500 women, 20-40 years of age, in ; Polish factory producing leather and rubber shoes with Benzene 31 ppm. Toluene 67 ppm. Xylene 5f ppm were compared with 100 non-exposed controls. 1971 Mukhametova Menstrual Disorders (Hyperpolymenorrhea 10.6* versus 3.2* in controls; acyclical disturbances 6.1* versus 1.9*). Spontaneous abortion (17.2* 4.9*). Late toxicoses (16.8* versus 8.4*); Premature birth (11.2* versus 4.2*); Threatened abortion (4.0* versus 1.5*). Incorrect implantation and detachment of the placenta (8.8* versus 4.2*); Fetal asphyxia (6.8* versus 2.6*); Higher perinatal mortality (6.3* versus 1.8*). 360 women, 20-40 years of age, working as gluing operatives in a mechanical-rubber product factory were studied. Petroleum and chlorinated hydrocarbons (including dichlorethane and methylene chloride) were included in the exposures. 616 women of comparable age but without exposure were used as controls. Induced abortion was the most common outcome of pregnancy in both groups. Only 65 births occurred among exposed and 79 in controls. 1959 Ragucci 7 spontaneous abortions, one stillbirth, 3 cases of uterine inertia, 4 normal births Case Series of Benzene Poisoning in in Pregnancy. 1957 Riera-Barta Maternal death due to hemorrhage Case of Benzene Related Aplastic Anemia 1972 Messerschmitt 2 abortions at 5 months, one delivery at 7 months, 4 maternal deaths, 3 child deaths. 5 case reports of pregnant women with benzene associated aplastic anemia. B. Cardio/Cerebro vascular (only abstracts were available in translation). Year First Author Effects Study Design 1973 Monaenkova Hypotonia of cerebral vasculature. Case series of 117 patients with occupational poisoning including 28 with benzene poisoning. SAL 000002687 -22 x TABLE III. OTHER POTENTIAL HAZARDS (continued) B. Cardlo/Cerebro vascular (continued) Year First Author Effects Study Design 1974 Reznik Ischemic heart disease; arterial hypertension Among cases, 26.62 had ischemic heart disease, and 522 had either arterial hypertension or arterial pressure within the lim its of a "transition zone" (un defined). Frequencies exceeded those among controls by three and two times respectively. 150 patients with a 15 - 26 year history of chronic poisoning with benzene derivatives were compared with controls. 1979 Karmaz Hypercholesterolemia, Hyperphosphatipidemia 250 workers in coke-benzene pro duction were compared with 120 workers not having contact with 120 workers having contact with aromatic hydrocarbons. u Neurologic/Psychologic Abnorma1 EEG 1969 Schneider 822 of benzene exposed workers had abnormal EEG findings. Case series of 71 workers age 30 + 1 years with 4.6 + 0.4 years of exposure (Abstract only). 1973 1985 Sobczyk Kellerova 40 2 of workers examined had abnormal EEGs. / 13 (32.52) of benzene exposed had a normal EEG versus 40 (83.32) of the non-exposed. 18 (452) versus 6 (12.52) had a threshold response and 9 (22.52) versus 2 (4.22) were abnormal. Abnormalities in the benzene exposed were episodic, diffuse or a combination of the two. Case series of 100 women employed at gluing of plastic elements at a Polish factory. All 100 had experienced symptoms and signs of benzene poisoning 3 to 4 years prior to EEG. (Abstract only). Case-control study of 40 benzene exposed workers (28 with benzene concentrations of 145-500 mg/m^ up to 1000 rng/m^ and 12 with benzene concentrations, "Only exceptionally" in excess of HPCP. Exposed included 37 men and 3 women. Controls were 48 healthy persons (42 men and 6 women). Average age of the 28 highly exposed was 32.4 years and exposure durations was 0.5-4 years. Average age for the 12 (continued) SAL 000002688 TABLE III. OTHER POTENTIAL HAZARDS (continued) -23 u. Neurologic/Psychologle (continued) Abnormal EE6 (continued) Year First Author Effects Study Desiqn 1985 Kellerova (continued) with generally acceptable expo sure was 41.5 years and exposure duration was 2-20 years. Compari sons were 20-53 years old. Addi tional comparison was made with a toluene-xylene exposed group and a vinyl chloride exposed group. Othe than age-sex differences, other potentially confounding factors were not discussed. Reference is made to eight previous EEG studies involving isolated cases. Physical Assessment 1971 Drogichina 95* of patients with chronic benzene poisoning had abnormal ities including: asthenoneurot- ic, astheno-vegetative, vegeta tive polyneuritis, asthenic and astneno-organic polyneuri tes. Case series of 250 patients with chronic benzene poisoning (Abstract only). 1984 Herregods Transverse myelitis Case report of benzene poisoning Psycholoqic 1973 Korolenko Various substances were studied with several abnormalities noted. Abnormalities specifically asso ciated with benzene were not defined. Case series of 142 persons suffer ing from chronic lead, ethylated petrol, mercury and benzine poisonings (Abstract only). 0. Immunologic 1980 Moszczynski Increased activities of acid phosphatase, beta-glucuronidase, NBT reduction and diminished gly cogen reserves in peripheral blood neutriphils. These changes were accompanied by diminished peroxidase and alkaline phospha tase activities. Stimulated NBT production was negatively corre lated with duration of exposure. Cross sectional survey of 106 workers in contact with organic solvents containing benzene and its homologues for periods up to 122 months (Abstract only). SAL 000002689 Immunologic (continued) Year First Author TABLE III. OTHER POTENTIAL HAZARDS (continued) Effects Study Design 1982 Moszczynski In workers with more than 55 months exposure, decreased T and non-T, non-B lymphocyte count is noted. Monocytes are increased. Same population as previous entry. (Abstract only). 1983 Moszczynski Progressing reduction of numbers of lymphocytes having AP-positive intact lysosomes. 108 workers with 31-122 months of exposure to benzene, toluene and xylene (0-370, 0-580 and 0-560 mg/ eum respectively. (Abstract only). 1984 Moszczynski N-acetyl-beta-D-glucosaminidase (NAG) deficiency in peripherals lymphocytes. Same population as above. 1984 Moszczynski Decreased T lymphocyte count without alterations in their functions. 72 workers with occupational con tact with benzene, toluene or xylene. (Abstract only). 1981 Chirco Increased endolymphocytic RNA. Increased capacity of Immuno globulin formation, particularly IgM. All are considered as early signs of enhanced immune reactivity. 270 workers with chronic benzene E. Miscellaneous 1970 Klavis Goodpasture Syndrome [glomerulonephritis, intraalveolar pulmonary hemorrhage, anti glomerular basement membrane anti body] Case Report (Abstract only) Heavy benzene exposure. 1976 1958 Dickson High pressure injection Injury of the hand. Widespread vessel thrombosis, absence of fat from fat loculi and coagulative necrosis of skin and subcutaneous tissue. A case which led to digital amputation is described. DiGuglielmo Segmented spontaneous infarction Case reports (Abstract only). of the Greater Omentum. SAL 000002690 -25 TABLE III. OTHER POTENTIAL HAZARDS (continued) E. Miscellaneous (continued) Year First Author Effects Study Desiqn 1971 Csata Nephrotoxic Anuria Case report of severe poisoning due to a combination of benzene, chloroform and acetone. 1977 Guingatul1ina Reduced intra-ocular pressure and transitory hypersecretory [intraocular] hypertension without marked changes in the blood supply of the ciliary body. Cases and controls were studied. No further description is pro vided. (Abstract only). SAL 000002691 Acute Toxicity REFERENCES -26 1. Drozd, J. and Bockowski, E.J. Acute benzene poisoning. J, Occup, Med. 9(1):9-ll, 1967. 2. Gerarde HW. 1960. Toxicology and biochemistry of aromatic hydrocarbons. New York: Elsevier Publishing Company. 3. National Academy of Sciences. 1976. Health effects of benzene: A review. Committee on Toxicology, Assembly of Life Sciences. National Research Council. Washington, DC. 4. Snyder . 1984. Draft criteria document for benzene prepared for U.S. Environmental Protection Agency. 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Flshbeck, W.A., Townsend J.C., Swank M.G. J. Occup. Med. 20:539-542, 1978. 33. Forni, A.M., Cappellini, A., Pacifico, E., Vigliani, E.C. Chromosome changes and their evolution in subjects with past exposure to benzene. Arch. Environ. Health 23:385-391, 1971. 34. Gadrat, J., Quercy, J., Fedou. Hemopathie atypique consecutive a une intoxication benzolique chronique. Soc. Med. Trav. Region Toulousaine, pp. 295-297, June, 1958. 35. Gallinelli, R.P Traldi, A. Benzene haemopathy. Three cases of chronic benzene poisoning with two deaths. Med. Lav. 54(3):169-182, 1963. 36. Girard, R., Mallein, M.L., Bertholon, 0. Coeur, P., Tolot, F. Leuco cyte alkaline phosphatase and benzene exposure. Med. Lav. 61:502-508, 1970. 37. Goldwater, L.J. Disturbances in the blood following exposure to benzol. J. Lab. Clin. Med. 26:957-973, 1941. 38. Gorini, P., Colombi, R., Pecorari, D. Investigation on the origin of the macrocytosis in the cytoplastic anemia from chronic benzene poisoning. Lav. 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