Benzene and Diseases of the Blood: Revisited (2006)
By Nachman Brautbar, M.D.
An etiologic association between benzene and diseases of the blood was shown more than 50 years ago, and has since been corroborated by epidemiologic studies, animal data, and by carcinogenic bioassays. Benzene is now considered, by national and international scientific and health organizations, to be a human carcinogen. The purpose of this review is to summarize the available information on benzene and its effects on the hematologic (blood) system (revisited from 1992 CWCE).
Industrial Production and Usage
Populations highly exposed to benzene are as follows: 1) workers engaged in its production, 2) workers engaged in chemical industries utilizing benzene, 3) workers in industries producing materials containing benzene, 4) workers utilizing or handling compounds containing benzene, 5) people living near factories producing or utilizing benzene, and 6) exposure to engine emissions and cigarette smoking. (Table 1 describes some of the industrial exposures to benzene).
Table 1. Potential Industrial Exposures to Benzene
The level of benzene allowed in the workplace varies from country to country. Until 1978, in the USA the OSHA standard for benzene was 10 parts per million (ppm) with an acceptable ceiling concentration of 25 ppm. OSHA's current standard for benzene exposure is 1 ppm with a 5 ppm ceiling limit for 15 minutes.
Following reports of toxicity, the use of benzene has been reduced significantly. However, Ringen et al. and Holmberg et al. noted that benzene exposure may still occur in industry and is detectable in workroom air in many industrial activities. Currently, the American Conference of Governmental Industrial Hygienists concluded that 0.5 ppm TLV/TWA is recommended as a regulatory, occupational level. The Collegium Ramazzini has recently recommended reducing levels of benzene exposure to the lowest possible level.
Route of Human Exposure
Although benzene is relatively soluble in water, commonly the magnitude of human exposure via water is probably negligible (unless there is groundwater contamination from either industrial releases or underground storage tank deterioration causing leaks which in turn contaminates the drinking water). The respiratory route is commonly the primary source of human exposure to benzene. Much of this exposure to the general population is by way of gasoline vapors and automobile emissions. In industrialized areas and heavily congested areas, levels of 15 parts per billion (ppb) up to 57 ppb were described, while the average background levels have been reported to be 2.7 to 20 ppb.
Benzene is absorbed through the skin, but skin contact is infrequent for the non-working general population. While the skin route is probably an insignificant source of exposure for the general population, it has been shown as a significant route of exposure in the working population.
Smoking may be a significant benzene exposure source for a portion of the population. Studies have described levels of benzene exposure in active smokers at the range of 7.2 to 17.8 ppb.
In recent years, the relationship between benzene and smoking-induced hematopoietic malignancies has been solidified. ,,,,,,, Korte et al. combined epidemiological data on the health effects of smoking with risk assessment techniques for low-dose extrapolation and assessed the proportion of smoking-induced total leukemia and acute myeloid leukemia attributable to benzene and cigarette smoke. This study was based on linear potency models (the conservative oriented version of a suggested non-linear method is not accepted with the major regulatory and scientific bodies). According to this study, benzene is estimated to be responsible for approximately one-tenth to one-half of smoking-induced total leukemia mortality and up to three-fifths of smoking related acute myeloid leukemia mortality. The paper by Korte et al. 13 lends support to the proposition that small amounts of benzene exposure renders the cellular detoxification system more sensitive to the cumulative exposure from benzene. Kasim et al. has recently reported that active smoking was observed to be associated with a substantial increased risk of leukemia (odds ratio, OR = 1.5, 95% confidence interval, C.I. = 1.1 to 2.0). The International Agency for Research on Cancer's (IARC) 2004 monograph on cigarette smoking states that cigarette smoking causes leukemia, and that cigarettes contain sufficient quantity of the leukemogen benzene. This is an important development in terms of leukemogenesis and low-level exposure to benzene. One pack of cigarettes a day for 20 years is equivalent to 15 ppb cumulative benzene exposure. This relatively new recognition (of well known, old data) further supports benzene leukemogenicity at levels lower than 1 ppm and based on IARC 16, levels as low as 15 ppb.
Effects of Benzene on the Hematological System
Table 2. Benzene Exposure and Lymphohematopoietic Disorders
Benzene has been known as a hematologic poison since the nineteenth century when aplastic anemia in workers fabricating tires was described. Many other hematological diseases have since been reported to be the result of benzene exposure. Many of the hematological disorders related to benzene may not be dose-dependent as the mechanism of these diseases are yet not completely understood, although it is strongly believed that benzene carcinogenicity is mediated via immune suppression and DNA cell changes.
A. Myelodysplastic Syndrome:
Myelodysplastic Syndrome (MDS) is a bone marrow diseases and is considered to be in a preleukemic stage. Several case reports, case studies, and epidemiological studies demonstrate that MDS is caused by benzene exposure at benzene exposure levels less than 10 ppm., It has been suggested that benzene-induced MDS is an early or predisposing event in the pathogenesis of benzene-induced hematologic diseases. The list of studies describing MDS caused by benzene includes: Travis et al., Linet et al., and Ward et al.
[Benzene and MDS Manuscript in Preparation]
B. Aplastic Anemia/Pancytopenia:
The induction time of aplastic anemia or thrombocytopenia in relation to exposure is of great interest. The following studies have been described: (1) A follow-up study of 125 workers in a shoe factory who were exposed to levels of 400 ppm of benzene, 9 years later noted some persistent cytopenias. One individual had developed acute leukemia and died. (2) Four individuals were reported to have persistent decrease in blood counts and one patient had died of aplastic anemia 9 years after cessation of exposure. (3) An outbreak of hematological toxicity in leather workers in 1975 was directly temporally related to the use of an adhesive containing benzene beginning in about 1960. (4) Thirty-two cases of significant aplastic anemia in people exposed to benzene for 4 months to 15 years were reported in the literature. Exposure levels ranging from 150 to 650 ppm were reported. (5) In another study, 51 of 217 apparently healthy workers were found to have some hematological abnormalities including 6 cases of pancytopenia. These workers are described as having been exposed to 30 to 210 ppm benzene for as short as 3 months to 17 years.
This data indicates that aplastic anemia and thrombocytopenia in relation to benzene exposure may develop as early as several months.
C. Acute Myeloblastic Leukemia:
The medical literature is replete with cases of acute myeloblastic leukemia in which benzene exposure has been shown as the causative agent. The relatively common description of aplastic anemia associated with benzene exposure followed through a pre-leukemic phase into acute leukemia further supports the concept that the bone marrow toxicity of benzene encompasses a wide spectrum of diseases presenting as anemia, thrombocytopenia, leukemia, or the other hematological diseases described in Table 2.
A published study in the New England Journal of Medicine, by Rinsky et al. quantitatively assessed the relation between benzene exposure and leukemia and examined the mortality rate of cohort with occupational exposure to benzene. Their findings are summarized in the following statements: (1) There is a strong positive exposure response relation between benzene and leukemia. (2) On the basis of their study, they conclude that exposure levels of less than 1 ppm annually, cumulative over a 40-year working lifetime increases the risk of leukemia by a factor of 1.7. (3) In the population studied, there was a statistically significant excess of death from multiple myeloma (multiple myeloma is another hematological cancer, of plasma cells). Of interest in this study is a description of a patient who died from leukemia 34 years after his exposure to benzene levels of 19.56 ppm over the years. Multiple myeloma, the cause of death in four members in this study, was described previously in relation to benzene, although in small numbers. Furthermore, it is of interest that these patients have a very long latency period from the time of exposure of over 20 years, and the lowest cumulative exposure of 40 ppm years. This paper also demonstrates a latency as short as 1 year.
D. Lymphoma and Lymphatic System:
E. Non-Hodgkin's Lymphoma
Several lines of evidence demonstrate that benzene causes non-Hodgkin's lymphoma (NHL). Italian investigators (Costantini et al.) presented a paper at the April 2005 American Association of Cancer Research. For benzene exposures of 15 years duration, researchers showed a significant excess risk for NHL and demonstrated a dose-response relationship when considering NHL subtypes. In 2004, Scandinavian researchers reported the results of a case-control study for NHL and occupational exposures. Risk of NHL was significantly increased for exposure to gasoline, oil products, and solvents.
F. Safety and Policy:
G. Levels of Exposure & Risk Assessment:
The concept of cumulative benzene exposure for the working population must be well understood before one can address levels of exposure. Studies by Hayes, et al, from the National Institute of Health17 provide extensive data on benzene exposure and hematological cancers. They clearly show that diverse hematopoietic malignancies can develop at benzene exposure levels of less than 10 ppm. The issues of exposure levels has been summarized in a recent paper by Melman and are revisited in the manuscript (in-press) entitled, "Leukaemia and low level benzene concentration: revisited".
It is also important to remember that although many of the material safety data sheets of industrial solvents do not indicate the presence of benzene, the testimony in front of OSHA and the scientific papers published in that regards clearly indicate that industrial solvents contain benzene and cannot be produced without benzene contamination.,  The recent papers by Mehlman 33 and Kopstein further detail the sources of benzene in industrial solvents. Therefore in the analysis of risk or causation one must take into account the knowledge that industrial solvents cannot be produced without contamination with benzene, and therefore they contain benzene.35,36
Benzene exposure levels are rarely available for most workers, because few workers are monitored for benzene exposure. The scientific medical literature allows the physician to extrapolate from the symptomatology of exposure, such as the threshold odor recognition for benzene, 61-91 ppm, and symptomatology of dizziness, which is extrapolated to levels of 300 ppm. This methodology has also been accepted by the U.S. Courts,  Therefore it is imperative that the examining physician take a good history of exposure and look for odor recognition to extrapolate the levels of exposure and/or alternatively, symptoms of dizziness to extrapolate the levels of exposure. When history by the reporting physicians cannot be obtained, relying on depositions, job analysis and industrial hygienist assessment are acceptable.
H. Low Level Exposure to Benzene and Leukemia:
[Manuscript in preparation.]
I. Genetic Studies and Markers and Chromosomal Change:
A patient who developed aplastic anemia after exposure to benzene, was shown to have significant chromatoid fragments. A cytogenic study which was carried out later, on a patient who developed leukemia after 22 years of continuous exposure to a high concentration of benzene, showed that later in the process there were changes in 47 chromosomes in the bone marrow. Sellyei et al. studied patients who developed pancytopenia after having been exposed for 18 months to benzene. Significant chromosomal changes were detected even 7 years after remission from the anemia and the presentation of leukemia. In line with these changes, Forni et al. have studied 25 subjects with a history of hematopoietic abnormalities and benzene exposure, and compared these to 25 matched controls. They have shown that 18 years after clinical and hematological symptoms chromosomal aberrations were increased as compared to the control group. In 1965, Tough et al. have studied chromosomes of workers exposed to benzene for periods varying from 1 to 18 years. They have also shown a small but significant increase in chromosomal changes compared to a control group. These same investigators looked at workers exposed to benzene levels from 25 to 120 ppm, and found that they had significant chromosomal aberrations as compared to the normal population (which has a general background exposure to benzene levels). Hartwich et al. looked at 9 healthy refinery workers who were exposed to low levels of benzene, and also found significantly increased chromosomal changes compared to the control group. The National Research Council Advisory Center and Toxicology Study concluded that a close correlation between occupational exposure to benzene and persistence of chromosomal aberrations can be considered only when there is an association between benzene induced hematopoietic disease and chromosomal aberrations, however, the absence of chromosomal changes, cannot be a determinant in the temporal relationship between exposure to benzene and hematopoietic diseases.
While it is true that these findings are in agreement with previous studies they still could not explain the 43% of the patients who were not exposed, and still had abnormal chromosomal changes. This is a very important observation, since some investigators in the field claim that the Absence of chromosomal changes in benzene exposed individuals negates the clinical causative diagnosis of benzene induced hematopoietic disease. Essentially, all of the studies show that benzene can cause chromosomal changes, but does not cause perceptible changes in all patients, and the absence of visible chromosomal changes cannot and does not rule out the exposure to benzene as a causative factor. This is so because genetic point mutations and other types of changes are not observable using the standard cytogenetic banding techniques or even more sophisticated techniques such as fluorescence in situ hybridization (FISH), spectral karyotyping (SKY) or polymerase chain reaction (PCR) methods. Indeed, the courts have considered this issue and concluded that the genetic-chromosomal changes are not the equivalent of fingerprints of benzene exposure. The recent study by Zhang et al. has examined chromosomal changes as a result of exposure to chemicals, such as benzene. Some leukemias have more typical chromosomal changes than others, but not all leukemias have typical chromosomal changes detected by ongoing research.
The most comprehensive study on the nature of chromosomal changes and benzene exposure has been published by Luoping Zhang in Critical Reviews in Toxicology.51 The essence of this study is that benzene causes changes in certain chromosomes in certain hematological diseases. The absence of chromosomal changes does not rule out benzene exposure and benzene as a cause for the hematopoietic malignancy.
[Manuscript in preparation.]
J. How to Make or Rule Out a Diagnosis of Benzene-Related Hematological Disease:
In summary, benzene is a hematological carcinogen based on both experimental animal studies and human studies, as well as in vitro studies. While the precise mechanism of benzene carcinogenicity is not clear evidence that benzene metabolites damage DNA and chromofome, and in turn affects the stem cell: immature cell of the hematopoietic system which can in turn develop into any of the hematological cells originating from the bone marrow and the lymphatic system. Table 3 summarizes the information required for evaluation of industrial causation in hematological diseases of benzene.
[Manuscript in preparation.]
Table 3. Information Required in the Analysis of Benzene Exposure and Hematological Malignancies
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