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
Benzene is produced in large quantities in the United States. A total of 4.4 million tons of industrial grades were projected in the United States in 1985. A very large portion of benzene is utilized as a component of gasoline, in an average concentration of less than one percent. Benzene is very important for unleaded fuels because of its anti-knock characteristics. In 1978, it is estimated that 1,650 million (1,650,000,000) gallons were used in gasoline. A much smaller amount, less than two percent, is used for solvent purposes in such products as industrial paints, rubber cement, adhesives, paint-remover, artificial leathers and laboratory solvents. Due to the volatility and high solubility of benzene it has the potential to migrate in the environment and contaminate water directly and enter surfaces where water can penetrate.
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
Human exposure to benzene of significance is by the following:
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
To date, a long list of hematologic diseases has been scientifically linked directly to benzene exposure (Table 2).
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:
Aplastic anemia is a relatively rare, often fatal disorder in man. Its diagnosis is usually made on the basis of a significant reduction in the formed elements of the blood, including decreased white blood cells, anemia, and thrombocytopenia. A decrease in all three of these blood cells counts is defined as pancytopenia. A marked decrease in the number of cells in the bone marrow is called aplastic anemia. It is accepted that these two are not two separate diseases but rather are part of a spectrum of bone marrow failure syndromes which can result from benzene toxicity. Indeed, a complete evaluation of a work force in a benzene-using plant revealed many affected individuals with effects ranging from a mild cytopenia to aplastic anemia of sufficient severity to warrant hospitalization; levels of exposure were 10-400 ppm of benzene.
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:
Acute myeloblastic leukemia is a cancer of the blood system in which there is an abnormal production of hematologic stem cells, granulocytic leukocytes, red blood cells and platelets. This disease is mostly observed in adults and has an increasing incidence with age, peaking in the 6th or 7th decade. There are a number of variants of acute myelogenous leukemia which can be considered to be part of the same disease. These include acute myelomonocytic leukemia, promyelocytic leukemia, and erythroleukemia.
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:
Recently, studies aimed at evaluating the effects of benzene and leukemia have also shown an increase in the relative risk of lymphatic system malignancies in benzene workers. A recent study by NIOSH described increased mortality from lymphoma and lymphocytic leukemia. A similar increased risk for lymphatic cancer has been reported by other investigators., Rubber chemical workers who were exposed to benzene had 4 to 5 fold higher risk of lymphoid malignancy than those unexposed.
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:
To reduce the risk of leukemia in industrial workers exposed to benzene, the United States Occupational Safety and Health Administration (OSHA) in 1978 reduced the permissible work place exposure of benzene from previous 10 ppm to 1 ppm. However, in 1980, the US Supreme court invalidated the OSHA benzene standard of 1 ppm. The court states that AOSHA had failed to provide substantial evidence of the need for regulation, and that it had not demonstrated a significant risk of material health impairment at the previous level of 10 ppm. Since then, three studies have been published, in each of which the amount of benzene exposure has been found to correlate strongly with the risk of death from leukemia. The study published in the New England Journal of Medicine on benzene and leukemia 24 further demonstrates that a cumulative benzene exposure of 400 ppm years is equivalent to a mean annual exposure of 10 ppm over a 40 year working lifetime. (Ten ppm was at that time the enforceable standard in the United States for occupational exposure to benzene.) They concluded that protection from benzene-induced leukemia would increase exponentially with any reduction in the permissible exposure limit enforceable to date. Obviously, the crucial question of who will develop a hematological disease as a result of exposure at the workplace to benzene is currently impossible to predict scientifically. Although a dose relation has been demonstrated, the fact that some cases have been described where exposure to benzene was not at excessive levels suggests that even strict protective efforts may not completely prevent industrially-related benzene exposure and hematological cancers.
G. Levels of Exposure & Risk Assessment:
The issue of what is a safe level of exposure to benzene and what is not a safe level of exposure, or as some would like to define it sufficient exposure to cause a hematological cancer has been addressed by several studies and regulatory agencies. The study by the Environmental Protection Agency (EPA) as well as the International Agency for Research on Cancer clearly indicates that there is no safe level of exposure to carcinogenic agents in the absence of epidemiological data of safety in humans. In the absence of safety studies in humans, experimental animal data must be applied from a policy and public health prevention point of view. Indeed, the American Petroleum Institute (API) stated that In as much as the body develops no tolerance to benzene and there is a wide variation in individual susceptibility, it is generally concluded that the only absolutely safe concentration for benzene is zero. Analysis of levels of exposure and risk assessment summarized by the 1998 position paper of the EPA clearly concludes that the dose-response relationship for benzene follows a linear line through zero.
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:
Several technologies developed in the last 10 years to evaluate chromosomal changes and DNA changes caused by environmental exposures, as well as a marker of environmental exposures. The use of chromosomal abnormalities as a biological marker of exposure in humans have become an important tool in the research. Several abnormalities are found, including structural and numerical chromosomal aberrations, sister chromatoid exchanges (SCEs) and micronuclear changes. These are markers of changes in the cellular genetic materials, and represent damage induced by chemicals. These methodologies are viewed as cytogenetic assays, and by themselves cannot provide a diagnosis, but they complement other methodologies which include gene mutation analysis, and DNA changes. Among the important uses of cytogenetics is as a biomarker is the relationship between chromosomal aberrations secondary to chemicals and carcinogeneses.
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:
The examining physician who is faced with the question of causation in a patient with hematological malignancy and benzene exposure must utilize available epidemiologic and scientific data in the evaluation process. Ideally material safety data sheets as well as job descriptions and industrial hygiene reports, specifying the frequency and amount of exposure of benzene levels in the air should be considered, and the examining physician should request information in relation to other exposures such as solvent, radiation, pesticides, and cigarette smoking. Odor threshold recognition obtained via history, spills, headaches, and dizziness are scientifically extrapolated to levels of exposure. Although the latency period may be important in the final analysis, one must remember that the scientific literature shows a range of anywhere from 6 months with an average of 12 years and up to 40 years in some cases. In some instances, it is probable that both the exposure to benzene on an industrial basis and exposure to other toxic chemical (such as cigarette smoking) on a nonindustrial basis are additive to causation. In that scenario the reporting physician must determine whether the exposure to benzene, regardless of the other exposures, was a substantial factor in the development of the patient's hematological cancer. A substantial factor has been defined by the California Supreme Court in the Rutherford decision as levels which increase the risk of cancer more than theoretically or infinitesimally.
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
This paper represents the current state of the art of the benzene literature and the author's opinions. Some of the opinions expressed here were adopted from court documents and writings of Dr. Brautbar.
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