Benzene and Diseases of the Blood: Revisited

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. (Table 1 describes some of the industrial exposures to benzene).

Table 1. Potential Industrial Exposures to Benzene

  1. Detergent Producers.
  2. Pesticide Producers.
  3. Gasoline Producers.
  4. Solvent Producers.
  5. Paint and Varnish Producers.
  6. Adhesive Producers.
  7. Rubber Industry Processors.
  8. Petroleum Industry Processors.
  9. Chemical Workers.
  10. Waste Management.
  11. Laboratory Technicians.
  12. Auto Mechanics, Painters, Printers, Degreasing Operations.
  13. Extraction & Sampling (Industrial Labs).
  14. Hauling, Loading, Unloading & Tank Cleaning Operations.
  15. Burning of Organically Originated Materials - Wood Burning, Garbage Burning, Insulation Materials, Hydraulic Fluids (Fire-Fighters, Law Enforcement, Technicians, Laborers).
  16. Rubber & Rubber Coating, Adhesives, Sealants.
  17. Engine Emissions.

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 ppm (parts per million) with an acceptable ceiling concentration of 25 ppm. In 1978, OSHA stated that 1 ppm with a 5 ppm ceiling limit for 15 minutes during the eight-hour day is the level which most adequately assures, to the extent feasible, the protection of workers exposed to benzene.

Following reports of toxicity, the use of benzene has been reduced significantly. However, Ringen, et al,(1) and Holmberg, et al,(2) noted that benzene exposure may still occur in industry and is detectable in workroom air in many industrial activities. This is of great concern to those of us in occupational medicine, toxicology, and regulatory medicine.

Route of Human Exposure
Human exposure to benzene of significance is by the following:

  1. Inhalation
  2. Dermal exposure
  3. Ingestion of water and other foods contaminated with benzene.

Although benzene is relatively soluble in water, commonly the magnitude of human exposure through 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 ppb (parts per billion) all the way 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 and skin contact is infrequent for the non-working general population. Therefore, the skin route is probably an insignificant source of exposure for the general population, but has been shown as a significant route of exposure in the working population.(3)

Smoking may be a significant benzene exposure source for a portion of the population. Studies have described that an individual who smokes one pack of cigarettes per day may be exposed to 10 mcg (micrograms) per cigarettes of benzene per day. In another report it was suggested that the average cigarette gives rise to about 31 mcg of benzene, so that the daily consumption of 10 cigarettes results in an uptake of about 310 mcg which is equivalent to the quantity of benzene inhaled over 24 hours when the air contains 7.5 mcg per cubic meter benzene at the respiratory minute value of 28.6 liters (for light work). In other words, under resting conditions the benzene concentration of the inhaled air would have to be at about 27 mcg per cubic meter in order for up to 310 mcg benzene to be inhaled in 24 hours.(4)

The literature as far as benzene and smoking-induced leukemia is not convincing. A recent study by Korte,(5) 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 problem with this study is that the author admitted that cigarette smoke contains several suspected leukemogens such as 1,3-butadiene, n-nitrosodi-n-butylamine, styrene, and radioactive elements, and therefore benzene in cigarettes is unlikely to be independently responsible for most smoking-induced leukemia. The majority of the scientific literature has concluded that there is no support for cigarette smoke as a cause of hematolymphatic malignancies. However, the paper by Korte,(5) et al, lends support to the proposition that small amount of benzene exposure renders the cellular detoxification system more sensitive to the cumulative exposure from benzene.

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 Hematologic Disorders

  1. Aplastic Anemia, Pancytopenia.
  2. Acute Myelogenous Leukemia.
  3. Erythroleukemia.
  4. Myelomonocytic Leukemia.
  5. Acute Promyelocytic Leukemia.
  6. Chronic Myelogenous Leukemia.
  7. Acute Lymphoblastic Leukemia.
  8. Hairy Cell Leukemia.
  9. Chronic Lymphocytic Leukemia.
  10. Hodgkin's Disease and Non-Hodgkin=s Lymphoma.
  11. Paroxysmal Nocturnal Hemoglobinuria.
  12. Multiple Myeloma.
  13. Lymphomas.
  14. Thrombocythemia.
  15. Thrombocytopenia.
  16. Myelofibrosis.
  17. Myelodysplastic Syndrome.

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 clearly understood.

A. 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 a spectrum of bone marrow failure secondary to 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 time of development 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.

B. 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,(6) 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 abnormality, whereby not related to the leukemia lymphoma group, it is still a chronic hematological disease of the bone marrow). 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.

C. 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,(7) described increased mortality from lymphoma and lymphocytic leukemia. A similar increased risk for lymphatic cancer has been reported by other investigators.(8,9) Rubber chemical workers who were exposed to benzene had 4 to 5 fold higher risk of lymphoid malignancy than those unexposed.

D. 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(6) 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 impossible to answer 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.

E. 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 Asufficient exposure to cause a hematological cancer has been addressed by several studies and regulatory agencies. The study by the Environmental Protection Agency (EPA)(10) as well as the International Agency for Research on Cancer,(11) 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) (12) 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. The most recent 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 the zero at low level (to be applied relevant to the Rinsky studies in the New England Journal of Medicine, 1987(6)). Specifically, that from an epidemiological point of view the cut-off point, is at 0.1 ppm cumulative exposure (40 years, 8 hours per day, workers) will equate to the background level of benzene risk for hematological cancers. Once the level of 0.1 ppm year cumulative exposure is established the risk will be that of background levels. Indeed, the studies by Infante(13) have shown that 35% of the workers exposed to benzene who died from leukemia or lymphoma were exposed to below 5 ppm average exposure levels. Picciano, et al(14) has shown chromosomal changes in workers exposed to levels of 1 ppm benzene. Increasing the level to 1 ppm year cumulative exposure, increases the risk exponentially to 1.7 as compared to the background level at 0.1 ppm year.(6)

The concept of cumulative benzene exposure for the working population must be well understood before one can address levels of exposure. The most recent studies by Hayes, et al, from the National Institute of Health,(15) provide the most 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.

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.(16,17) 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.(16,17)

As far as levels of exposure, it is difficult for a physician to establish a level absent the data provided from the employer. These data are commonly not available, are not provided, or measurements are not done. 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,(18) and symptomatology of dizziness, which is extrapolated to levels of 300 ppm.(19) This methodology has also been accepted by the U.S. Courts (20,21) Therefore it is imperative that the examining physician take a good history and look for odor recognition to extrapolate the levels of exposure and/or alternatively, symptoms of dizziness to extrapolate the levels of exposure.

F. Genetic Studies and Markers:
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 translocation as a biological marker of exposure in humans have become an important tool in the research, as well as in some instance a marker of exposure. Several methodologies have utilized and include structural 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 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.(22) A cytogenic study which was carried out later,(23) 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,(24) 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,(25) 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,(26) 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,(27) 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(28) concluded that close correlation between occupational exposure to benzene and persistence of chromosomal aberrations can be discussed 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(29) 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 Aabsence 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 it in all patients, and the absence of chromosomal changes cannot and does not rule out the exposure to benzene as a causative factor. Indeed, the courts have analyzed this issue and concluded that the genetic-chromosomal changes are not fingerprints of benzene exposure.(30)

G. 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 analysis description, industrial hygiene report, and investigative report, specifying the frequency and amount of exposure of benzene levels in the air should be provided, and the examining physician should request information in relation to other exposures such as solvent, radiation and pesticides. 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 15 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 on a nonindustrial basis may be additive. 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 . The substantial factor is defined by the California Supreme Court in the Rutherford decision as Alevels which are not theoretical or infinitesimal@(31)

As an example, I will discuss a case of leukemia in a 58-year-old petroleum engineer. He describes exposure to benzene on a frequent weekly basis, and described the smell of benzene. (The odor recognition for benzene is 61-91 ppm, and therefore equates to levels of exposure of at least 61 ppm). His leukemia was diagnosed 5 years after his last exposure to benzene (he was exposed over a period of 5 years). An investigative report, job analysis and material safety data sheets clearly showed no other exposures to chemicals (such as nonindustrial) and very clearly indicated a daily exposure to benzene with its inhalation over a period of 5 years. Based on the levels of exposure, safety data sheets and absent any other chemical exposure (the latency period of 10 years was compatible with the diagnosis of benzene induced leukemia), and in the medical records it was concluded that this patient=s leukemia was the result of his benzene work exposure at levels of at least 61 ppm (latency period: from the date of first exposure to the date of diagnosis).

In summary, benzene is a hematological carcinogen based on both experimental animal studies(32) and human studies, as well as in vitro studies. While the precise mechanism of benzene carcinogenicity is not clear, it has been well-established that benzene affects the stem cell - meaning the 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.

Table 3. Information Required in the Analysis of Benzene Exposure and Hematological Malignancies

  1. Detailed history of exposure, including, frequency, duration and symptoms during exposure.
  2. Job analysis description with detailed exposure history.
  3. Air level measurements, if available from employer (commonly this information is unavailable).
  4. Nonindustrial exposure to other hematological toxins.
  5. Industrial and non-industrial exposure to solvents, pesticides & herbicides.

Disclosure
This paper represents the current state of the art of the benzene literature and the authors opinions.

References

  1. Ringen K & Addis P, Protecting Workers From Benzene Exposure. In: Mehlman MA, ed, Carcinogenicity and Toxicity of Benzene, Princeton, NJ, Princeton Scientific Publishing, 77-89, 1983
  2. Holmberg B & Lundberg P, Benzene Standards, Occurrence, and Exposure. American Journal of Industrial Medicine, 7:373-383, 1985
  3. Kalnas J & Teitelbaum D, Dermal Absorption of Benzene: Implications for Work Practies and Regulations, Int J Occup Environ Health, 6:(2):114-121, April-June, 2000
  4. World Health Organization/International Agency for Research on Cancer, Environmental Carcinogens: Methods of Analysis and Exposure Measurement, Fishbein L & O=Neill IK, editors, Volume 10 - Benzene and Alkylated Benzenes, IARC Publications No. 85, Lyon, 1988
  5. Korte JE, et al, The Contribution of Benzene to Smoking-Induced Leukemia, Environmental Health Perspectives, 108(4):333-339, April, 2000
  6. Rinsky RA, et al, Benzene and Leukemia: An Epidemiologic Risk Assessment, New England Journal of Medicine, 316:1044-1050, 1987
  7. NIOSH Revised Recommendation for an Occupational Exposure Standard for Benzene, Cincinnati, Ohio: National Institute for Occupational Safety and Health, 1976. (DHEW publication no. (NIOSH) 76-137-A)
  8. Wong O, An Industry Wide Mortality Study of Chemical Workers Occupationally Exposed to Benzene. I. General Results. British Journal of Industrial Medicine, 44:365-381, 1987
  9. Yin SN, et al, A Cohort Study of Cancer Among Benzene-Exposed Workers in China: Overall Results, American Journal of Industrial Medicine, 29:227-235, 1996
  10. Cairns, T. The ED01 study: Introduction, objectives and experimental design. Innovations in Cancer Risk Assessment (ED01 Study). Staffa JA and Mehlman MA (Eds). Pathotox Publishers, Inc. Forest Park South, IL. 1-7, 1979
  11. World Health Organization/International Agency for Research on Cancer, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volumes 1-42, Supplement, 1987.
  12. American Petroleum Institute, API Toxicological Review, Benzene, September 1948
  13. Infante PF and Book SA, Chemicals and Human Cancer, Lancet, 340(8832):1408-1409, December 5, 1992
  14. Picciano DJ, Monitoring Industrial Populations by Cytogenetic Procedures. In: Infante PF and Legator MS, Editors, Proceedings of the Workship on Methodology for Assessing Reproductive Hazards in the Workplace, U.S. Government Printing Office, Washington, D.C, 293-306, 1980
  15. Hayes RB, et al, Benzene and the Dose-Related Incidence of Hematologic Neoplasms in China, Journal of the National Cancer Institute, 89(14):1065-1071, July 16, 1997
  16. Federal Register, Department of Labor, Occupational Safety and Health Administration, 29 CFR Part 1910, Occupational Exposure to Benzene: Final Rule, 09/11/87
  17. Testimony of R.S. Proctor - Before the Occupational Safety and Health Administration, In Re: Proposed Revised Permanent Standard for Occupational Exposure to Benzene, OSHA Docket No. H-059, 07/11/77
  18. American Industrial Hygiene Association, Odor Thresholds for Chemicals with Established Occupational Health Standards, 1989
  19. Patty's Industrial Hygiene and Toxicology, Third Revised Edition, Volume 2B, Toxicology, Edited by GD Clayton and FE Clayton, a Wiley-Interscience Publication, 1978
  20. Westbury v. Gislaved Gummi AB, U.S. 4th Circuit Court of Appeals, Nos. 98
  21. Mike Curtis, et al, v M&S Petroleum, Inc., et al, United States Court of Appeals, Fifth Circuit, No 97-60685, May 13, 1999
  22. Pollini G and Colombi R, Lymphocytic Chromosome Damage in Benzene Blood Dyscrasia Med Lav, 55:641-645, 1964
  23. Forni A and Moreo L, Cytogenetic Studies in a Case of Benzene Leukaemia, Eur J Cancer, 3:251-255, 1967
  24. Sellyei M and Kelemen E, Chromosome Study in a Case of Granulocytic Leukaemia with >Pelgerisation= 7 Years After Benzene Pancytopenia, Eur J Cancer, 7:83-85, 1971
  25. Forni AM, et al, Chromosome Changes and Their Evolution in Subjects with Past Exposuer to Benzene, Arch Environ Health, 23:385-391, 1971
  26. Tough IM and Court Brown WM, Chromosome Aberrations and Exposure to Ambient Benzene, Lancet, I, 684, 1965
  27. Hartwich G and Schwanitc G, Chromosome Studies After Chronic Benzol Exposure, Dtsch. Med. Wschr, 87:45-49, 1972
  28. National Research Council Advisory Centre on Toxicology, Washington D.C., Health Effects of Benzene: A Review. Prepared for the Environmental Protection Agency. Report No. NAS/ACT/P-829, (June, 1976)
  29. Golomb HM, et al, Correlation of Occupation and Karyotype in Adults With Acute NonLymphocytic Leukemia, Blood, 60(2):404-411, August, 1982
  30. Ida James v Bessember Processing Corporation, Inc, et al, A-115, 116, 117, 118, 119, 120-97, New Jersey Supreme Court, 1998
  31. Rutherford v Owens Illinois Inc, 16 CAL, 4th, 953, 67, Cal Rpt 2d 16, 1997
  32. C. Maltoni, et al, Benzene, a Multipotential Carcinogen, American Journal of Industrial Medicine, 4:589-630, 1983

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