Benzene, Aplastic Anemia, and Leukemia

I. There are natural and industrial sources of benzene exposure. Occupational exposures have dropped markedly since the early 1960s.

"Benzene is a natural component of crude and refined petroleum. . . . In the United States, gasoline typically contains less than 2% benzene by volume, but in other countries the benzene concentration my be as high as 5%. . . . Benzene was also an important component of many industrial cleaning and degreasing formulations, but now has been replaced mostly by toluene, chlorinated solvents , or mineral spirits. Although benzene is no longer added in significant quantity to most commercial products, traces of it may still be present as a contaminant." [ATSDR Case Studies in Environmental Medicine: Benzene Toxicity. June, 2000. p. 7]

"Natural source of benzene include volcanoes and forest fires. Benzene is also a natural part of crude oil, gasoline, and cigarette smoke." [ATSDR ToxFAQs]

"The major uses of benzene include the manufacturing of industrial chemicals (e.g., polymers, detergents, pesticides, dyes, plastics, resins) and explosives, and as a solvent for waxes, resins, oils, and natural rubber, among other materials. In addition, until the early 1960s benzene was a major component used for printing and lithography, adhesives, and coatings. Benzene was also used extensively in the tire industry and shoe factories, as a thinner for paints, and as a degreasing agent. In the United States, benzene exposure is most commonly found in industrial sectors that produce benzene (i.e., petrochemical plants, petroleum refineries, and the coke and coal chemical manufacturing facilities), the rubber tire manufacturing industry, and companies engaged in the bulk storage and transportation of benzene or petroleum product s containing benzene (i.e, petroleum bulk terminals and gasoline service stations." [van Wijngaarden E, Stewart PA, 2003, p. 678]

". . . the recommended standard for benzene before 1947 was 100 ppm, which was reduced to 50 ppm in 1947, and further reduced to 35 ppm in 1947." [Wong. 1999, p. 218] Currently, the PEL is 1 ppm, and the TLV is 0.5 ppm.

"Estimated mean annual TWA benzene exposures were said to decrease from a high of 137 ppm in 1940 to 4 ppm in 1970." [ACGIH Documentation of TLVs and BEIs]

II. Severe chronic benzene poisoning at doses >100 ppm is an established cause of aplastic anemia and leukemia.

"Aplastic anemia caused by bone marrow suppression is the classic cause of death in chronic benzene poisoning. The association between benzene exposure and bone marrow suppression has been recognized since 1897. Leukemia in workers exposed occupationally to benzene was first recognized in the 1920s." [Rom, p. 1125]

"The number of reported cases of severe chronic benzene poisoning with aplastic anemia gradually decreased after World War II, because of better engineering controls, progressive reduction of the PELs, and efforts to substitute less toxic solvents for benzene in numerous industrial processes." [Wallace, p. 624]

"Before 1950, benzene was the single most common cause of toxic aplastic anemia. With chronic doses of greater than 100 ppm, isolated cytopenias and aplastic anemia were common. The cytopenias usually resolved after termination of exposure; even with persistent exposure, spontaneous remissions have been described. At exposures of 100 ppm or higher, some workers will develop fatal aplastic anemia. . . . The initial prognosis in benzene-related aplastic anemia is better than that for idiopathic aplastic anemia; up to 40% of patients may recover completely after removal from the source of exposure. If hypocellularity persists for more than several months, recovery is not likely to occur. Exposure is also associated with the development of acute nonlymphocytic leukemia and chronic myelogenous leukemia--either de novo or in workers who have recovered from a bout of aplastic anemia--and in cases of irreversible aplastic anemia." [LaDou, p. 219-20]

III. Animal experiments and epidemiology studies of workers have established a threshold dose. Below this threshold dose, the hepatic cytochrome P-450 system is not saturated and there is no evidence of injury to blood cell precursors in the bone marrow.

"Hematopoietic depression in rodents was observed at benzene concentrations as low as 103 ppm after a 5-day exposure. . . . When groups of 40 CD-1 mice were exposed 6 hours/day, 5 days /week for life to benzene in air at 100 or 300 ppm, 2 mice in the high-dose group developed myelogenous leukemia. No leukemia was observed in the 100-ppm group." [ACGIH Documentation of TLVs and BEIs]

"Spear et al. proposed that, at an 8 ppm/hour exposure, the body's hepatic cytochrome P-450 system would not be saturated; thus, the nonlinear basis of tissue damage associated with benzene exposure would dictate that only if little or no margin of safety was attendant to the TLV or Permissible Exposure Limit (PEL) would peak, short-term, high-exposure levels contribute substantially to the toxicologic response." [ACGIH Documentation of TLVs and BEIs, p. 11]

"Because no single benzene metabolite reproduces the myelotoxic and hematotoxic effects of exposure  to benzene, the mechanisms of toxicity remain somewhat speculative." [Sullivan, p. 755]

"Benzene toxicity may present as an acute illness or as a chronic disease developing up to 30 years after exposure. Chronic or recurrent exposure to concentrations of benzene exceeding 100 ppm (320 mg/m3) leads to a very high incidence of cytopenias. When the exposure ends, there is usually spontaneous remission. Among workers who have been exposed to atmospheric concentrations of benzene in excess of 300 ppm for at least 1 year, as many as 20% will acquire pancytopenia or aplastic anemia. The chronic form of illness is related to the effect of benzene on the bone marrow, where benzene appears to exert a colchicine-like effect, blocking mitosis of the marrow proliferative cells. This then results in mutagenic effects that play a role in the subsequent development of leukemia. Aplastic anemia generally occurs in subjects while they are still exposed to high concentrations of benzene; leukemia may occur at the same time or shortly after cessation of exposure. Leukemia often develops in subjects with benzene-induced hyporegenerative anemia or long-standing pancytopenia and represents the acute terminal stage of the disease. Approximately 1 patient in 60 with benzene-induced pancytopenia or aplastic anemia and 1 patient in 10 with unremitting, progressive marrow failure who survive beyond 1 year will develop acute nonlymphocytic leukemia." [LaDou, p. 258-9]

"He [Wong] reported relative risks on the order of 100 for individuals exposed to extremely high concentrations (400 ppm per year) but no significant excess risks were observed below 200 ppm per year. These results are actually consistent with those previously reported by Rinsky et al., who reported a statistically significant excess in leukemia above 200 ppm per year. For virtually all other occupational and environmental agents, the evidence for leukemogenesis remains questionable." [Sullivan, p. 757]

"In contrast, in populations of workers reported to have an increased risk of AML in previous studies, exposure to benzene was much higher. For example, it was reported that shoemakers in Turkey, who used solvents containing up to 88% benzene, were exposed to concentrations of benzene in air as high as 650 ppm, and Pliofilm workers in Ohio to peaks as high as 750 ppm and 8 h TWAs as high as 260 ppm." [Wong. 1999, p. 220]

"A TLV-STEL of 2.5 ppm is recommended to protect against excess risk of leukemia due to the dose-rate-dependent hematopoietic toxicity of benzene. The hypothesis supporting an approach to control peak exposures suggests that bone marrow toxicity  occurs only after the critical delivered (threshold) dose to target hematopoietic progenitor cells is exceeded." [ACGIH Documentation of TLVs and BEIs, p. 17]

"Routine complete blood counts (CBCs) to detect benzene-induced marrow depression, and urinary phenols to detect excessive benzene exposure not likely to be sensitive enough to be useful at current levels of exposure in the developed world, except for indicating serious breaches of industrial hygiene, leading to overexposures greater than 10-fold the permissible exposure limit (PEL)." [Rosenstock, p. 746-7]

IV. Acute effects of benzene exposure are euphoria and central nervous system depression after ingestion, inhalation, or skin absorption.

"In animal studies, nearly 100 per cent of benzene is absorbed orally but 20-40 per cent is absorbed dermally. Nearly 50 percent of inhaled benzene is absorbed through the lung. Lipophilic properties permit passage through alveolar membranes and accumulation in the brain, resulting in rapid and potent euphoria." [Ford, p. 803]

"Benzol jag" is a term workers use to describe symptoms of confusion, euphoria, and unsteady gait associated with acute benzene exposure."  [ATSDR Case Studies in Environmental Medicine: Benzene Toxicity. June, 2000. p. 12]

"As an acute poison, benzene produces narcotic effects comparable to those of toluene." [ACGIH Documentation of TLVs and BEIs]

"Benzene dermal absorption was 0.05% when neat liquid benzene was applied directly to a human forearm at 0.0022 mg/cm2 and allowed to dry." [ACGIH Documentation of TLVs and BEIs]

"While percutaneous absorption of liquid benzene through intact human skin can be limited (e.g., 0.05% of the applied dose), the absorbed dose via direct dermal contact combined with that received from body surface exposure to benzene in workplace air is such that a substantial fraction (20% -40%) of the total exposure is due to skin absorption; thus, the Skin notation is assigned to benzene." [ACGIH Documentation of TLVs and BEIs, p. 17]

V. After a latency period, severe chronic benzene poisoning can cause aplastic anemia. Many cases of aplastic anemia go into remission, but some cases progress to myelodysplastic syndrome and acute myeloid leukemia.

". . . it must be kept clearly in mind that there generally is not a significant latency period between exposure to a causal agent for aplastic anemia and the resultant syndrome. For this reason, the search should be confined largely to events and environments to which the patient has been exposed over the previous 6 months." [Rosenstock, p. 466]

"The natural history of aplastic anemia follows one of four pathways. . . Some cases evolve directly into myeloproliferative syndrome or acute leukemia within months to years." [Rosenstock, p. 466]

"From these studies, we can infer that MDS [myelodysplastic syndrome] is not rare and probably precedes leukemia in a substantial proportion of all cases. There has been enough careful follow-up of patients who have been exposed to ionizing radiation and chemotherapy to know that these agents strongly predispose individuals to the delayed occurrence of MDS, usually 3 to 10 years after treatment with apparently normal intervening marrow recovery. . . From this viewpoint, it appears that organic solvent exposure may be an important risk for MDS. This impression is strongly reinforced by a review of well-described cases of benzene-related disease, over half of which now appear to be most consistent with MDS as opposed to aplastic anemia. It is likely, therefore, that agents that may cause aplastic anemia during exposure can cause MDS later, but full epidemiologic and experimental confirmation for these relationships is still needed. . . . MDS either smolders for a long time or evolves into frank leukemia." [Rosenstock, p. 467]

"In recent years it has become increasingly appreciated that myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) are stages in the progression of a common transformation process that is frequently observed following cancer chemotherapy with alkylating agents or following chronic exposure to high concentrations of benzene. Moreover, many historical references to aplastic anemia occurring as a consequence of chronic exposure to hematotoxic agents may with hindsight have been more appropriately diagnosed as MDS." [Sullivan, p. 750]

"Aksoy et al. and Aksoy studied Turkish shoe and handbag production workers who inhaled an average of 150 to 210 ppm when benzene-containing adhesives were used and 15 to 30 ppm at other times. Peak benzene exposures varied between 210 and 640 ppm, and the duration of exposure was estimated to average 9.7 years. Of the 44 cases of pancytopenia, 23 (52%) experienced remission of the aplastic anemia, 14 (32%) died from complications of aplastic anemia or pancytopenia, and 6 (4%) later died from leukemia." [ACGIH Documentation of TLVs and BEIs, p. 9]

"The initial prognosis in benzene-related aplastic anemia is better than that for idiopathic aplastic anemia; up to 40% of patients may recover completely after removal from the source of exposure." [LaDou, p. 219]

VI. Chronic high-level benzene exposure is an established cause of acute myeloid leukemia after a median latency of about 12 years.

"In the United States there are approximately 24,000 new cases of leukemia a year, which represent about 3% of all malignancies. AML and it variants account for 46% of all leukemias; chronic myelogenous leukemia (CML), 14%; acute lymphatic leukemia (ALL), 11%; and chronic lymphatic leukemia (CLL), 29%. These numbers are generally comparable among Western countries. In adults, AML constitutes almost 90% of all acute leukemias." [Sullivan, p. 751]

Leukemias represent 3% of all malignant neoplasms. Ionizing radiation, benzene, and cytotoxic drugs are known causes of acute leukemia. In atomic bomb survivors, the incidence of acute leukemias peaked at 2 to 5 years and declined after 10 years. After chemotherapy, the incidence peaks at 5 to 8 years. Acute lymphocytic leukemia (ALL) is limited mainly to the first 2 decades of life. [Rosenstock, p. 746]

Acute myeloid leukemia is a sentinel health event (occupational) in occupations exposed to benzene. [Mullan, p. 781]

"Exposure to benzene has been associated with development of a particular type of leukemia called acute myeloid leukemia (AML)." [ATSDR Public Health Statement: Benzene]

"Aksoy et al. found that the induction period ranged from 6-14 years (median, 11 years). Vigliani reported an induction period of 3 to 23 years (median, 9 years), and Rinsky indicated a median latency of 12 years (2-22 years)." [ACGIH Documentation of TLVs and BEIs, p. 11]

VII. Gasoline is not an established cause of leukemia.

"A typical gasoline composition would be 80% paraffins, 14% aromatics, and 6% olefins. The mean benzene content was found to be approximately 1%. . . . A TLV-TWA of 300 ppm to minimize the potential for ocular and upper respiratory tract irritation is recommended for bulk handling of gasoline . . . In light of clear evidence for rodent carcinogenicity [kidney cancer] after lifetime exposure to gasoline, an A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, notation is assigned to gasoline." [ACGIH Documentation of TLVs and BEIs]

"When compared with contemporaneous occupational health standards, our review indicates that most activities performed on marine vessels from the 1970s to 1990s usually did not result in benzene exposures that exceeded these standards." [Williams et al. 2005, p. 586]

"There is limited evidence that working in petroleum refineries entails a carcinogenic risk. This limited evidence applies to skin cancer and leukaemia; for all other cancer sites on which information was available, the evidence is inadequate. . . . Occupational exposure in petroleum refining are probably carcinogenic to humans (Group 2A)." [IARC]

"Gasoline is possibly carcinogenic to humans. (Group 2B)." [IARC]

"Human epidemiologic studies on lung cancer, kidney cancer, leukemia, and multiple myeloma have not shown statistically significant increases following chronic gasoline vapor exposure." [Rosenstock, p. 1055

"Epidemiological evidence from relatively low-dose occupations, such as service station attendants and auto mechanics, has suggested a relationship of benzene with leukemia, but the evidence is not regarded as conclusive." [Rosenstock, p. 752]

"Several case reports describe hematologic effects in persons with known long-term exposure to gasoline vapor. In these case reports, the blood dyscrasias described (i.e., anemia, hypochromia, thrombocytopenia, and neutropenia) were thought to be due to the benzene in gasoline mixture. . . . A recent study of U.S. gasoline workers in land-based distribution and marine operations found no evidence of increased cancer risk associated with gasoline exposure. . . . A meta-analysis in 1989 of several epidemiologic studies did not reveal any clear association between gasoline exposure and leukemia." [ATSDR Case Studies in Environmental Medicine: Gasoline Toxicity. September, 1993. p. 10-11]

VIII. Jet fuel is not an established cause of leukemia.

"A cohort of men exposed to jet fuel, aviation kerosene and other fuels in the Swedish Air Force had no increased cancer risk during ten years of follow-up." [IARC: Jet Fuel (Group 3)]

Jet fuel (JP-4 and JP-7) contains <0.5% benzene. "No reports of possible effects of JP-4 or JP-7 on hematologic parameters have been reported in exposed humans. Leukopenia was reported in animal studies, possibly from the benzene in jet fuel." [ATSDR Case Studies in Environmental Medicine: Jet Fuel Toxicity. September, 1993. p. 4, 9]

IX. A causal relationship has been established between occupational exposure to benzene and two forms of leukemia: myelodysplastic syndrome and acute myeloid leukemia.

"One salient example is a continuing ambiguity over the differential diagnosis of CML and MDS. While the evidence linking the development of MDS and AML with chemical or drug exposure is unequivocal, the same has not been convincingly demonstrated for CML. . . . Because the morphological and cytological parameters of CML can be difficult or impossible to distinguish from myelodysplastic syndrome (MDS), cytogenetic or molecular analysis is important in the classification of patients with the disease. . . . Case reports, either isolated or collected, are important for suggesting a possible relationship between exposure and disease and for providing a rationale for the conduct of more rigorous and detailed studies. Yet despite their importance in this regard, they cannot be used to establish a causal relationship." [Sullivan, p. 751]

"Chronic myeloid leukemia has been reported among benzene-exposed workers in China and the United States, but the small numbers or cases preclude precise quantification of risk and the association requires confirmation in other benzene-exposed populations." [Schottenfeld, p. 852]

"While some case-control studies have suggested a link with CLL, large cohort studies in the United States and China have shown little evidence of increased risk of CLL associated with benzene exposure . . . " [Schottenfeld, p. 857]

X. In conclusion, benzene is causally linked to acute myeloid leukemia based on studies of workers exposed to high levels of benzene in the past. Gasoline and jet fuel are not causally linked to leukemia.

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Revised: April 11, 2011

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