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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