PRINCIPLES OF TOXICOLOGY

104 HEMATOTOXICITY: CHEMICALLY INDUCED TOXICITY OF THE BLOOD
Not all of benzene’s metabolites cause bone marrow suppression. Phenol, hydroquinone, catechol,
trihydroxy benzene, and muconaldehyde act in concert to cause bone marrow changes; by themselves
these metabolites have less marrow toxicity. The precise mechanism by which these metabolites act
alone or in concert to cause marrow suppression is uncertain, although these issues are among the
topics of ongoing research.
4.11 CHEMICAL LEUKEMOGENESIS
Bone marrow injury may promote the development of myelodysplastic syndromes and acute myelogenous
leukemia. Therefore, by damaging the bone marrow, benzene, chloramphenicol, and cancer
chemotherapeutic agents increase an individual’s risk of contracting bone marrow cancer. However,
critical issues regarding exposure and dose, as well as the weight of evidence from epidemiologic and
animal studies all influence the relative risk. The cancer biology of chemically induced leukemia is
complex, and one or more of the following mechanisms may be involved in the progression toward
myelodysplastic syndrome and possibly leukemia: bioactivation of the parent molecule to reactive
intermediates, disruption of marrow physiology (e.g., interference with the mitotic spindle), inhibition
of topoisomerases, formation of DNA adducts, chromosomal alterations, oncogene activation, and
suppressor gene inactivation. As with any chemically induced cancer, benzene-induced AML follows
a continuum or progression of events that includes repeated bone marrow injury and suppression,
chromosomal changes, the development of dysplastic and metaplastic features, and the ultimate
expression of AML.
Awareness of benzene’s role in acute myelogenous leukemia came later. The mounting evidence
of benzene-induced leukemias finally surfaced in the 1970s and 1980s with publication of NIOSHconducted
studies of Pliofilm workers from two plants in Ohio, the Turkish studies of shoemakers who
used glues with high benzene content, and Italian rotogravure printers who used benzene-containing
solvents, for example. The collective findings of these studies clearly implicated benzene in the
development of AML. Recent Chinese studies suggest that other hematological tumors may occur at
a higher incidence among benzene-exposed workers. However, the evidence for benzene-induced
hematological cancers, other than AML, is still rather limited, and further investigations are needed.
Industries with less benzene exposure (average benzene exposures of 1 part per million or less among
refinery workers, rubber workers, and gasoline workers) and chemical workers exposed to benzene
have not shown an increased incidence of AML. effects.
The Pliofilm studies have contributed information involving exposure estimates and dose–response
relationships. For instance, Rinsky et al. (1988) first proposed a risk–exposure relationship:
OR = e(0.0126 × ppm⋅year)
where OR stands for the odds ratio for leukemia relative to the unexposed workers in a worker who
has acquired a specific cumulative ppm⋅year of benzene exposure. Based on this risk model a
background exposure of 0.1 ppm⋅year generates a risk estimate no greater than background, that is, an
odds ratio of 1.0. More recent studies of the Pliofilm workers have concluded that a threshold level of
benzene as high as 50 ppm (or even higher) must be exceeded before a significant risk of developing
AML exists.
In summary, epidemiologic evidence has established that high-level benzene exposure in the
workplace is associated with an increased risk of acute myelogenous leukemia. Clear evidence that a
causal relationship exists between benzene exposure and AML comes primarily from the studies on
Pliofilm workers. When these studies are further evaluated for a dose–response relationship, the level
of occupational exposure that bears a significant risk may be 50 ppm or greater. There is no sound
evidence that benzene causes other types of cancer such as other types of leukemia, non-Hodgkin’s
lymphoma, or solid tumors such as lung cancer. Currently, the OSHA standard of 1.0 ppm should
provide adequate protection against both benzene-induced bone marrow depression and a risk of AML.