Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Remark: Benzene is a ubiquitous occupational hematotoxin and
leukemogen, but people vary in their response to this toxic
agent. To evaluate the impact of interindividual variation
in enzymes that activate (i.e., CYP2E1) and detoxify (i.e.,
NQO1) benzene and its metabolites, we carried out a
case–control study in Shanghai, China, of occupational
benzene poisoning (BP; i.e., hematotoxicity), which we show
is itself strongly associated with subsequent development
of
acute nonlymphocytic leukemia and the related
myelodysplastic syndromes (relative risk, 70.6; 95%
confidence interval, 11.4–439.3). CYP2E1 and NQO1 genotypes
were determined by PCR–RFLP, and CYP2E1 enzymatic activity
was estimated by the fractional excretion of chlorzoxazone
(fe(6–OH)) for 50 cases of BP and 50 controls. Subjects
with
both a rapid fe(6–OH). and two copies of the NQO1 609C––>T
mutation had a 7.6–fold (95% confidence interval, 1.8–31.2)
increased risk of BP compared to subjects with a slow
fe(6–OH) who carried one or two wild–type NQO1 alleles. In
contrast, the CYP2E1 PstI/RsaI polymorphism did not
influence BP risk. This is the first report that provides
evidence of human susceptibility to benzene–related
disease.
Further evaluation of susceptibility for hematotoxicity
and
hematological malignancy among workers with a history of
occupational exposure to benzene is warranted.
Benzene poisoning, a risk factor for hematological
malignancy, is associated with the NQO1 609 C ––>T mutation
and rapid fractional excretion of chlorzoxazone
Source: EXXON Biomedical Sciences East Millstone, NJ
Reliability: (1) valid without restriction
07–JUL–2005 (965)
Remark: Risk of cancer and exposure to gasoline vapors.
Until the introduction of self–service around 1970, service
station workers in the Nordic countries were exposed to
gasoline vapors. Based on measurements reported in the
literature, the 8–hour time–weighted average benzene
exposure was estimated to be in the range of 0.5–1 mg/m3.
We
studied the cancer incidence in a cohort of 19,000 service
station workers from Denmark, Norway, Sweden, and Finland.
They were identified from the 1970 censuses and followed
through 20 years, where 1,300 incident cancers were
observed. National incidence rates were used for
comparison.
The incidence was not increased for leukemia [observed =
28,
standardized incidence ratio (SIR) = 0.9, 95% confidence
interval (CI) 0.6–1.3] not for acute myeloid leukemia
(observed = 13, SIR = 1.3, 95% CI 0.7–2.1). The incidence
was slightly elevated for kidney cancer observed = 57, SIR
=
Appendix D: Benzene SIDS Dossier
– 749/957 –