Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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might be responsible for differences in human susceptibility
to poisoning by benzene, and cite the following in support
of this hypothesis:
* NQO1 with a C to T substitution in cDNA at nucleotide 609
is associated with decreased or absent enzyme activity;
* Individuals with the NQO1 T/T genotype and high levels of
CYP2E1 exhibit an increased sensitivity to benzene
poisoning;
* A single nucleotide polymorphism (substitution of A for G)
in the c.–463 promoter gene may decrease expression of MPO;
* Individuals with a GSTT1 null genotype exhibit increased
susceptibility to myelodysplasic syndrome.
Result: There was no significant difference between the patients and
the controls with regard to age, exposure duration and
intensity of exposure.
Appendix D: Benzene SIDS Dossier
GENETIC POLYMORPHISMS
A random sample of 24 patients and 24 controls were examined
for possible genetic variations in NQO1, CYP2E1 and MPO
genes using direct sequencing. Seventeen single nucleotide
polymorphisms (SNPs) were identified in the screened regions
of NQO1, CYP2E1 and MPO, and 6 SNPs in CYP2E1 and MPO
genotyped in all subjects using denaturing HPLC. Comment:
The publication contains extensive supporting information on
sequence variation, allele frequency and genotype frequency.
EFFECTS OF GENETIC POLYMORPHISMS ON BENZENE POISONING
The distribution of 8 independent polymorphisms was compared
in patients and controls, however there was no association
between genetic polymorphism and susceptibility to benzene
poisoning for the two groups. The frequency of patients with
2 copies of a variation in NQO1 (25.7%) was slightly higher
than the controls (19.6%), however this difference was not
statistically significant. There was little difference in
odds ratio when adjusted for sex and exposure duration and
intensity.
MODIFICATION OF RISK OF BENZENE POISONING BY LIFESTYLE AND
GENETIC POLYMORPHISM
The frequency of genotype NQO1 c.609 T/T in regular smokers
was 44.4% for patients and 9.7% for controls (P = 0.01).
There was a 7.73–fold increased risk of benzene poisoning
for smokers carrying this gene than for those with the
heterozygous or wild type gene. Adjustment for sex, exposure
duration/intensity and alcohol consumption had minimal
impact on the results.
Smokers carrying the CYP2E1 c.–1293G/C or C/C genotypes had
a 3.3–fold increase in risk of benzene poisoning compared
with smokers carrying the wild type gene (G>C or G/G)
however this was no–longer apparent after adjustment for
sex, exposure duration/intensity and alcohol consumption.
Among alcohol drinkers, NQO1 c.609 T/T occurred in 61.1% of
the patients compared with 12.5% of the controls. Alcohol
drinkers with NQO1 c.609 T/T had an 11–fold greater risk of
benzene poisoning than alcohol drinkers with a NQO1 c.609
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