Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
______________________________________________________________________________
Type: other: The benzene metabolites hydroquinone and catechol act
in synergy to induce dose–dependent hypoploidy and –5q31 in a
human cell line.
Remark: Chronic exposure to high concentrations of benzene is
associated with an increased incidence of myelodysplastic
syndrome (MDS) and acute myelogenous leukemia (AML). Studies
of patients occupationally exposed to benzene show a pattern
of cytogenetic aberrations involving loss of all or part of
chromosomes 5 and/or 7 as well as trisomy 8 and we have
previously reported that hydroquinone (HQ) induces deletions
of 5, 7 and 8. Benzene metabolism is a requirement for bone
marrow toxicity and the phenolic metabolites, HQ and
catechol (CAT), have been implicated in benzene
hematotoxicity. A research project was designed to determine
whether CAT by itself and in conjunction with HQ could
directly induce loss of chromosome 5 and/or 7 and gain of
chromosome 8. Using fluorescence in situ hybridization with
chromosome–specific 5, 7, and 8 probes we demonstrate that 5
to 150 uM CAT does not produce chromosomal aberrations,
however CAT and 25 uM HQ can act in synergy to induce dose
dependent loss of these chromosomes. In addition HQ/CAT
selectively induces –5q which is not observed for HQ only.
These results demonstrate for the first time that CAT/HQ act
in synergy to induce specific chromosome loss found in
secondary MDS/AML.
Source: EXXON Biomedical Sciences East Millstone, NJ
Reliability: (1) valid without restriction
24–JUL–2000 (1090)
Type: other: Loss of p53 in benzene–induced thymic lymphomas in
p53+/– mice: evidence of chromosomal recombination.
Remark: The purpose of this study was to examine the role of
chromosomal recombination in mediating p53 loss in
benzene–induced thymic lymphomas in C57BL/6–Trp53
haplo–insufficient (N5) mice (p53+/– mice). The authors
characterized loss of heterozygosity (LOH) on chromosome 11
using 7 microsatellite markers in 27 benzene–induced and 6
spontaneous thymic lymphomas. Eleven patterns of LOH were
found between the induced and spontaneous tumors, with only
1 pattern being in common between the tumor groups. Nearly
90% (24 of 27) of benzene–induced tumors exhibited loss of
the functional p53 allele locus, and 83% (20 of 24) of these
tumors retained 2 copies of the disrupted p53 allele. Thus,
benzene induces a high frequency of LOH on chromosome 11 in
p53+/– mice, likely mediated by aberrant chromosomal
recombination.
Source: ExxonMobil Biomedical Sciences Inc. Annadale, New Jersey
04–JUL–2005 (130)
Appendix D: Benzene SIDS Dossier
– 785/957 –