Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Type: Metabolism
Remark: Benzene is metabolized by cytochrome P450 2E1 to various
phenolic metabolites which accumulate in the bone marrow.
Bone marrow contains high levels of myeloperoxidase which
can catalyze the further metabolism of the phenolic
metabolites to reactive free radical species. Redox
cyclingof these free radical species produces active oxygen.
This active oxygen may damage cellular DNA (known as
oxidative DNA damage) and induce genotoxic effects. HL60
cells (a human leukemia cell line) contain high levels of
myeloperoxidase and were used as an in vitro model system.
Exposure of these cells to phenol, hydroquinone, and
1,2,4–benzenetriol resulted in an increased level of
oxidative DNA damage. An increase in oxidative DNA damage
was also observed in the mouse bone marrow in vivo 1 h
afterbenzene administration. A dose of 200 mg/kg benzene
produced a 5–fold increase in the 8–hydroxydeoxyguanosine
level. Combinations of phenol, catechol, and hydroquinone
also resulted in significant increases in steady state
levels of oxidative DNA damage in the mouse bone marrow but
were not effective when administered individually.
Administration of 1,2,4–benzenetriol alone did, however,
result in a significant increase in oxidative DNA damage.
This represents the first direct demonstration of active
oxygen production by benzene to phenolic metabolites and
thesubsequent production of oxidative DNA damage may
therefore play a role in the benzene–induced genotoxicity,
myelotoxicity, and leukemia.
Source: Deutsche Shell Chemie GmbH Eschborn
06–JAN–1997 (628)
Type: Metabolism
Remark: Hepatocytes isolated from the adult male NMRI mouse or
Wistar rat were incubated for 1 h with 0.5 mM 14C–benzene,
the supernatant was separated from the cells, and analysed
for benzene metabolites. Separately, formation of sulphate
conjugates during benzene metabolism was studied in
hepatocytes in the presence of 35S–sulphate. In addition
sulphate conjugation of the benzene metabolites
hydroquinoneand 1,2,4–trihydroxybenzene was investigated in
mouse liver cytosol supplemented with
3’–phosphoadenosine–5’–phospho–35S–sulphate. Two novel
metabolites, not detectable in rat hepatocyte incubations,
were found in mouse hepatocytes, and were identified as
1,2,4–trihydroxybenzene sulphate and hydroquinone sulphate.
Formation of the 35S–labelled conjugates could be
demonstrated in incubations of mouse liver cytosol with
hydroquinone or 1,2,4–trihydroxybenzene supplemented with
3’–phosphoadenosine–5’–phospho–35S–sulphate, and in mouse
hepatocytes incubated with benzene and 35S–sulphate. In
comparison with hepatocytes from the Wistar rat,
hepatocytesfrom the NMRI mouse were almost three times more
effective in metabolizing benzene. The higher formation of
hydroquinone, and the formation of trihydroxybenzene
Appendix D: Benzene SIDS Dossier
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