Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Type: Metabolism
Remark: Benzene metabolism is a requirement for toxicity and the
phenolic metabolites of benzene have been repeatedly
implicated in hematotoxicity. Peroxidase–mediated
metabolism of benzene–derived phenolic compounds generates
reactive and cytotoxic quinones which have been proposed to
be responible for benzene–induced toxicity. Human as well
as animal (i.e. rat and mouse) bone marrow contains high
peroxidase activity and can readily bioactivate phenolic
metabolites of benzene in a peroxidase–mediated process.
Thus, bone marrow cells containing significant peroxidase
activity can be considered as potential targets of benzene
toxicity. In this study, the authors examined the
peroxidase activity of murine hematopoietic progenitor cells
(HPC) by two different approaches. Conventional biochemical
techniques were used to quantitatively determineperoxidase
activity in enriched progenitor cell populations, purified
as lineage–negative cells using a cocktail of antibodies to
remove cells with lineage–specificmarkers. Peroxidase
activity in enriched progenitor cells and in whole bone
marrow was also measured directly using flow cytometry. In
addition, the peroxidase activity of HPCdefined as
CD34–enriched populations was also measured. Thedata
demonstrate that both murine and human HPC contain
peroxidase activity and thus may be potential targets of
xenobiotics that are bioactivated by peroxidases.
Source: Deutsche Shell Chemie GmbH Eschborn
06–JAN–1997 (1011)
Type: Metabolism
Remark: The administration of [3H]benzene by S.C. injection to mice
resulted in the decreased incorporation of Fe into red
cellsand the accumulation of benzene and its metabolites in
bone marrow and other tissues. Toluene protected against
the benzene–induced depression of red cell Fe uptake and
reducedthe levels of benzene metabolites in bone marrow
without affecting the level of benzene in this tissue. The
results of this study suggest that toluene exerted its
protective effect by inhibiting benzene metabolism and that
a metabolite of benzene probably mediates the observed
hemopoietic toxicity of benzene.
Source: Deutsche Shell Chemie GmbH Eschborn
06–JAN–1997 (33)
Type: Metabolism
Remark: Metabolite information is used to construct an internal
dose(a surrogate of the biologically effective dose) for a
givenadministered dose. The relationship between the
administered dose and this internal dose is nonlinear and
iswell described by a Michaelis–Menten function. The
administered doses from the National Toxicology Program’s
rodent carcinogenicity study of benzene are transformed
Appendix D: Benzene SIDS Dossier
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