Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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800 mg/kg) body weight for 2 days were incapable of
processing the 34–KD pre–IL–1 alpha to the mature 17–Kd
cytokine when stimulated in culture with LPS. Stromal
macrophages from mice coadministered BZ and indomethacin, a
prostaglandin H synthase (PHS) inhibitor that has been shown
to prevent BZ–induced myelotoxic and genotoxic effects in
mice when coadministered with benzene were able to convert
the pre–IL–1 alpha to mature cytokine. Adminstration of
recombinant murine IL–1 alpha to mice before a dose of BZ
that causes severe depression of BM cellularity completely
prevents BM depression, most probably by bypassing the
inability of the stromal macrophage in BZ–treated animals
toprocess pre–IL–1 alpha to the mature cytokine.
Source: Deutsche Shell Chemie GmbH Eschborn
06–JAN–1997 (933)
Type: other: Leukemogenesis
Remark: Leukemias are monoclonal tumors that arise from cells in
thehematopoietic stem and progenitor cell compartment.
Consistent with emerging models of carcinogenesis,
leukemogenesis is an evolutionary process involving
multipleindependent genetic and epigenetic events. Leukemia
can develop secondary to alkylating drug therapy or exposure
to benzene in which progressive dysplastic changes,
accompaniedby a distinct pattern of clonal cytogenetic
abnormalities, give rise to acute myelogenous leukemia.
Characterization of these clonal chromosomal aberrations
together with observed alterations in other growth–promoting
genes, provides a useful framework for studying chemical
leukemogenesis and for use in understanding the origins and
development of leukemia in general.
Source: Deutsche Shell Chemie GmbH Eschborn
06–JAN–1997 (571)
Type: other: Leukemogenesis
Remark: Interleukin–3 (IL–3) and granulocyte/macrophage colony
stimulating factor (GM–CSF) are responsible for maintaining
survival and stimulating growth of early dormant
hematopoietic progenitor cells (HPC). Previous studies
haverevealed that pretreatment of murine HPC with
hydroquinone (HQ) but not phenol, catechol or
trans,trans–muconaldehyde, results in a selective
enhancement of GM–CSF, but not IL–3–mediated clonogenic
response. HQ pretreatment of murine HPC did not induce
either an up– or a down–regulationof GM–CSF–receptors or any
change in receptor affinity. CD34+ cells, which represent
between 1 and 5% of human bone marrow, contain virtually all
clonogenic stem and HPC. Pretreatment of CD34+ cells with
HQ also results in enhancedclonogenic response with GM–CSF
but not IL–3. These findingssuggest that an early step in
chemical leukemogenesis may involve transient alterations in
the regulation of cytokine response to GM–CSF.
Source: Deutsche Shell Chemie GmbH Eschborn
Appendix D: Benzene SIDS Dossier
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