Project Details
Description
DESCRIPTION
Environmental exposures occur as mixtures, while most toxicologic and
pharmacokinetic studies have been done on single compounds. Benzene is a
widespread contaminant that occurs as part of environmental mixtures. It
has an extensive data base on toxicity based on single compound exposure or
dose. The applicants propose to study benzene in mixtures using in vivo and
in vitro experiments. The hypotheses to be tested are: 1) the same
fraction of benzene is eliminated as the ring hydroxylated and ring opened
metabolites by humans when inhaled at environmental levels alone or as part
of a mixture of methyl tertiary-butyl ether (MTBE) or metals that can
generate reactive oxygen species (ROS), such as iron, and 2) the toxicity of
environmental pollutant mixtures, such as benzene and MTBE, iron or
chromium, is due, in part, to interactive cellular effects induced by the
reactive intermediates of the individual components of the mixture. The
specific aims and goals to test these hypotheses are: 1) expose humans in
vivo to binary mixtures of benzene and MTBE or benzene and iron with and
without antioxidant ingestion; 2) expose HL-60 cells in vitro to the toxic
benzene metabolites muconaldehyde and hydroquinone, the toxic MTBE
metabolite formaldehyde, and Cr(VI) or Fe(II) singly and in combination; and
3) relate the pharmacodynamic effects observed in the controlled exposures
in the in-vivo studies to the effects observed in the in-vitro experimental
studies. The in vivo studies will be done in a Controlled Environmental
Facility at environmentally relevant concentrations and durations using
isotopically labeled benzene. The goals of the study include: compare the
fraction of total inhaled benzene by humans excreted as ring hydroxylated
metabolites, hydroquinone, and phenol, ring opened metabolite, trans, trans
muconic acid, and unmetabolized benzene by human subjects following exposure
to benzene alone and as binary mixtures of benzene and MTBE or iron with and
without antioxidant ingestion; determine the Michaelis-Menten constants for
the elimination of benzene and the formation rate of benzene metabolites; in
I-IL-60 cells, examine the effects of the benzene metabolites muconaldehyde
and hydroquinone, the MTBE metabolite formaldehyde, iron (as Fe(II)) and
chromium (as (Cr(Vl)) singly and in combination on AP-I and NF-kB DNA
binding activity, cell cycle analysis, apoptosis, and DNA strand breaks;
develop response surfaces for each of the toxicological endpoints; and
compare significant differences in pharmacodynamic effects between the in
vivo and in vitro studies.
Status | Finished |
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Effective start/end date | 8/15/98 → 7/31/02 |
Funding
- National Institute of Environmental Health Sciences: $332,552.00
ASJC
- Cell Biology
- Pharmacology
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