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EDRI Federal Project Inventory:
57423-03 Mechanisms of Carcinogenesis–Halogenated Biphenyls
- Sponsor Organization: NIH/NCI
- Project Title: 57423-03 MECHANISMS OF CARCINOGENESIS--HALOGENATED BIPHENYLS
- Project Focus: EXPOSURE ASSESSMENT, HUMAN HEALTH EFFECTS
- Description: Polyhalogenated biphenyls, particularly polychlorinated biphenyls
(PCBs), are industrial chemicals which are stableand persist in our
environment. Their lipophilicity and resistance to chemical or
biological degradation result in theiraccumulation in fatty tissues of
humans and other animals and eventual secretion into milk fat. These
characteristics raiseconcern about the health risks associated with
long-term exposure to these compounds. Numerous studies have
foundthat PCBs and the closely-related polybrominated biphenyls (PBBs)
induce hepatocellular carcinomas in mice and rats,but the mechanism by
which they do so has not been determined. We and others have shown
that PCBs/PBBs act aspromoters of liver carcinogenesis; but their
initiating or DNA-damaging activity has not been
conclusivelydemonstrated. We therefore propose to test the hypotheses
that biphenyl and halogenated biphenyls 1) induce
mutations,cytogenetic damage and cell transformation in in vitro
systems, 2) form quinoid metabolites that (at least in part)
areresponsible for genotoxic effects seen, 3) induce DNA adducts in
rats. The potential of biphenyl and halogenatedbiphenyls to induce
mutations in mammalian cells will be examined, while their ability to
interact with cellular DNAwill be monitored by sensitive 32P-
postlabeling methods. Of particular interest is the identification of
the reactivespecies responsible for the genotoxicity. Using these
test systems, we shall define structure-activity
relationships,identify critical metabolic parameters (which enzymes,
cofactors are involved), identify mammalian targets anddetermine the
structures of active metabolites. Our preliminary data indicate that
several lower halogenated biphenylsare mutagenic in Salmonella and in
V79 cells in the presence of an exogenous activation system. The
spectra ofgenotoxicity seen with these compounds indicate that two
mechanisms of activation (via expoxides and quinones) areoperative.
Our most recent data showing that mono- and dichlorobiphenyls are
enzymatically activated to species thatform adducts with guanine
and/or adenine strongly support the involvement of quinones in the
genotoxicity of thesecompounds. Clarification of the mechanism by
which individual PCBs cause liver tumors will form a basis for
thehuman health risk assessment for exposure to these chemicals.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: MAMMALIAN, LABORATORY, IN VITRO
- Keywords for Experimental Endpoints: CARCINOGENESIS, RISK ASSESSMENT, XENOBIOTIC METABOLISM
- Chemical Agents: PCBs, PBBs
- Performing Institution: UNIVERSITY OF KENTUCKY
- Contact: CONTACT PERSON:ELAINE C. LEE; BUILDING 31; 11A21, NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301 496-5515;
LEEE@0D.NCI.NIH.GOV
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