Analysis of body fluids has been used in the past to detect mutagens in the urine of smokers and of some occupationally exposed groups. The analysis of mutagenic metabolites in human blood is at present a completely unexplored area. To study the feasibility of this approach, this project will examine the plasma of rats exposed to some important contaminants. Other components will be using lymphocytes form the same animals. Aqueous and organic-extractable material will be assayed by the Microscreen assay, a small-scale multi-endpoint genetic assay. dose- response relationships and duration of response after exposure will be determined for each endpoint. Another aspect of this project involves using the Microscreen assay on known metabolites in order to determine which are genetically active. Preliminary data are presented on the metabolites of benzene. Only on metabolite tested, trans, trans muconic acid (ttMA), was mutagenic, and its activity was increased after metabolism by rat liver enzymes (S9). The ultimate genotoxic metabolite(s) of benzene will be deduced by an analysis of DNA adducts formed by ttMA in the presence and absence of metabolic activation. Antibodies will be elicited against the major DNA adducts, and their use in screening for exposure to benzene will be explored. Time permitting, a similar analysis of DNA adducts and mutagenic mechanism will be performed for metabolites of trichloroethylene and two different PCB congeners. Knowledge about the active DNA-binding and mutagenic metabolites of agents will be useful in devising more sophisticated approaches to identifying mutagens in blood.
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