We will determine whether two lymphocyte functional assays, the B-cell colony forming (B-CFC) assay and a variant of the T-cell mixed lymphocyte culture (MLC) assay, can be used as sensitive indicators of exposure to low concentrations of compound commonly found in toxic waste. In a series of prior studies, the immunotoxic effects of inhaled benzene were assessed using seven different lymphocyte functional assays. In order to make the experiments as relevant as possible, the assays were performed either on intact mice exposed to benzene via inhalation or on lymphocytes isolate from such mice. Marked disruptions of all assays were observed, but the B-CFC and MLC exhibited by far the most sensitivity to the benzene exposures. Marked changes in the responses of these latter assays were observed after relatively brief exposures to low concentrations of benzene. The reaction of electrophilic intermediates or metabolites with membrane bound sulfhydryl groups is believed to be the common pathway by which exogenous contaminants disrupt the immune response. Benzene is known to be metabolized to quinones which react with sulfhydryl groups. Unmetabolized benzene does not react with sulfhydryl groups. The B-CFC and MLC assays, therefore, were sufficiently sensitive to be markedly disrupted by presumably very low levels in vivo produced electrophilic benzene metabolites. It is likely that other toxicants which produce electrophilic intermediates will also markedly disrupt the lymphocyte functions measured by these assays. This is the hypothesis to be tested. We will evaluate the B-CFC and MLC assays by employing protocols that investigate dose/response, time course response, persistence after exposure and structure activity relationships. Compounds typical of those commonly found in toxic waste will be delivered to mice and rats by routes of exposure that are relevant to human exposure to toxic waste. The compounds to be studied are: the aromatic hydrocarbons benzene, toluene, and xylenes; the chlorinated hydrocarbons methylene chloride, chloroform, and carbon tetrachloride; the mixture of chlorinated aromatic hydrocarbons aroclor 1254; and the metal salts nickel acetate, potassium chromate, and methylmercuric chloride.
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