Numerous studies in laboratory animals have demonstrated the importance of respiratory epithelial cells as targets for both inhaled and ingested chemicals. There are, however, significant uncertainties in estimating the risks to humans from exposure to chemicals which are respiratory cytotoxicants in animals. These uncertainties are both species- and dose- related. The overall goals of the work proposed in this application are to develop markers of exposure, effect and susceptibility for chemicals which produce lung toxicity in animals. This work is based on the premise that the development of markers capable of signalling that an exposure has been at a level sufficient to result in cytotoxicity is dependent upon a complete understanding of essential biochemical and metabolic steps involved in toxicity in animals. Accordingly, this work will define the importance of specific protein and nonprotein targets of electrophilic intermediates to cytotoxic injury for three chemicals that produce focal injury to the respiratory epithelium by virtue of cytochrome P450 dependent metabolism. These chemicals are naphthalene, nitronaphthalene and trichloroethylene. The well established difference in sensitivity of various species and the highly focal nature of the injury within the respiratory system will be used as an experimental tool to indicate which protein adducts are important to toxicity. This will then guide the development of biomarkers which are closely related to the mechanism of toxicity.
The specific aims of the work are to: (l) validate immunochemical methodology for determination of diastereomeric mercapturic acids of naphthalene as an index of the rate and stereochemistry of formation of naphthalene epoxides, (2) identify critical protein targets for reactive metabolites generated from naphthalene, nitronaphthalene, and trichloroethylene, (3) use the information obtained in (2) to develop markers which can be monitored in nasal lavage, bronchiolar lavage, blood or urine as indices of exposure, effect and susceptibility and (4) refine new systems capable of evaluating samples obtained from hazardous waste sites for the possible presence of pulmonary toxic chemicals. This work is intended to reduce the uncertainty inherent in current assessments of risks associated with human exposure to pulmonary toxic chemicals by developing methodologies that are capable of distinguishing exposures that occur at levels sufficient to cause toxicity from those that are without significant effect. These studies should also provide the tools necessary for determining whether the metabolic and biochemical factors which lead to toxicity in animals are operative in human lungs and whether there are significant interindividual differences in these metabolic and biochemical pathways with human populations.
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