The long-term objectives and specific aims of this work is to develop methods which can be simple enough to be used routinely for screening chemicals for their potential pneumotoxic effects. The methods should also be adaptable to recognize acute as well as chronic effects and permit evaluation of recovery, if any, following pneumotoxic unanesthetized guinea pigs. Further characterization of the sites or causes of pneumotoxocity will necessitate some invasive procedures. Once this work is completed we will be able to use the simpler methods without such additional procedures. The basic hypothesis in the development of these methods is that when the respiratory upon the type of pneumotoxic effect. Secondly, because of the reserve capacity of the respiratory system, these stimuli help in unmasking small toxic effects not demonstrable at rest. Since both CO2 and exercise challenge are widely used in humans for evaluation of pulmonary performance, there is a chance to compare our results in guinea pigs with results obtained in humans with pulmonary diseases or during exposures to common air pollutants. Thus extrapolation of the results in this animal should be possible and with a sufficient data base on a variety of pneumotoxicants, prediction of """"""""safe"""""""" level of exposure could be arrived at. Similarities noted in guinea pigs exposed to methyl isocyanate (MIC) with humans surviving exposure to this agent in Bhopal are encouraging for calibration of this animal model which is a major objective of the research work described. The fact that a single exposure to MIC can be followed by obstructive and restrictive conditions of a permanent nature in both guinea pigs and humans points to the importance of being able to recognize such possible action of chemicals in accidental spills. We will characterize better its action, particularly using exercise as the stimulus to obtain an objective evaluation of how much impairment occurred. Furthermore, the uptake in blood and fractional uptake by the respiratory tract of this volatile and reactive chemical will be characterized. The results should provide guidelines to develop principles governing uptake of similar chemicals of industrial importance which in comparison to the principles governing uptake of industrial solvents are poorly understood.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of Pittsburgh
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