Direct induction of mutation by environmental chemicals or their metabolites is one means by which they might effect the age-specific incidence of cancer. If this were so then tissues exposed to mutagenic and carcinogenic chemicals found in environmental mixtures such as cigarette smoke or urban air particulate would have more mutations with a different patter or spectrum of mutations than unexposed tissue. To discover if human bronchial epithelial cells exposed to these mixtures in vivo do nor do not have higher numbers of mutant colonies we propose to dissect some fifty human lungs and measure the number and kind of mutations as a function of anatomical position in the upper bronchial tree. Lung donors will differ in age, smoking status and residential location (rural/urban). We have already developed two methods with the sensitivity required to measure and identify point mutations in genes in human tissues. Because we propose to study a sufficiently large number of lung samples and scan at least 1000 base pairs of nuclear DNA sequence and measure 10 specific point mutations associated with human lung cancers, we expect to be able to discover if the mutational spectra or are not significantly different from spontaneous spectra for these same sequences in human cells. Environmental chemicals may, however, exert their major carcinogenic effect by changes tissue kinetic or turnover parameters, i.e. cell division and death rates. If overall mutation rates in normal tissues were proportioned to cell division rate, than an increase in overall turnover rate by a pseudo-hormonal pathway or forced repopulation by chronic cell toxicity would increase the number of mutants found in a tissue but not necessarily change their mutational spectrum. We therefore propose to enumerate the number of mitototic and apoptotic cells among the epithelial cells of the upper bronchial tree from the same lung donors and discover if there are any differences attributable to age, smoking status or residential location. An especially critical target for effects on cell turnover may be the slowing growing intermediate pre-neoplastic colonies called areas of dysplasia in the lung and adenomas in the colon. Our quantitative working model (Project 1) leads us to expect that high division and death rates are so closely matched that there would be less thana 1% difference in favor of new growth. Factors which change cell division or death rates by even a small increment would be expected to have major effects on the age- specific lung cancer mortality rates. We therefore further propose to determinate the rates of cell death and division in the """"""""areas of dysplasia"""""""" in both dissected lung sections and pathology specimen libraries to discover if these parameters vary with age, smoking status or place of residence.
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