We want to understand how combustion processes produce mutagens and how to minimize their escape into the atmosphere. For the past ten years, combustion engineers, analytical chemists and toxicologists in this program have focussed on the polycyclic aromatic hydrocarbons formed and incompletely destroyed in flame processes in a number of experimental and practical combustors. We have, in a number of instances, been able to ascribe the preponderance of biological activity in experimental assay systems to one of a few effluent components. Because the PAH alone have been found to account for only part of the biological activity observed, we propose now to extend our scope to the identification of the oxygen and nitrogen-containing aromatics to which we attribute this additional activity and also to their formation through partial oxidation and pyrolysis. These present new, challenging problems to engineers, analytical chemists and toxicologists. The biological endpoints upon which we rely to nominate compounds for further study will continue to be gene mutation in bacteria and human cells as well as induction of lung adenomas in the infant mouse. We also want to discover if present combustion emission components are actually entering humans and causing biological damage. Thus, a major new component in our program is a proposal to study the process of biological damage by combustion-related mutagens and carcinogens using newly developed analytical tools which are intended for eventual use in human population studies. Using compounds such as fluoranthene, a major contributor to PAH activity in nearly all effluents studied to date, we propose to measure the temporal cascade of formation of protein and DNA covalent adducts, the appearance of specific sets of mutations (human B cells) and the appearance of both mutations and lung adenomas in mice. Our program is thus a characterization of two processes of mass transfer: - fuel to mutagens in exhaust - exhaust mutagens through macromolecular reaction products to stable genetic change and cancer.

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National Institute of Environmental Health Sciences (NIEHS)
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Massachusetts Institute of Technology
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Tomita-Mitchell, Aoy; Ling, Losee Lucy; Glover, Curtis L et al. (2003) The mutational spectrum of the HPRT gene from human T cells in vivo shares a significant concordant set of hot spots with MNNG-treated human cells. Cancer Res 63:5793-8
Tomita-Mitchell, A; Kat, A G; Marcelino, L A et al. (2000) Mismatch repair deficient human cells: spontaneous and MNNG-induced mutational spectra in the HPRT gene. Mutat Res 450:125-38
Durant, J L; Lafleur, A L; Busby Jr, W F et al. (1999) Mutagenicity of C24H14 PAH in human cells expressing CYP1A1. Mutat Res 446:1-14
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Durant, J L; Busby Jr, W F; Lafleur, A L et al. (1996) Human cell mutagenicity of oxygenated, nitrated and unsubstituted polycyclic aromatic hydrocarbons associated with urban aerosols. Mutat Res 371:123-57
Palotas, A B; Rainey, L C; Feldermann, C J et al. (1996) Soot morphology: an application of image analysis in high-resolution transmission electron microscopy. Microsc Res Tech 33:266-78
Wang, J S; Busby Jr, W F (1996) Bacterial and human cell mutagenicity and mouse lung tumorigenicity of the oxygenated polynuclear aromatic hydrocarbon phenalenone. Fundam Appl Toxicol 33:212-9
Wang, J S; Busby, W F; Wogan, G N (1995) Tissue distribution of DNA adducts in pre-weanling BLU:Ha mice treated with a tumorigenic dose of fluoranthene. Cancer Lett 92:9-19

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