Tobacco Documents Online

H t®0121 105 5. Smoke-Induced Short-Term Endpoints a. SUMMARY Title: INCREASED SISTER CHROMATID EXCHANGE IN BONE MARROW OF MICE EXPOSED TO WHOLE CIGARETTE SMOKE Authors: W.F. Benedict, A. Banerjee, K.K. Kanagalingam, D.R. Dansie, and C.J. Henry Using defined smoke exposure conditions, BC3F1/Cum mice were exposed to whole cigarette smoke and examined for the number of sister chromatid exchanges (SCE's) per metaphase chromosome in bone marrow. Smoke from two different reference cigarettes were sho wn to produce a two fold increase over controls after only 1 week or up to 46 weeks of daily smoke exposure. The increased incidence of SCE's persisted for at least I week after cessation of smoke exposure. Status: Final draft scheduled for 9/81. 11 /1

HT®0121106 b. Title: LACK OF SIGNIFICAt4T IMMUNOSUPPRESSION FOLLOWING EXPOSURE OF BC3F1/CUM MICE TO WHOLE CIGARETTE SMOKE Authors: R.A. Lubet, H.B. Herscowitz, K.K. Kanagalingam, D.R. Dansie, R.E. Kouri, and C.J. Henry SUMMARY Employing the SEM smoking machine, mice were exposed either chronically or acutely to smoke from 2R1 cigarettes. The effects of such exposures on the subsequentt induction of plaque forming cells (PFC) in the spleens of mice following intraperi- toneal injection of sheep red blood cells were then determined. BC3F1/Cum hybrid or BALB/c mice showed no significant imm unosup- pression (PFC/1D cells) following acute exposure to smoke. Similarly, BC3Fl~Cum animals chronically exposed (54 weeks) to cigarette smoke showed no effect on the imm une response. The chronic regimen of smoke exposure resulted in 400-500 ug total particulate matter deposited in the pulmonary tissue per mouse per day. Animals injected with cyclophosphamide displayed a striking dose dependent immunosuppression. Status: Second draft scheduled for 9/81. IS

Ht®0121107 c. Title: AUTORADIOGRAPHIC ANALYSIS OF DNA SYN- THESIS IN PULMONARY TISSUES OF MICE EX- POSED TO WHOLE CIGARETTE SMOKE Authors: K.K. Kangalingam, S.M. Reed, R.C. Knipscher, D.R. Dansie, R.E. Kouri and C.J. Henry SUMMARY i DNA replica tion, as measured by estimation of Labeling Index (LI), was determined in BC3F1/Cum mice after exposure to whole cigarette smoke from 3A1 and 2R1 reference cigarettes. Mice were sacrificed after a 1-hour pulse with tritiated thymi- dine following a 3-6 month smoke exposure period, and lung and other tissues processed for autoradiography. Of the 4,000-6,000 cells counted in both sham- and shelf-control mice not more than 3 cells had any significant number of grains. In comparison the percent of total cells labelled was about 20-fold and 14-fold greater mice exposed to smoke from the 3A1 and 2R1 cigarettes, respectively. The distribution of cells with grains was not uni- form. No labelling of cells of the bronchial epithelium was found, rather the uptake of 3H-thymidine was confined to alveolar cells. Of these the type II cells seemed most responsible. No evidence of necrosis was found to suggest increases ir. labelling index as being due to proliferation of new cells to replace cells damaged by cigarette smoke. Histologically no hyperplastic cells were recognized to account for the increases in LI. In the tra- chea exposure to 2R1 cigarette smoke was more potent than expo- sure to 3A1 cigarette smoke in inducing increased cellular pro- liferation. All other tissues examined showed no discernible d5f'ercr.ce in LI among smoke-exposed, sham-exposed or unexposed groups. Status: Second draft scheduled for 10/81. I9

HT®012110$ d. Title: DNA REPLICATION AND UNSCHEDULED DNA SYNTHESIS IN LUNGS OF MICE EXPOSED TO CIGARETTE SMOKE Authors: R.E:. Rasmussen, C.H. Boyd, D.R. Dansie, R.E. Kouri, and C.J. Henry SUMMARY i Mice of the hybrid strain BC3F1/Cum (C57B1/Cum x C3H/Anf Cum) we:e chronically exposed to measured amounts of machine- generated whole Rentucky reference 2A1 cigarette smoke. DNA re- plication and unscheduled DNA synthesis (UDS) were measured in lung tissue in vitro using a short-terro organ culture method. Within one week of beginning smoke exposure, DNA replicative activty, as indicated by incorporation of 3H-thymidine into total lung DNA, was increased more than two-fold over sham-exposed con- tro'.s and remained elevated as long as smoke exposure was contin- ued. Treatment of lung tissues in vitro with either the lung carcinogen 4-nitroquinoline-l-oxide or methylmethane sulfonate stimulated UDS, measured as incorporation of 3H-thymidine into lung DNA in the presence of hydroxyurea, presumably as the result of DNA repair activity. Until the 10th to 12th week of smoke exposure, at which time the accumulated deposition of total par- ticulate material in the lung was approximately 4G mg, the level of UDS stimulated by the alkylating chemicals declined to approximately 50% of that seen in lung tissue from sham-exposed control mice. If the mice were removed fiom smoke exposure, DNA replicative activity returned to normal levels within one week, but the UDS response to DNA damage remained depressed up to five months after ending smoke exposure. The results show that both transient and apparently permanent changes are produced in mouse lung as the result of exposure to cigarette smoke. The role of these changes in lung neoplasia is under investigation. Status: Published in Cancer Research, 41, 2583-258B, 1981. ~v