Tobacco Documents Online

r;1-801L1 j89 b. Status of Publications 1. Lung Cancer a. Title: A LUNG CANCER MODEL SYSTEM USING INBRED STRAINS OF MICE Authors: C.J. Henry, L.H. Billups, M.D. Avery, T.R. Rude, D.R. Dansie, A. Lopez, B. Sass, C.E. Whitmire, and R.E. Kouri S Uf,MARY A model system has been established for studying lung carcinogenesis using intratracheal instillation of 3-methylchol- anthrene (MCA) in C3H/Anf Cum and BC3F1/Cum mice. The animals in these studies were screened for adventitious agents and were free throughout their lifetime of two important lung viruses, Sendai virus and pneumonia virus of mice. Under these condi- tions, the occurrence of spontaneous and chemically-induced lung cancers was determined over the lifetime of the animals. Data were analyzed by the actuarial method for lung tumor probability. Probability was found to be dose and time dependent. Over 95% of the MCA treated B:.3F1/Cum and over 88% of the C3H/Anf Cum mice were found at death to have pulmonary carcinomas. Tumors o bser-- ved in animals which died up to 40 weeks on test were almost al- ways squamous cell carcinomas (SCC) (-85$), while tumors which were observed in anSmals which died after 50 weeks were mainly alveolar adenocarcinomas (AAC) (-808). Both tumor types metasta- sized widely. Spontaneous lung cancers (only AAC were observed) occurred in these two strains at low frequency and were expressed late in life. Thus, the system described affords a suitable model to study the induction, expression, and prcgression of lung tumors under conditions where a vast majority of animals develop neoplasia. Status: Accepted for publication 7/81, Cancer Research. l

NiJ0121 uy0 b. Title: THE EFFECT OF EXPOSURE TO WHOLE CIGA- RETTE SMOKE ON 3-METHYLCHOLANTHRENE (MCA) INDUCED LUNG TUMORS IN BC3F1/CUM M,ICE Authors: C.J. Henry, L.H. LillL ')s, M.D. Avery, D.R. Dansie, A. Lopez, L.A. Breth, H.D. Mullinax, W.C. Hall, and R.E. Kouri SUMMARY The effect of exposure to whole cigarette smoke on MCA induced lung carcinogenesis has been studied in BC3F1/Cum mice. Freshly diluted smoke (10%, v/v) from Kentucky reference 2A1 cigarettes (40 mg tar, 0.5 mg nicotine) was generated using the large capacity (480 mice) SEM II B dynamic smoke exposure ma.:hine. Animals are restrained about the neck in stock type holders so as to allow "nose-only" exposure. Deposition and dosimetry studies show that greater than 90% of smoke total par- ticulate matter (TPM) is found in the respiratory tract, result- ing in an average pulmonary deposition of 80-100 ug TPM/ciga- rette/mouse. Mice were exposed to a regimen of ten cigarettes/ day. The effect of this daily smoke or sham exposure on MCA- induced lung carcinomas was studied over 80 weeks. MCA (250 ug) was given biweekly via intratracheal instillation over 18 weeks. Smoke and sham exposures were initiated 3 days after the first MCA treatment. The incidence of MCA ind uced alveologenic and squamous pulmonary lesions was analyzed at 4 week intervals using the Nantel-Haentzel statistic. A total of 407 M:.A + smoke ani- mals and 268 MCA + sham animals were analyzed during the test period. Over 50 different types of combinations of lung lesions were observed. A total of 247 premalignant lesions and 330 malignant carcinomas were found during the experiment. The inci- dence and distributi:-i with time of the premalignant and malig- nant lesions were evenly distributed in the MCA + smoke and MCA + sham groups (p = 0.21). Thus, although cigarette smoke does pos- sess properties of a promoter (induction of ODC and depression of DNA repair capscity), its capacity to promote lung carcinogenesis is not readily observable when a strong complete carcinogen such as MCA is used. Status: First draft scheduled 10/81. .L

c. Other H i U0121091 ` (1) Title: PATHOLOGY AND BIOLOGIC BEHAVIOR OF CHEMICALLY INDUCED LUNG TUMORS IN INBRED STRAINS OF MICE Author: L.H. Billups, C.J. Henry, B. M.D. Avery, L.A. Breth, W.C. Hall, and R.E. Kouri SUMMARY Sass, During the course of studies on the chemical induction of pulmonary neoplasia by various carcinogens in inbred mouse strains, a variety of neoplastic and non-neoplastic lung lesions were encountered. Data were gathered from several experiments, primarily dealing with 3-methylcholanthrene and benzo(a)pyrene. Transplantation studies were performed on all types of lesions. The behavior following transplantation was correlated with mor- phologic appearance. Tumors encountered were both benign and malignant and occurred primarily in the peripheral lung. These consisted of alveologenic adenomas and adenocarcinomas, squamous cell carcinomas, adenosquarnous and poorly differentiated carcino- mas. Adenocarcinomas and poorly-differentiated carcinomas were locally invasive, metastasized to regional lymph nodes and infre- quently to distant sites. Squamous cell carcinoma occurred ear- lier than adenocarcinoma and metastfasis was usually by way of pulmonary veins. The adenosquamouscarcinomas may represent col- lision neoplasms of two different cell types. A small number of tumors of another cell type containing diastase-resistant PAS positivE .,ytoplasmic material which also resisted hyaluronidase digestion were encountered. Non-neoplastic proliferative lesions (squamous metaplsia and adenomatosis) occurred frequently. Two morphologically dis- tinct types of adenomatosis were observed. Status: First draft scheduled for 9/81.

H r®012109n (2) Title: LUNG TUMOR INCIDENCE AND PROGRES- SION OF CHEMICALLY-INDUCED LUNG CANCER IN BC3F1/CUM MICE Author: C.J. Henry, L.H. Billups, M.D. Avery, D.R. Dansie, W.C. Hall, and R.E. Kouri SUMMARY The incidence of chemically-induced preneoplastic and neoplastic lung lesions was determined by periodic random sacri- fice of mice prior to, and during, the expression of pulmonary carcinomas. Statistical treatment of the incidence data utilized chi square analysis of contingency tables made up of various les- ions observed at the various time intervals. Under these condi- tions, the incidence of these lesions as a function of time after chemical treatmeat was quantitated and the data suggest a pattern of progression from preneoplasia to neoplasia. Analysis sugges- ted a significant time-related factor in the distribution of the pulmonary lesions. The logical progression of alveologenic tumors are probably alveolar non-compressing nodule > alveolar compressing nodule > alveolar adenocarcinoma. The progression of squamous lesions is less clear but most likely is squa mous neo- plasm > squamous carcinoma. Status: First draft scheduled for 10/81.

(3) Title: I1t®0121 p93 7,8-DIHYDRO-7,B-DIHYDROXY-BENZO- (A)PYRENE (BAP-7,8-DIOL) IS A POTENT LUNG CARCIN OGEN FOR C3H/f cuM MICE Authors: R.E. Kouri, T.R. Rude, L.H. Billups, M.D. Avery, H. Yagi, D.M. Jerina, and C.J. Henry SUMMARY BaP, BaP-7,8-diol and 9,10-dihydro-trans -7,8-dihydro-7,8- dihydroxy-BaP (BaP-H4-7,8-transdiol) were intratracheally instil- led into C3H/Anf Cum mice. Animals treated with BaP-7,8-diol were observed to have a higner incidence and shorter latency of pulmonary carcinonas, compared to the other two chemicals. The types of pulmonary tunors observed were squamous cell carcinomas, alveolar adenocarcinomas, and adenosquamous carcinomas. Data were analyzed by the actuarial method for lung tumor probability. Probability was found to be time and chemical de pendent: BaP- 7,?-diol»>BaP»BaP-H4-7,8-transdiol. BaP-H4-7,8-transdiol was observed to be a weak lung carcinogen, suggesting that hydro- genation of the double bond at the 9,10 position of the BaP-7,8- diol results in almost complete inactivation of BaP as a lung carcinogen in vivo. Status; Second draft scheduled for 11/81. S

nf®0121094 (4) Title: COMPAR:SGN OF SUSCEPTIBILITY TO CHEMICALLY INDUCED LUNG CANCER IN SEVEh INBRED STRAINS OF MICE Authors: C.J. Henry, W.C. Hall, D.R. Dansie, M.D. Avery, D. Putman, R.A. Lubet, and R.E. Kouri SUMMARY Six inbred strains of mice and one first filial hybrid strain were evaluated for their susceptibility to chemically- induced lung cancer. Three strains are responsive at the Ah locus, C3H/Anf Cum, C57L1/6 Cum, and the BC3F1/Cum (C57B1/Cum x C3H/Anf Cum), while four strains are non-responsive at the Ah locus, DBA/2J, SWK/J, 129/J and the NZB/BLNJ. Male and female mice were administered 3-methylcholanthene by intratracheal ino- culation at a dose which would induce lung cancers in susceptible animals after 12-18 months. Data are being analyzed by the actuarial method of probability analysis. Comparisons of induced tumor types, latency, biologic behavior, as we'1 as, spontaneous occurence of neoplasia will be made among these seven mouse strains. Status: Animals still on test. First draft scheduled for 1/82. 4