Ziel
IT HAS BEEN ESTABLISHED THAT, WHEN PEOPLE ARE EXPOSED TO CARCINOGENIC AGENTS, THE INCIDENCE OF TUMOURS CAN BE INCREASED IN SMOKERS RELATIVE TO NON-SMOKERS DUE TO A SYNERGISTIC EFFECT WITH CIGARETTE SMOKE. IN THE ASBESTOS INDUSTRY FOR EXAMPLE, THE INCIDENCE OF MESOTHELIAL TUMOURS IS MUCH GREATER IN SMOKERS THAN IN NON-SMOKERS AND THE DEGREE OF ENHANCEMENT IS SUCH AS TO SUGGEST A MULTIPLICATIVE RATHER THAN AN ADDITIVE EFFECT (SELIKOFF AND LEE, 1978). THERE IS ALSO STRONG EVIDENCE FOR A SYNERGETIC EFFECT OF CIGARETTE SMOKE IN THE INDUCTION OF BRONCHIAL TUMOURS IN MINERS EXPOSED TO RADON DAUGHTER PRODUCTS. ALTHOUGH THIS EFFECT HAS BEEN DEMONSTRATED IN RATS (CHAMEAUD ET AL., 1979) IN BEAGLE DOGS EXPOSED TO RADON, EXPOSURE TO CIGARETTE SMOKE WAS FOUND TO HAVE A MITIGATING EFFECT ON RADON DAUGHTER-INDUCED TUMOURS (CROSS ET AL., 1982). IN THE REPORT ON US FEDERAL RESEARCH (FREIR) IT WAS POINTED OUT THAT STUDIES ARE REQUIRED ON THE SIGNIFICANCE OF CARCINOGENS SUCH AS CIGARETTE SMOKE AND ASBESTOS, ON THE DEVELOPMENT OF RADIATION-INDUCED LUNG CANCER.
IN THE CURRENT PROGRAMME, SYSTEMS FOR THE EXPOSURE OF MICE TO CIGARETTE SMOKE ARE BEING EVALUATED. THE SMOKING MACHINE SELECTED WILL THEN BE USED FOR:
A) STUDIES OF CIGARETTE SMOKE DOSIMETRY USING RADIOACTIVE TRACER TECHNIQUES,
B) STUDIES OF THE EFFECT OF CIGARETTE SMOKE ON THE LUNG RETENTION OF PUO2-239 FOR DOSIMETRY PURPOSES AND
C) TO ESTABLISH CONDITIONS OF EXPOSURE WHICH ARE WELL TOLERATED BY MICE SO THAT MORTALITY DUE TO SMOKE EXPOSURE ALONE, WILL BE NEGLIGIBLE.
IN ADDITION, PUO2-239 WILL BE ADMINISTERED TO MICE TO ESTABLISH THE DOSE-RESPONSE RELATIONSHIP FOR LUNG TUMOURS IN THE CBA/H STRAIN AT 1 YEAR POST EXPOSURE.
THE MAIN INITIAL AIM OF THE PROPOSED STUDY WILL BE TO ESTABLISH WHETHER OR NOT THE INCIDENCE OF LUNG TUMOURS INDUCED BY PUO2-239 IS ENHANCED BY CIGARETTE SMOKE.
IN THE FIRST YEAR, GROUPS OF MICE WILL BE EXPOSED AS FOLLOWS.
GROUP 1 (PUSS) MICE WILL BE EXPOSED AT 9 WEEKS OF AGE TO SIZED PUO2-239 TO GIVE AN INITIAL ALVEOLAR DEPOSITION (IAD) WHICH WILL RESULT IN THE MAXIMUM LUNG TUMOUR INCIDENCE. STARTING AT 10 WEEKS OF AGE, THEY WILL BE EXPOSED TO CIGARETTE SMOKE 5 DAYS/WEEK FOR A PERIOD OF ONE YEAR.
GROUP 2 (PUSS) MICE WILL BE EXPOSED AT 9 WEEKS OF AGE TO SIZED PU02-239 TO GIVE A SIMILAR IAD TO GROUP 1.STARTING AT 10 WEEKS OF AGE, THEY WILL BE 'SHAM' SMOKED 5 DAYS/WEEK FOR A PERIOD OF ONE YEAR. ON THE COMPLETION OF THESE STUDIES IN 1986, IT WILL BE CLEAR IF THERE IS SYNERGY BETWEEN CIGARETTE SMOKE AND PU02-239. IF THE EFFECT APPEARS TO BE SMALL, THE STUDY WILL BE TERMINATED. HOWEVER, IF THERE IS A MARKED SYNERGY, THE PERIOD 1987-88 WILL BE USED TO INVESTIGATE THE EFFECT OF CIGARETTE SMOKE ALONE USING THE FOLLOWING GROUPS.
GROUP 3 (S) MICE WILL BE EXPOSED TO CIGARETTE SMOKE STARTING AT 10 WEEKS OF AGE 5 DAYS/WEEK FOR A PERIOD OF ONE YEAR.
GROUP 4 (SS) MICE WILL BE 'SHAM' SMOKED STARTING AT 10 WEEKS OF AGE 5 DAYS/WEEK FOR A PERIOD OF ONE YEAR.
IN THE PERIOD 1988-89, AN ATTEMPT WILL BE MADE TO REPRODUCE MORE REALISTIC EXPOSURE CONDITIONS IN WHICH MICE WILL BE EXPOSED TO CIGARETTE SMOKE FOR POSSIBLY 18 MONTHS WITH A SINGLE EXPOSURE TO PUO2-239 AFTER SMOKING FOR SOME TIME.
WHEN MICE ARE KILLED, THE LUNGS WILL BE DISSECTED OUT AND CLEARED FOR VISUAL SCORING OF CELLULAR NODULES. SUCH NODULES WILL BE EXCISED, EMBEDDED AND SECTIONED FOR CONFIRMATION OF NEOPLASTIC NATURE AND IDENTIFICATION OF TUMOUR TYPE.
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