lung cancer incidence after exposure of rats to low doses of radon: influence of dose rate

1
Abstracts /Lung Cancer I.? (1995) 265-329 mortality was found during several follow-up periods. The rate ratios were 1.6- 3.8 for different latency periods. Lung cancer risk increased with the length of exposure and latency. Lung cancer morbidity in 1953-1987 showed an excess for the red and grey granite areas the rate ratio being 2.5 for 2O-year latency. Only one hng cancer case came from the black granite area. The cancer cases from the grey area had B shoner latency than those from the red area. The mineral composition differed for each arca. The strongest ROS-inducing activity ofgrcy and red granite was seen in the quark-containing fractions. In the cytotoxicity tests the quat’Wcont.cining fractions of the grey and red granite also caused the strongest lactic dehydrogenasc (LDH) release. However, plagioclasc, the main constihrent of black granite (60%). had approximately the same ability to induce ROS as the qualt+c0ntcining fractions of red and grey granite. Conc/usionx The CB~CCTmorbidity and mortality figures ofthc three different graniteareas, combined with the found differences in biological activity of granite dusts and a hypothesis that there is a c-mea-inducing mechanism for ROS, point to a direct role for quartz in cancer induction. Integrated optical density (IOD), syntactic structure aoalysis, and mvival io operated longcarcinoma patieata Kayser K, Liewald F, Kremcr K, Tacke M. Deporlmenl of Pathology, Thorarklinik, Amaliensb: 5, 691.76 Heidelberg. Pathol Rcs Pmct 1994; 190: 103 I - 8. Histological sections of formalin fixed, paratlincmbcddcd tissue comprising 195 specimens of human lung carcinomas were Feulgcn stained. The nuclei of the histomorphological images were segmented using an automated image analyzing system, and the attributed minimum spanning trees (MST) were calculated. Features related to the DNA-content of the nuclei (integrated optical density (IOD), IOD-cntropy, S-phase related fraction, percentage > SC, etc.), and structoml parameters (minimum distance between tomorcell nuclei, minimum distance between tumor oclls and neighboring lymphocytes, MST-entropy, MST- current of entropy (entmpicfluss), distance between neighboring proliferating tumor cells,etc.)were measured. The following rcsultswcmobtained: the measured IOD and MST features showed significant differences bctwcen the primary carcinomas and m&static carcinomas in the intmpulmonay lymph nodes. The survival of patients was remarkably improved if the carcinomas displayed a low S-phase related fraction, a low percentage of tumor cells > SC, a low number of stem lines, and a low MST-current of entropy. A mortality study of lung cancer among Swiss professional drivers: Accoootiagfortbemmkingrelatedfractioo by anadtivariakappmach Ptluger DH, Mindcr CE. Dept. of Social-/Preventive Medicine, University of Beme. Finkenhubelweg II. CH-3012 Beme. Soz-Pmvcntivmed 1994;39:372-8. The mortality due to lung cancer among ‘chauffeurs’, who have a presumably long-term exposure to d&cl exhaust fumes, was analyzed. As controls. men in industrial occupations of similar so&economic status were selected. Cases were drawn from the Swiss mortality register for the years 1979-1983. Person- years were obtained using data from the 1980 census records. These two data tiles wcrc combined by occupation, age class and so&economic status. Age adjustcd incidence rates were calculated applying Poisson regression. To control for tobacco related lung cancer mortality an indirect adjustment was undertaken. Using information about the smoking habits of the people in the occupations under study, smoking-attributable lung cancer mortality was accounted for by incorporating Ax&on’s technique into multivariate regression modeling. The mortality ratio for lung cancer for chauffeurs with respect to the controls was 2.27, which is significantly in excess of 1:95% Cl (1.99, 2.58). Other tobacco related diagnoses such as bladder cancer, esophageal cancer and isehcmic heart diseases showed excess risks as well. After accounting for smoking, a slight but slgniticant incrcasc in lung cancer mortality remained among chauffeurs (mortality ratio 1.48, 95% Cl: 1.30, 1.68). In summary, the present results do support the hypothesis that diesel exhaust is a significant cause of lung cancer. Long cancer incidence after exposure of rats to low doses of radon: Ioflueace of dose rate Morher JP, Morin M, Monchaux G, Fritsch P, Pinesu JF, Chameaud J et al. Lob. de Cancerologie Experimmlale. LCEDPTE~SVKXA. BP 6. 92265 Fontenay our Roses Cedex. Radiat Prot Dosim 1994,561 93-7. To study the e&et on lung cancer incidence of a long exposure to low levels of radon, 500 male 3-months-old Sprague-Dawley rats, were exposed to a cumulative dose of 25 WLM of radon and its daughters, 6 hours a day, 5 days a week, during 18 months. Exposure conditions were controlled in order to maintain adefmcd PAEC:42 x IO* J. m”(2 WL),in the mngcofdomcsticandenvironmental cxposuns. Animals wcn kept until they died or given euthanasia when moribund. Mean survival times were similar in both irradiated and control groups’ 828 days (SD = 169) and 830 days (SD = 137), as well as lung cancer incidence, 0.60% at 25 WLM and 0.63% for controls. The incidence of lung lesions was compared statistically with controls and those previously obtained at cumulative exposures of 25 and 50 WLM delivered over a 4-6 month period, inducing a significant increase of lung canocc, 2.2% and 3.8% respectively. Such a comparison showed a decrcascd lung cancer incidence related to a dccrcasc in the dose rate for low levels of radon exposure. Mortality of iroa foundry workers. III. Lung cancer cPsecontrol study Andjelkovich DA, Shy CM, Brown MH, Janszen DB, Levine RJ, Richardson RB. Chemical Indusby Toxicologv Ins~.. PO. Box 12137, Research Triangle Park, NC 27709. J Gccup Mcd 1994:36:1301-9. A nested casccontrol stody was undertaken to identify the determinants of lung cancer mortality in a cohort of 8147 foundly men among whom an excess of lung cancer deaths was previously observed. The present study consisted of all lung eanoer deaths (N = 220) that occurred within this cohort behveen 1950 and 1989. Both living and dead controls, matched on race and attained age, wcrc selcctcd in the ratio of IO:1 (N = 2200) by means of the incidence density sampling procedure. All cases and two controls per case. randomly s&&d from each case’s IO controls, were included in a smoking history survey Basic smoking history information was obtained for about 7 I% of these study subjects. For the purpose of this study, formaldehyde exposure levels were categorized as high, medium, low, and none. Airborne silica exposure was categorized only as high, medium, and low levels, because all foundry workers were known to bc exposed to silica. Conditional logistic regression analyses indicated that cigarette smokmg was a strong predictor of lung canea mortality in this cohort. Neither exposure to formaldehyde nor silica exposure level, nor employment in any of the six major work areas within the foundry, showed an association with lung cancer. Diiereot susceptibility to smokiag-iadoced DNA damage among mate sod female lung cancer patients Rybcrg D, Hewer A, Phillips DH, Haugen A. Deparfment o/ Toxrcologv. NW. Inst. of Occupational Health, PO. Box 8249, N-0033 Oslo. Cancer Res 1994,54:5801-3. The levels of aromatichydrophobic DNA adducts were analyzed in normal lung tissue fmm 63 lung cancer patients and examined in relation to exposure and genetic factors. Adduct lcvcls were significantly higher in smokers than in nonsmokers, but among smokers the number of cigarettes smoked per day had only low significance for the variation in adduct levels. An inverse correlation was found bctwcen years of smoking and DNA adduct levels (r = 0.52, P = 0.001). Thus, patients with high adduct levels generally had shortcr duration of smoking and/or lower smoking dose before the clinical onset of the disease, which fits expcctcd bchavlor of cancer susceptible individuals. The data indicated an excess of individuals with glutathione S- transfcrasc Ml deficiency among male patients with high adduct levels. Among females the DNA adduct levels were higher than in males when adjusted for smoking dose. There was a highly significant difference in the distribution of males and females when smokers were divided into quartile groups according to adducts per pack year (trend test; 2-sided P = 0.005). This may indicate that women arc at greater risk oftobacco-induced lung cancer. Deposition sod reteotioo of iobaled ftbres: Effects oo iocideoce of long cancer and mesothelioma Lippmann M. Nelson InstofEntironmen. Medicine, New York University. Medical Cc&c Tuxedo, NY 10987. Occup Environ Med 1994;51:793-8. A review of the literature on chronic inhalation studies in which rats were exposed to mineral tibres at known tibrc number concentrations was undertaken to examine the specific roles of tibte length and composition on the incidences of both lung cancer and mesothelioma. For lung cancer, the percentage of lung turnours (y) could be described by a relation of the form gamma = a + bf + cr. where f is the concentration of tibre numbers and a. b, and c are fitted constants. The correlation coefficients for the fitted curves were 0 76 for >S im Yml, 0.84

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Page 1: Lung cancer incidence after exposure of rats to low doses of radon: Influence of dose rate

Abstracts /Lung Cancer I.? (1995) 265-329

mortality was found during several follow-up periods. The rate ratios were 1.6- 3.8 for different latency periods. Lung cancer risk increased with the length of exposure and latency. Lung cancer morbidity in 1953-1987 showed an excess for the red and grey granite areas the rate ratio being 2.5 for 2O-year latency. Only one hng cancer case came from the black granite area. The cancer cases from the grey area had B shoner latency than those from the red area. The mineral composition differed for each arca. The strongest ROS-inducing activity ofgrcy and red granite was seen in the quark-containing fractions. In the cytotoxicity tests the quat’Wcont.cining fractions of the grey and red granite also caused the

strongest lactic dehydrogenasc (LDH) release. However, plagioclasc, the main constihrent of black granite (60%). had approximately the same ability to induce ROS as the qualt+c0ntcining fractions of red and grey granite. Conc/usionx The CB~CCT morbidity and mortality figures ofthc three different graniteareas, combined

with the found differences in biological activity of granite dusts and a hypothesis that there is a c-mea-inducing mechanism for ROS, point to a direct role for quartz in cancer induction.

Integrated optical density (IOD), syntactic structure aoalysis, and mvival io operated longcarcinoma patieata Kayser K, Liewald F, Kremcr K, Tacke M. Deporlmenl of Pathology, Thorarklinik, Amaliensb: 5, 691.76 Heidelberg. Pathol Rcs Pmct 1994; 190: 103 I - 8.

Histological sections of formalin fixed, paratlincmbcddcd tissue comprising 195 specimens of human lung carcinomas were Feulgcn stained. The nuclei of the histomorphological images were segmented using an automated image analyzing system, and the attributed minimum spanning trees (MST) were calculated. Features related to the DNA-content of the nuclei (integrated optical density (IOD), IOD-cntropy, S-phase related fraction, percentage > SC, etc.), and structoml parameters (minimum distance between tomorcell nuclei, minimum distance between tumor oclls and neighboring lymphocytes, MST-entropy, MST- current of entropy (entmpicfluss), distance between neighboring proliferating tumor cells,etc.)were measured. The following rcsultswcmobtained: the measured IOD and MST features showed significant differences bctwcen the primary carcinomas and m&static carcinomas in the intmpulmonay lymph nodes. The survival of patients was remarkably improved if the carcinomas displayed a low S-phase related fraction, a low percentage of tumor cells > SC, a low number of stem lines, and a low MST-current of entropy.

A mortality study of lung cancer among Swiss professional drivers: Accoootiagfortbemmkingrelatedfractioo by anadtivariakappmach Ptluger DH, Mindcr CE. Dept. of Social-/Preventive Medicine, University of Beme. Finkenhubelweg II. CH-3012 Beme. Soz-Pmvcntivmed 1994;39:372-8.

The mortality due to lung cancer among ‘chauffeurs’, who have a presumably long-term exposure to d&cl exhaust fumes, was analyzed. As controls. men in industrial occupations of similar so&economic status were selected. Cases were drawn from the Swiss mortality register for the years 1979-1983. Person- years were obtained using data from the 1980 census records. These two data tiles wcrc combined by occupation, age class and so&economic status. Age adjustcd incidence rates were calculated applying Poisson regression. To control for tobacco related lung cancer mortality an indirect adjustment was undertaken. Using information about the smoking habits of the people in the occupations under study, smoking-attributable lung cancer mortality was accounted for by incorporating Ax&on’s technique into multivariate regression modeling. The mortality ratio for lung cancer for chauffeurs with respect to the controls was 2.27, which is significantly in excess of 1:95% Cl (1.99, 2.58). Other tobacco related diagnoses such as bladder cancer, esophageal cancer and isehcmic heart diseases showed excess risks as well. After accounting for smoking, a slight but slgniticant incrcasc in lung cancer mortality remained among chauffeurs (mortality ratio 1.48, 95% Cl: 1.30, 1.68). In summary, the present results do support the hypothesis that diesel exhaust is a significant cause of lung cancer.

Long cancer incidence after exposure of rats to low doses of radon: Ioflueace of dose rate Morher JP, Morin M, Monchaux G, Fritsch P, Pinesu JF, Chameaud J et al. Lob. de Cancerologie Experimmlale. LCEDPTE~SVKXA. BP 6. 92265 Fontenay our Roses Cedex. Radiat Prot Dosim 1994,561 93-7.

To study the e&et on lung cancer incidence of a long exposure to low levels of radon, 500 male 3-months-old Sprague-Dawley rats, were exposed to a

cumulative dose of 25 WLM of radon and its daughters, 6 hours a day, 5 days a week, during 18 months. Exposure conditions were controlled in order to maintain adefmcd PAEC:42 x IO* J. m”(2 WL),in the mngcofdomcsticandenvironmental cxposuns. Animals wcn kept until they died or given euthanasia when moribund. Mean survival times were similar in both irradiated and control groups’ 828 days (SD = 169) and 830 days (SD = 137), as well as lung cancer incidence, 0.60% at 25 WLM and 0.63% for controls. The incidence of lung lesions was compared statistically with controls and those previously obtained at cumulative exposures of 25 and 50 WLM delivered over a 4-6 month period, inducing a significant increase of lung canocc, 2.2% and 3.8% respectively. Such a comparison showed a decrcascd lung cancer incidence related to a dccrcasc in the dose rate for low levels of radon exposure.

Mortality of iroa foundry workers. III. Lung cancer cPsecontrol study Andjelkovich DA, Shy CM, Brown MH, Janszen DB, Levine RJ, Richardson RB. Chemical Indusby Toxicologv Ins~.. PO. Box 12137, Research Triangle Park, NC 27709. J Gccup Mcd 1994:36:1301-9.

A nested casccontrol stody was undertaken to identify the determinants of lung cancer mortality in a cohort of 8147 foundly men among whom an excess of lung cancer deaths was previously observed. The present study consisted of all lung eanoer deaths (N = 220) that occurred within this cohort behveen 1950 and 1989. Both living and dead controls, matched on race and attained age, wcrc selcctcd in the ratio of IO:1 (N = 2200) by means of the incidence density sampling procedure. All cases and two controls per case. randomly s&&d from each case’s IO controls, were included in a smoking history survey Basic smoking history information was obtained for about 7 I% of these study subjects. For the purpose of this study, formaldehyde exposure levels were categorized as high, medium, low, and none. Airborne silica exposure was categorized only as high, medium, and low levels, because all foundry workers were known to bc exposed to silica. Conditional logistic regression analyses indicated that cigarette smokmg was a strong predictor of lung canea mortality in this cohort. Neither exposure to formaldehyde nor silica exposure level, nor employment in any of the six major work areas within the foundry, showed an association with lung cancer.

Diiereot susceptibility to smokiag-iadoced DNA damage among mate sod female lung cancer patients Rybcrg D, Hewer A, Phillips DH, Haugen A. Deparfment o/ Toxrcologv. NW. Inst. of Occupational Health, PO. Box 8249, N-0033 Oslo. Cancer Res 1994,54:5801-3.

The levels of aromatichydrophobic DNA adducts were analyzed in normal lung tissue fmm 63 lung cancer patients and examined in relation to exposure and genetic factors. Adduct lcvcls were significantly higher in smokers than in nonsmokers, but among smokers the number of cigarettes smoked per day had only low significance for the variation in adduct levels. An inverse correlation was found bctwcen years of smoking and DNA adduct levels (r = 0.52, P = 0.001). Thus, patients with high adduct levels generally had shortcr duration of smoking and/or lower smoking dose before the clinical onset of the disease, which fits expcctcd bchavlor of cancer susceptible individuals. The data indicated an excess of individuals with glutathione S- transfcrasc Ml deficiency among male patients with high adduct levels. Among females the DNA adduct levels were higher than in males when adjusted for smoking dose. There was a highly significant difference in the distribution of males and females when smokers were divided into quartile groups according to adducts per pack year (trend test; 2-sided P = 0.005). This may indicate that women arc at greater risk oftobacco-induced lung cancer.

Deposition sod reteotioo of iobaled ftbres: Effects oo iocideoce of long cancer and mesothelioma Lippmann M. Nelson InstofEntironmen. Medicine, New York University. Medical Cc&c Tuxedo, NY 10987. Occup Environ Med 1994;51:793-8.

A review of the literature on chronic inhalation studies in which rats were exposed to mineral tibres at known tibrc number concentrations was undertaken to examine the specific roles of tibte length and composition on the incidences of both lung cancer and mesothelioma. For lung cancer, the percentage of lung turnours (y) could be described by a relation of the form gamma = a + bf + cr. where f is the concentration of tibre numbers and a. b, and c are fitted constants. The correlation coefficients for the fitted curves were 0 76 for >S im Yml, 0.84