Risk Of Lung Tumors Research Articles

Estimation of a lifetime unit lung cancer risk for benzo( a)pyrene based on tumour rates in rats exposed to coal tar/pitch condensation aerosol

Female Wistar rats were exposed to coal tar/pitch condensation (CTP) aerosol containing either 20 or 46 mg/m 3 benzo( a)pyrene (BaP) among other polycyclic aromatic hydrocarbons (PAH) 17 h/day and 5 days/week for 10 or 20 months followed by a clean air period of up to 20 or 10 months, respectively. Based on the inhaled BaP, given as BaP exposure concentration multiplied by the total exposure time, the cumulative dose of inhaled BaP of the 4 exposure groups was 71, 142, 158 and 321 mg BaP/m 3 × h and the corresponding lung tumour rates were 4.2, 33.3, 38.9 and 97.2%. There was no lung tumour in the control group. Using the US Environmental Protection Agency (EPA) linearized multistage model, the lifetime lung tumour risk for rats exposed to 1 mg/m 3 BaP as a constituent of a complex PAH mixture may be 2% or correspondingly 2 per 100 000 with a BaP concentration of 1 mg/m 3. The estimation of the unit lung cancer risk for BaP based on epidemiological data from coking plants was 7–9%.

Carcinogenicity of mercury and mercury compounds.

Mercury and mercury compounds are widely used in modern society, but only sparse data are available on their carcinogenicity. Methylmercury chloride causes kidney tumors in male mice. Mercury chloride has shown some carcinogenic activity in male rats, but the evidence for female rats and male mice is equivocal. Other mercury compounds and metallic mercury have not been tested adequately in experimental animals. Epidemiologic data are available for chloralkali workers, dentists and dental nurses, and nuclear weapons workers, three groups occupationally exposed to low levels of mercury and its compounds, but those highly exposed in the past, such as miners, or populations which have suffered massive environmental exposure have not been adequately studied. However, the sparse epidemiologic data point toward the possibility of a risk of lung, kidney, and central nervous system tumors. Better data are needed on the carcinogenicity of mercury and mercury compounds in humans and experimental animals.

Lifespan studies in rats exposed to 239PuO2 aerosol. III. Survival and lung tumours.

Female, young adult, Wistar rats were given a single inhalation exposure to a submicron sized aerosol of high-fired 239PuO2 and observed during their lifespan for primary lung tumours. Rats were distributed among sham-control (n = 1052) and exposed (n = 2105) groups. Survival was significantly reduced only in rats with lung doses > 30 Gy. A total of 99 primary lung tumours were found, of which 92% were malignant and 80% were carcinomas. Of malignant lung tumours, 49 were squamous cell carcinoma, 23 adenocarcinoma, nine hemangiosarcoma, seven adenosquamous carcinoma, and three fibrosarcoma. One adenocarcinoma was found in controls and only four adenomas were seen in the exposed rat at lung doses < 1.5 Gy. The lowest doses at which lung tumours appeared in exposed rats were 1.5 Gy for squamous cell carcinoma, 3.1 Gy for adenocarcinoma. 4.1 Gy for hemangiosarcoma, and about 9 Gy for adenosquamous carcinoma and fibrosarcoma. Pulmonary squamous metaplasia was not seen in controls and was first seen in exposed rats only at lung doses > 1 Gy. Primary lung tumours were the presumed cause of death (fatal) in 60% of rats with malignant lung tumours; causes of death were equally distributed among all tumour types and doses. The incidence of all lung tumours was 0.095% in control rats, 0.21% in 1877 rats with lung doses < 1 Gy, and 41% in 228 rats with doses > 1 Gy. Lung tumour incidence increased in a linear manner from 6.9% at 2.3 Gy to an incidence of 64-88% at 16-44 Gy. Absolute malignant lung tumour risk averaged 270 lung tumours per 10(4) rat-Gy above a lung dose of 1 Gy. All types of malignant lung tumours induced by inhaled 239PuO2 exhibited a threshold at a lung dose > 1 Gy.

The effects of Thorotrast and quartz on the induction of lung tumors in rats.

In a long-term animal study, the combined and separate effects of Thorotrast (colloidal 232ThO2) and silica dust on the induction of lung tumors were investigated. Female Wistar rats were exposed for 29 d to aerosol concentrations of quartz of either 6 mg m-3, 30 mg m-3, or 0 mg m-3 (6 h d-1, 5 d wk-1). After inhalation, one-half of all exposed animals received a single intravenous injection of enriched Thorotrast (600 microL, 2960 Bq 228 Th mL-1). In all quartz-exposed groups the incidence of benign and malignant lung tumors turned out to be more than 40%. The additional Thorotrast treatment (lifelong exhalation of 220Rn) led to a marked shortening of latency times (first lung tumor was found 1 y after treatment) and to a higher total incidence in the animals exposed to 30 mg m-3 quartz (57 of 87 animals with lung tumors = 65.5%). In the group treated only with Thorotrast, three of 87 animals developed lung tumors. Statistical methods that correct for intercurrent mortality showed a significant increase of the lung tumor risk with respect to Thorotrast treatment, even for the low quartz groups with nearly similar incidences of lung tumors (in the group with ThO2, 39 out of 87 = 44.8%; in the group without ThO2, 37 out of 82 = 45.1%). The tumors were found predominantly in the peripheral regions of the lung and were preceded by proliferation and hyperplasia of the alveolar and bronchiolar epithelium. The results demonstrate a pronounced interactive effect of quartz and Thorotrast on carcinogenesis of the lung. The underlying possible mechanisms are discussed.

Modifying Effects of Preexisting Pulmonary Fibrosis on Biological Responses of Rats to Inhaled 239PuO2

We investigated the modifying effects of preexisting, bleomycin-induced pulmonary fibrosis on the deposition, retention, and biological effects of inhaled 239PuO2 in the rat. Among rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kilogram body mass were similar whether or not pulmonary fibrosis was present. However, clearance of 239Pu from the lungs was significantly decreased in the rats with preexisting pulmonary fibrosis. The incidence of lung lesions (epithelial hyperplasia, diffuse macrophage increases and aggregation, and loose and dense connective tissue) was significantly greater among rats with preexisting pulmonary fibrosis than among the exposed controls. Rats with preexisting fibrosis had shorter life spans than 239PuO2-exposed control rats. When groups of rats with similar alpha doses to the lungs were compared, the incidences of neoplastic lesions in the lung, the times to death of rats with lung neoplasms, and the risk of lung tumors per unit of alpha dose to the lungs in rats with or without pulmonary fibrosis were similar. The results of this study suggest that humans with uncomplicated pulmonary fibrosis may not be more sensitive to the carcinogenic effects of inhaled 239PuO2 than are individuals with normal lungs, assuming that the total alpha doses to the lungs are similar.

The carcinogenic potential of inhaled diesel exhaust: a particle effect?

An analysis of literature data on effects of both diesel exhaust and of particle overload shows that the experimentally induced lung tumors in rats after diesel exposure may be explained by a particulate effect only. This conclusion is also supported by results from inhalation and instillation studies with pure carbon black (Heinrich, 1990; Kawabata, 1986) which showed no difference in the lung tumor inducing potency between diesel exhaust and carbon black. It appears that the surface area of the retained particles plays a decisive role. In contrast to the rat, the observed elevated lung tumor rate in diesel-exposed workers cannot be explained by a particle effect since the predicted extrapolated lung tumor risk for humans based only on the particle phase is much lower than found in an epidemiological study of diesel exposed railroad workers (Garshick et al. 1988). If this increased lung tumor incidence in the railroad workers can be verified in further epidemiological studies in diesel -exposed cohorts then additional effects besides those of the particles must play a role in humans, e.g., effects of the organic compounds or gas phase components.

Comparative Toxicology of Inhaled 239PuO2 in Dogs and Rats

Inhaled plutonium is a potent carcinogen in both dogs and rats. Young adult beagle dogs and Wistar rats, in lifespan studies designed to examine the relationship between dose and lungtumor incidence, were given a single exposure to high-fired 239PuO2 (AMAD values, 2.3 μm and 1.6 μm, respectively). Dosimetry and histopathology have been completed on 122 of 136 dogs and on 1436 of 3192 rats, including most animals with lung doses > 1 Gy (100 rad). Initial lung depositions (ILD) ranged from 1.073 to 1850 Bq g−1 (0.029 to 50 nCi g−1) for dogs and 10.36 to 2775 Bq g−1 (0.28 to 75 nCi g−1) for rats. About 80% of the ILD in rats was cleared with a half time of 200 d. Lung clearance in dogs was described by a single exponential function with a half time of 1100 d. Final lung doses ranged from 0.1 Gy (10 rad) to 60 Gy (6000 rad) in dogs and 0.06 Gy (6 rad) to 25 Gy (2500 rad) in rats. In dogs, about 40% and 20% of the ILD were present in thoracic lymph nodes and liver, respectively, by 5 to 15 y after exposure; <0.05% of the ILD was present in either tissue of rats at 1.5 y. Median survival of control dogs was about 14 y; for control rats it was 2.2 y. Significant life-shortening was observed only in groups of dogs or rats with lung doses of 10 Gy (1000 rad). Early deaths from radiation pneumonitis were infrequent in both species at lung doses of 20 Gy (2000 rad). Maximum percentage of animals with lung tumors was 80 to 90% at about 10 Gy (1000 rad) in rats and 25 Gy (2500 rad) in dogs, with a rapid increase between 1 Gy (100 rad) and 10 Gy (1000 rad). Percentage of animals with tumors was similar in dogs and rats despite large differences in the fate of inhaled 239PuO2 in the two species. This suggested that total accumulated dose to the lung is a useful dosimetric parameter in estimating lung-tumor risk for humans.

Influence of Radiation Dose Patterns on Lung Tumor Incidence in Dogs That Inhaled Beta Emitters: A Preliminary Report

Different radiation dose patterns to the lung from inhaled beta-emitting radionuclides may influence the frequency and kind of biological effects. To determine the magnitude of this influence, groups of Beagle dogs were exposed to aerosols of 90Y, 91Y, 144Ce, or 90Sr in relatively insoluble particles and observed for their life spans. Different dose patterns were achieved by using these radionuclides having similar beta emissions and chemical form but having physical half-lives ranging from 2.6 days to 28 years. The range of initial lung burdens of radionuclides studied resulted in a range of biological effects from early deaths at the highest radiation doses to no discernible effects at the lowest doses. The effective half-lives of the four radionuclides in the lung ranged from 2.5 to 600 days. Within 1.5 years after exposure, some dogs died with radiation pneumonitis and pulmonary fibrosis. Between 1.5 and 10 years after exposure, 42 pulmonary carcinomas and 28 pulmonary sarcomas were observed in 163 dogs that died. Protracted irradiation of the lung from 90Sr or 144Ce resulted in a relatively high radiation dose and produced more total lung tumors but fewer lung tumors per rad than less protracted irradiation from 90Y or 91Y. At 10 years after inhalation exposure, the difference in risk per rad among the different dose patterns was a factor of 4 to 8, indicating that the different radiation dose patterns from inhaled beta emitters do influence lung tumor risk factors, at least at high (greater than 20,000 rad) doses to lung.

Metabolic and dosimetric studies after inhalation of 227Th in rats with regard to the risk of lung and bone tumors.

227Th (alpha-emitter, half-life 18.7 days) was inhaled by rats from solution in nitrate form. Organ doses were calculated after whole body measurements and measuring of activity concentrations in the organs over a longer incorporation period. An initial deposition of 100 nCi 227Th in the lung resulted in mean total doses of 150 rad in lung and 36 rad in bone. The data for kidney and liver were 2 rad and 0.1 rad, respectively. For long-term experiments two dosages were applied to two groups of animals with mean values of 900 rad and 300 rad in the lung. The consequences for lung and bone tumor induction are discussed.