Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats.

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.

The acute toxicity of inhaled beryllium metal in rats.

We exposed rats once by nose only for 50 min to a mean concentration of 800 micrograms/m3 of beryllium metal (initial lung burden, 625 micrograms) to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed to chronic-active inflammation by 115 dpe. This inflammation worsened progressively, as did alveolar macrophage and epithelial hyperplasia, becoming severe at 171 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Throughout the experiment, total numbers of cells were elevated within the BAL samples due primarily to increased numbers of neutrophils. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), beta-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. beta-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe. Results indicate that inhalation of beryllium metal by rats results in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. Chronic beryllium lung disease of man is an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions.

The induction of chromosome damage in CHO cells by beryllium and radiation given alone and in combination.

Studies were conducted to determine the effects of BeSO4 or X rays, alone and in combination, on cell cycle kinetics, cell killing, and the production of chromosome aberrations in Chinese hamster ovary (CHO) cells. The concentration of BeSO4 required to kill 50% of CHO cells exposed to BeSO4 for 20 h was determined to be 1.1 mM with 95% confidence intervals of 0.72 to 1.8 mM. During the last 2 h of the 20-h beryllium treatment (0.2 and 1.0 mM), cells were exposed to 0.0, 1.0, or 2.0 Gy of X rays. Exposure to either BeSO4 or X rays produced a change in cell cycle kinetics which resulted in an accumulation of cells in the G2/M stage of the cell cycle. However, combined exposure to both agents resulted in a block similar to that observed following exposure to X rays only. The background level of chromosome damage was 0.05 +/- 0.015 aberrations/cell in the CHO cells. Seven hours after the end of exposure to 0.2 and 1.0 mM beryllium, 0.03 +/- 0.003 and 0.09 +/- 0.02 aberrations/cell, respectively, were observed. The data for chromosome aberrations following X-ray exposure were fitted to a linear model with a coefficient of 0.14 +/- 0.01 aberrations/cell/Gy. When beryllium was combined with the X-ray exposure the interactive response was predicted by a multiplicative model and was significantly higher (P less than 0.05) than predicted by an additive model. The influence of time after radiation exposure on the interaction between beryllium and X rays was also determined. No interaction between beryllium and X-ray exposure in the induction of chromosome-type aberrations (P greater than 0.05) was detected. The frequency of chromatid-type exchanges and total aberrations was significantly higher (P less than 0.05) in the radiation plus beryllium-exposed cells when compared to cells exposed to X rays only, at both 9 and 12 h after X-ray exposure. These data suggest that the multiplicative interaction may be limited to cells in the S and G2 stages of the cell cycle.

The current approach of the ICRP Task Group for modeling doses to respiratory tract tissues.

For radiation protection purposes, the International Commission on Radiological Protection (ICRP) Task Group proposes to apportion radiation risk within the respiratory tract according to the tumor mortality rates observed in the different anatomical regions. This approach requires that doses absorbed by extrathoracic tissues must be considered, in addition to those in the lung. For the extrathoracic region, the tissues at highest potential risk are the pharyngeal parts of the nasopharynx and oropharynx and a part of the larynx. In the lung, all tissues are potentially at risk, and it is necessary to consider doses absorbed by bronchial tissues, the lung parenchyma, and lymph nodes. This paper outlines the methods proposed by the Task Group to evaluate the heterogeneous doses absorbed by sensitive cells in these tissues from radioactive decays of alpha-emitters. The objective is to evaluate doses to broad regions of the respiratory tract, where the regions are defined to reflect substantial differences in potential risk when taking into account deposition and clearance behavior. The Task Group proposes to represent the respiratory tract by three generic regions: an extrathoracic region and two thoracic regions, one clearing fast and one slowly. The models of aerosol deposition and clearance applied for each region are outlined. To illustrate the use of the model, doses are evaluated for the key cases of short-lived radionuclides and long-lived insoluble alpha-emitters and are discussed with regard to current ICRP recommendations.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.

Alterations in particle accumulation and clearance in lungs of rats chronically exposed to diesel exhaust.

F344 rats were chronically exposed to diesel exhaust at target soot concentrations of 0 (control, C), 0.35 (low, L), 3.5 (medium, M), and 7.0 (high, H) mg/m3. Accumulated lung burdens of diesel soot were measured after 6, 12, 18, and 24 months of exposure. Parallel measurements of particle deposition and clearance were made to provide insight into the mechanisms of particle accumulation in lungs. The fractional deposition of inhaled 67Ga2O3 particles after 6, 12, 18, and 24 months of exposure and of inhaled 134Cs-fused aluminosilicate particles after 24 months were similar for all groups. Progressive increases in lung burdens of soot particles were observed in M and H exposed rats, reaching levels of 11.5 +/- 0.5 and 20.5 +/- 0.8 mg/lung (mean +/- SE), respectively, after 24 months. Rats in the L group had smaller relative increases in lung burden, reaching levels of 0.60 +/- 0.02 mg/lung after 24 months. Tracheal mucociliary clearance measurements, using 99mTc-macroaggregated albumin deposited in the trachea, showed no changes at anytime. There were statistically significant increases in clearance half-times of inhaled radiolabeled particles of 67Ga2O3 as early as 6 months at the H level and 18 months at the M level; no significant changes were seen at the L level. Rats inhaled fused aluminosilicate particles labeled with 134Cs after 24 months of diesel exhaust exposure to measure long-term components of pulmonary clearance. The long-term clearance half-times were 79 +/- 5, 81 +/- 5, 264 +/- 50, and 240 +/- 50 days (mean +/- SE) for the C, L, M, and H groups, respectively. Differences were significant between the C and both the M and H exposure groups (p less than 0.01). Lung burdens of diesel soot were more than expected at the H and M levels and were also associated with impaired particle clearance while smaller responses were observed in both burdens and clearance at the L level.

Cancer incidence patterns in the Denver metropolitan area in relation to the Rocky Flats plant.

This study considered whether geographic patterns of cancer suggest any relation with Rocky Flats, a facility located near Denver, Colorado that processes plutonium components for nuclear weapons. The study was based upon cancer incidence data for the years 1969 to 1971 and 1979 to 1981, and census tract data for 1970 and 1980. Data for 1979 to 1981 showed little association with Rocky Flats, even though considerations of the timing of releases of radioactivity from the plant and cancer latency indicate that data from this period should be more indicative of an effect of Rocky Flats than data from the earlier period. The explanatory variable found to be most closely associated with cancer incidence was an urban factor measured by distance from the Colorado State Capitol located in downtown Denver. Indications of correlations of cancer incidence with proximity to Rocky Flats largely disappeared for both time periods when analyses were stratified by this urban factor. This negative finding was not surprising because persons living in the vicinity of the plant have been shown to have no more plutonium in their tissues than persons living in other areas of Colorado.

Health effects of diesel exhaust. A contemporary air pollution issue.

Extracts of diesel exhaust particles are mutagenic in bacterial and mammalian cell assays; they contain hundreds of identifiable organic compounds, some of which are known mutagens and carcinogens. The particles are readily respired and about 20% to 30% of them are deposited in the pulmonary region, where they are retained for long periods. At low diesel exhaust concentrations, typical of those likely for human exposure, particle deposition and clearance rates are essentially normal and particle concentrations in the pulmonary region are expected to remain quite low. At very high concentrations of diesel exhaust, clearance processes may be overwhelmed and lung burdens of particles may continue to increase over long periods. Evidence from laboratory animals suggests that pulmonary injury and reduced respiratory function would occur in humans at these high concentrations. Epidemiologic data and laboratory studies appear to indicate that the human lung cancer risk from exposure to diesel exhaust would be quite low, even if use of diesel vehicles increased substantially.

Projected uptake and toxicity of selenium compounds from the environment.

Industrial workers and members of the general public may be exposed to selenium by inhalation of selenium in the workplace or atmosphere or by ingestion of selenium in food. A model has been developed to evaluate the potential uptake of selenium in body tissues by these two exposure routes. Rates were estimated for transport of selenium between five compartments including lung, gastrointestinal tract, blood, liver and other tissues. Results of model simulations were compared to published tissue distribution information obtained from single inhalation exposures of rats and dogs to radiolabeled selenium compounds at concentrations from 20 mg/m3 to 20 micrograms/m3 with initial body burdens of selenium ranging from 28 to 0.09 micrograms Se/kg body wt. The model was then modified to predict equilibrium organ concentrations of selenium in people after continual exposure to selenium in the air or in the diet. Daily intake levels of 100 micrograms/day and a fractional absorption value of 0.8 were used. With an air concentration of 1 ng Se/m3, model predictions indicated that most of the total body selenium in people is likely to come from their diet because selenium in the urban atmosphere contributes a very small part of the total body selenium. However, continual inhalation of selenium at the threshold limit value (TLV; 200 micrograms/m3) could contribute significantly to the total body burden of selenium. Levels of selenium predicted in lung, liver, and blood after inhalation of selenium at the TLV were 22,000, 1200, and 440 ng Se/g tissue. Predicted lung concentrations were near those that produced toxic effects in animals after ingestion of Se.

A double isotope method for characterizing hygroscopic selenious acid aerosols used in inhalation exposures.

Methods of generating and characterizing selenious acid aerosols for use in deposition and toxicity studies are described. Selenious acid aerosols were nebulized and heat treated at varied temperatures. Because selenious acid is hygroscopic, a solution containing 3H2O and 75Se was nebulized to determine the water content in selenium aerosols after generation. The stable aerosol was a hydrate of selenious acid, H2SeO3 X 1/2 H2O, at New Mexico ambient relative humidity (ca. 20%). The mass median aerodynamic diameter of the collected droplets was 0.6 micron with a geometric standard deviation of 1.3.

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.

Risk assessment relationships for evaluating effluents from coal industries.

Public awareness of the risks associated with traditional coal combustion and newer coal gasification and liquefaction industries is increasing. Assessing the health risks for people exposed to effluents from these industries generally involves four major steps: (1) characterizing the pollutant sources, (2) projecting the release and dispersion of toxic substances in workplaces and in the environment, (3) estimating their uptake by people through inhalation and ingestion and their contact with skin, and (4) evaluating their potential for causing health effects. Pollutants of special concern include toxic gases, carcinogenic organic compounds and trace metals. Relationships between the levels of pollutants released to the environment and the magnitudes of human exposures and methods of formulating exposure-dose-effect relationships for use in human risk assessment are discussed.

Absorption, distribution, and retention of inhaled selenious acid and selenium metal aerosols in beagle dogs.

We studied the distribution and retention of inhaled selenious acid and selenium metal aerosols which were similar in size and chemical form to selenium aerosols that may be produced during fossil fuel combustion. Beagle dogs were given 10 to 61 micrograms Se/kg of body weight by inhalation. Aerosols generated for the inhalation exposures were also collected and instilled into the upper respiratory tracts or stomachs of additional dogs to measure systemic absorption at these sites. Selenium-75, incorporated into the aerosols, was used to determine the Se content in the whole animal, excreta, and individual tissues as a function of time. Virtually all of the inhaled selenious acid aerosol was rapidly absorbed into the blood from the lungs, gastrointestinal tract, and the nasal membranes. Selenium metal aerosols were less rapidly absorbed. Selenium that was absorbed into the blood was translocated to the liver, kidney, spleen, and heart. Selenium-75 in these organs had a biological half-life of 30 to 40 days. Approximately 50% of the deposited Se was eliminated with a biological T1/2 of 1.2 days. Urine was the major route of excretion, accounting for 70 to 80% of the excreted Se. The long-term component of the whole-body retention function for both inhaled aerosols had a half-life of about 34 days and accounted for about 20% of the initial Se dose. The data suggested that although absorption of selenious acid into blood following inhalation was more rapid than absorption of selenium metal, once absorbed the disposition of both compounds was similar.

Bioassay model for estimating body burdens of 241Am from excretion analyses.

A simple bioassay model for predicting the organ burdens of 241Am from excretion rates is presented for inhalation exposures. The model uses three compartments representing lung, liver and skeleton. The model was developed using data from studies in laboratory animals of inhaled or injected 241Am and was validated for people by comparison to cases of accidental inhalation exposures to 241Am. The data for people have a large amount of variability but indicate that the retention half-time of 241Am in liver is approximately 2 yr and in skeleton is approximately 30 yr. These parameters can be used in the model to estimate body and organ burdens from excretion rates after inhalation of 241Am or the model can be fitted to an individual's measured excretion rates.

Inhalation toxicology of diesel exhaust particles.

Our present knowledge of the health effects of diesel exhaust particles can be summarized as follows: 1. Diesel exhaust particles are very small in size and consist of a carbonaceous core with a myriad of adsorbed hydrocarbon compounds that are readily extracted with organic solvents. 2. The particle extracts are cytotoxic and mutagenic in in vitro bacterial and mammalian cell cultures. 3. The particle extracts area carcinogenic when painted on mouse skin along with a suitable promoter. 4. Inhaled particles readily deposit in the respiratory tract, a portion is rapidly cleared and a substantial portion is retained for long periods of time (over 100 days) in the lung. 5. Adsorbed hydrocarbon compounds slowly dissociate from the particles in biological media and presumably in the lung. 6. Detoxification mechanisms act on the hydrocarbon compounds released from the particles to minimize effects in in vitro systems and presumably in vivo.

Systemic absorption of selenious acid and elemental selenium aerosols in rats.

Absorption of Se from the nasal passages, lungs, gastrointestinal tract, and skin was studied in Fischer-344 rats. Radiolabeled selenious acid and elemental Se particles were administered by inhalation, gavage, nasal instillation, and iv injection. Selenious acid was always absorbed into the general circulation more rapidly and to a greater extent than elemental Se. By 4 h after inhalation of selenious acid and elemental Se aerosols, 94% of the selenious acid and 57% of the elemental Se deposited in lungs was absorbed into blood. Of the selenious acid instilled into nasal passages, 18% was absorbed into blood; 16% of the elemental Se was absorbed. Gastrointestinal absorption was 87% for selenious acid and 50% for elemental Se. Selenious acid solutions were also painted onto the pelts of rats. From 10 to 30% of the selenious acid was absorbed through the skin. Following inhalation or injection of either Se compound, most of the Se was excreted in the urine. Significantly more Se appeared in feces of animals receiving elemental Se by gavage than animals receiving selenious acid. Results indicate that if people were to absorb inhaled Se from the upper respiratory tract in a manner similar to that of rats, one-third more selenious acid would be absorbed into the general circulation than elemental Se. All Se deposited in the lungs would be absorbed into blood. However, selenious acid would be absorbed more rapidly than elemental Se.