Gerald E. Dagle

Lung changes in rats following inhalation exposure to volcanic ash for two years

Rats were exposed by inhalation to 5 or 50 mg/m3 Mount St. Helens volcanic ash, to 50 mg/m3 quartz (positive controls), or to filtered room air (sham-exposed controls), for 6 hr/day, 5 days/week, for up to 24 months to investigate biological effects of chronic inhalation exposure to volcanic ash under controlled laboratory conditions. Exposure-related lung changes comprised accelerated respiratory frequency; alveolar macrophage accumulation; interstitial reaction; lymphoreticular reaction in peribronchiolar regions and in mediastinal lymph nodes; alveolar proteinosis in the 50- mg/m3 ash- or quartz-exposed groups; increase in fresh lung weights; decreased body weight and increased mortality in the quartz-exposed group; and epidermoid carcinomas especially in the quartz-exposed females and, to a lesser extent, in the 50-mg/m3 ash-exposed females. The observed changes reflect significant dose-response and agent-response relationships.

Inhalation bioassay of cigarette smoke in rats

Abstract Groups of 80 female rats were exposed to cigarette smoke from three types (code 13 = high tar, low nicotine; code 27 = low tar, medium nicotine; code 32 = high tar, high nicotine) of cigarettes in Maddox-ORNL smoking machines, eight cigarettes per day, 7 days per week, for up to 24 months. An additional group received sham exposures and a fifth group served as untreated controls. The sham-exposed animals had significantly lower body weights than the untreated controls. The smoke-exposed animals had significantly lower weights than the sham-exposed controls; the weights were lower for the code 27 and code 32 animals than for the code 13 animals during the second year of exposure. The survival of the code 13 animals was similar to that for the sham-exposed and untreated control group; survival times of the code 27 and code 32 animals were shorter. Body weight and survival reflected the high- and low-nicotine dose groups indicated by in vivo dosimetry measurements. Smoke-induced histopathologic lesions consisted primarily of pulmonary smoke granulomas; the smoke granulomas were less severe in the code 27 exposure group than in the groups exposed to smoke from code 13 or code 32 cigarettes. Additional changes included pulmonary alveolar epithelial hyperplasia, and squamous metaplasia and basal cell hyperplasia of laryngeal and tracheal epithelium. One primary epidermoid carcinoma was found in the lung of a code 27 rat. The rats tolerated the chronic exposures relatively well and certain of the smoke-induced lesions allowed differentiation between the different types of cigarettes.

Acute and subchronic inhalation exposures of hamsters to nickel-enriched fly ash

Abstract One 6-hr inhalation exposure of hamsters to Ni-enriched fly ash (NEFA) aerosol (respirable aerosol concentration ∼200 μg/liter) deposited about 80 μg in the deep lung, of which 75 μg was still present 30 days postexposure. The animals tolerated the exposure well during the 30-day postexposure observation period. Two-month exposures of hamsters to NEFA or fly ash (FA) aerosols (∼185 μg/liter) resulted in a deep lung burden of about 5.7 mg, dark discoloration of lungs, heavily dustladen macrophages, and significantly higher lung weights than in controls, but only minimal inflammatory reaction and no deaths. There was no difference between NEFA and FA effects. The NEFA contained 9% Ni; FA contained 0.03% NI. The results of this study indicate low acute and subchronic toxicity and slow lung clearance of NEFA and FA.

Biological Effects of Inhaled 239PuO2 in Beagles

Seven groups of 8–24 Beagle dogs, exposed to 239PuO2 aerosols by inhalation [mean initial lung depositions (ILD) of 0.0, 0.14, 0.63, 3.2, 13, 44 and 210 kBq] were observed throughout their lives to determine tissues at risk and dose-effect relationships. The mean average pulmonary retention half-time of 239Pu was 1,192 days. Most (70%) of the plutonium recovered at death in dogs surviving >10 years after exposure was found in the thoracic lymph nodes with ∼15% in lung, ∼10% in liver and ∼2% in bone. Eight dogs at the highest exposure levels died from radiation pneumonitis prior to a minimal 3-year latency period after exposure for the observation of lung tumors, with the first succumbing 337 days after exposure. Of 108 plutonium-exposed Beagles with ILD <100 kBq, 51 (47%) had lung tumors with significantly increased incidence in those dogs with total lung dose of ≥1.1 Gy at death. The primary non-neoplastic effects observed were lymphopenia, atrophy and fibrosis of the thoracic lymph nodes, radiation pneumonitis and pulmonary fibrosis, and bacterial pneumonia. Lesions of the thoracic lymph nodes were observed in 98 of 108 exposed dogs, but there were no primary neoplasms of the lymph nodes. Bacterial pneumonia was observed in 13 plutonium-exposed dogs and was the most notable non-neoplastic cause of death, with survival nearly the same as that of controls. Setting of dose limits on the basis of detrimental effects commonly considers and differentiates between stochastic and deterministic effects, raising the question of whether the non-neoplastic effects found in this study were deterministic. The International Commission on Radiation Protection (ICRP), National Council on Radiation Protection & Measurements (NCRP), and similar organizations generally consider effects that increase in incidence and severity to meet the definition of deterministic. We demonstrated the radiation dose-related nature of effects such as pneumonitis and fibrosis graphically and lymphopenia numerically, rather than by quantified estimates. It is clear, however, that both incidence and severity increased with ILD and radiation dose and should be considered as deterministic effects.

Chronic inhalation exposure of hamsters to nickel-enriched fly ash

Abstract Hamsters were chronically exposed to ∼70 μg/liter respirable nickel-enriched fly ash (NEFA) aerosol, ∼17 μg/liter NEFA, or ∼70 μg/liter fly ash (FA) for up to 20 months. A control group received sham exposures. The NEFA particles of respirable size contained approximately 6% nickel, compared to about 0.3% for FA. Five hamsters/group were sacrificed after 4, 8, 12, or 16 months of exposure. An additional five hamsters/group were withdrawn from exposure at the same intervals for lifelong observations. Exposures to NEFA had no significant effect on body weight and life span of the animals although heavy deposits of NEFA in the lungs were demonstrated. However, lung weights of the high NEFA- and of the FA-exposed animals were significantly higher than those of the low-NEFA group and the controls, and mean lung volumes were significantly larger for the high-NEFA group and the FA group than for the low-NEFA group and the controls. Dust was deposited (anthracosis) in the lungs of all exposed hamsters. Incidence and severity of interstitial reaction and bronchiolization were significantly higher in the dust-exposed groups than in the sham-exposed controls. The severity of anthracosis, interstitial reaction, and bronchiolization was significantly lower in the low-NEFA group than in the high-NEFA and FA groups. While two malignant primary thorax tumors were found in two hamsters of the high-NEFA group, no statistically significant carcinogenesis was observed. Of the exposure-related changes, only anthracosis decreased after withdrawal from exposure. Pulmonary nickel burdens after 20 months of exposure suggest that the pulmonary clearance rate was slower in the high-NEFA group than in the low-NEFA group.

Statistical modeling of carcinogenic risks in dogs that inhaled 238PuO2

Combined analyses of data on 260 life-span beagle dogs that inhaled 238PuO2 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets.

Hematological effects of inhaled plutonium dioxide in beagles.

A life-span study indicated that plutonium activity in the thoracic lymph nodes is a contributor to development of lymphopenia in beagles exposed to 239PuO2. Significant lymphopenia was found in 67 (58%) beagles given a single nose-only exposure to 239PuO2 to result in mean initial lung depositions ranging from 0.69 to 213.3 kBq. Lymphoid atrophy and sclerosis of the thoracic lymph nodes and lymphopenia were observed in exposure-level groups with initial lung depositions > or = 2.5 kBq. Those dogs with final plutonium concentrations in the thoracic lymph nodes > or = 0.4 kBq/g and dose rates > or = 0.01 Gy/day developed lymphopenia. Marked differences existed between chronically lymphopenic dogs and intermittently lymphopenic dogs with regard to initial lung deposition, time to lymphopenic events and absolute lymphocyte concentrations. Linear regression analysis revealed moderate correlation between reduction in lymphocyte values and initial lung deposition, in both magnitude and time of appearance after exposure. Cumulative dose and dose rate appeared to act together to produce initial effects on lymphocyte populations, while dose rate alone appeared to be responsible for the maintenance and subsequent cycles of lymphopenia seen over the life span. No primary tumors were associated with the thoracic lymph nodes in this study, although 70% of the lymphopenic dogs developed lung tumors.

Asbestos cement dust inhalation by hamsters

Two groups of 96 male Syrian golden hamsters were exposed to respirable asbestos cement aerosol at concentrations of approximately 1 and approximately 10 micrograms/liter, respectively, 3 hours/day, 5 days/week. Average fiber counts ranged from 5 to about 120 fibers/cm3. Each group was randomly divided into six subgroups of 16 animals. The first subgroup was sacrificed after 3 months of exposure, the second after 6 months, and the third after 15 months. The fourth subgroup was withdrawn from exposure after 3 months, observed for an additional 3 months, and then sacrificed. The fifth and sixth subgroups were withdrawn after 3 and 6 months of exposure, respectively, and maintained for observation up to the 15-month exposure point of the third subgroup at which time all surviving animals were sacrificed. All other experimental procedures were similar to those delineated in a previous publication describing the development of an animal model, techniques, and an exposure system for asbestos cement dust inhalation (A. P. Wehner, G. E. Dagle, and W. C. Cannon, 1978, Environ. Res. 16, 393-407). The asbestos cement exposures had no significant effect on body weight and mortality of the animals. Higher aerosol concentration and longer exposure times increased the number of macrophages and ferruginous bodies found in the lungs of the exposed animals. Recovery periods had no effect on the incidence of macrophages and ferruginous bodies. The incidence of very slight to slight fibrosis in the animals sacrificed after 15 months of exposure shows a significant (P less than 0.01) trend when the untreated control group and the 1 and 10 microgram/liter dose level groups are compared, indicating a dose-response relationship. Development of minimal fibrosis continued in animals withdrawn from exposure. No primary carcinomas of the lung and respiratory tract and no mesotheliomas were found.

Development of an animal model, techniques, and an exposure system to study the effects of asbestos cement dust inhalation

Abstract An aerosol exposure system and procedures for delivering asbestos cement (AC) dust to the lungs of hamsters are described. Groups of hamsters were exposed to AC aerosol concentrations of 1 and 10 μg/liter, respectively, 3 hr/day, 5 days/week, for 3 and 6 months and were sacrificed for histopathologic examination. One subgroup from both the 1- and the 10-μg/liter exposure group was withdrawn from exposure after 3 months and sacrificed after a 3-month recovery period to determine whether or not some of the histologic changes might be reversible. There was an apparent dose — response relationship between AC exposure and the number of asbestos bodies and small randomly distributed foci of alveolar macrophages. No other treatment-related lesions were observed. The 3-month recovery period had no apparent effect.

Evaluation of beeswax-tricaprylin vehicle for pulmonary carcinogenesis studies

Abstract The release properties of three compounds, representative of three different subfractions of cigarette smoke condensate (CSC), were characterized from a beeswax-tricaprylin matrix. These compounds were nicotine (weak base fraction), 3-methylcholanthrene (a polycyclic hydrocarbon similar to compounds in the neutral fraction), and phenol (weak acid fraction). The release profiles for the three materials vary greatly, indicating that the beeswax-tricaprylin vehicle does not provide a uniform administration of whole CSC or multicomponent fractions of CSC to the implant site. The pellets will produce a varying exposure of the CSC components to the tissue, based on the chemical nature of the individual component. The release of nicotine from the beeswax-tricaprylin vehicle was found to be rapid and dependent on the geometry of the pellet and concentration. The in vitro release data for nicotine correlated well both with the single component in vivo data and with in vivo data where nicotine was part of whole CSC in the implant pellet. The release of 3-methylcholanthrene was slow and had approximately zero-order kinetics. The phenol release profile was between nicotine and 3-methylcholanthrene, which correlates with the relative polarity of the three materials. Modeling the release characteristics of a component of CSC by testing its individual release properties in vitro was found to be a promising method (i) to establish the dose and dose rate of various components of CSC from implant vehicles, and (ii) to evaluate in vivo exposure data in terms of the exposure rate of the various components of CSC.