Inhalation Toxicology Research Research Articles

Exposure Effects Beyond the Epithelial Barrier: Transepithelial Induction of Oxidative Stress by Diesel Exhaust Particulates in Lung Fibroblasts in an Organotypic Human Airway Model.

In vitro bronchial epithelial monoculture models have been pivotal in defining the adverse effects of inhaled toxicant exposures; however, they are only representative of one cellular compartment and may not accurately reflect the effects of exposures on other cell types. Lung fibroblasts exist immediately beneath the bronchial epithelial barrier and play a central role in lung structure and function, as well as disease development and progression. We tested the hypothesis that in vitro exposure of a human bronchial epithelial cell barrier to the model oxidant diesel exhaust particulates caused transepithelial oxidative stress in the underlying lung fibroblasts using a human bronchial epithelial cell and lung fibroblast coculture model. We observed that diesel exhaust particulates caused transepithelial oxidative stress in underlying lung fibroblasts as indicated by intracellular accumulation of the reactive oxygen species hydrogen peroxide, oxidation of the cellular antioxidant glutathione, activation of NRF2, and induction of oxidative stress-responsive genes. Further, targeted antioxidant treatment of lung fibroblasts partially mitigated the oxidative stress response gene expression in adjacent human bronchial epithelial cells during diesel exhaust particulate exposure. This indicates that exposure-induced oxidative stress in the airway extends beyond the bronchial epithelial barrier and that lung fibroblasts are both a target and a mediator of the adverse effects of inhaled chemical exposures despite being separated from the inhaled material by an epithelial barrier. These findings illustrate the value of coculture models and suggest that transepithelial exposure effects should be considered in inhalation toxicology research and testing.

The influence of changing dose rate patterns from inhaled beta-gamma emitting radionuclide on lung cancer

Purpose: Dose and dose rate are both appropriate for estimating risk from internally deposited radioactive materials. We investigated the role of dose rate on lung cancer induction in Beagle dogs following a single inhalation of strontium-90 (90Sr), cerium-144 (144Ce), yttrium-91 (91Y), or yttrium-90 (90Y). As retention of the radionuclide is dependent on biological clearance and physical half-life a representative quantity to describe this complex changing dose rate is needed.Materials and methods: Data were obtained from Beagle dog experiments from the Inhalation Toxicology Research Institute. The authors selected the dose rate at the effective half-life of each radionuclide (DRef).Results: Dogs exposed to DRef (1–100 Gy/day) died within the first year after exposure from acute lung disease. Dogs exposed at lower DRef (0.1–10 Gy/day) died of lung cancer. As DRef decreased further (<0.1 Gy/day 90Sr, <0.5 Gy/day 144Ce, <0.9 Gy/day 91Y, <8 Gy/day 90Y), survival and lung cancer frequency were not significantly different from control dogs.Conclusion: Radiation exposures resulting from inhalation of beta-gamma emitting radionuclides that decay at different rates based on their effective half-life, leading to different rates of decrease in dose rate and cumulative dose, is less effective in causing cancer than acute low linear energy transfer exposures of the lung.

Cellular Effects in anIn VitroHuman 3D Cellular Airway Model and A549/BEAS-2BIn VitroCell Cultures Following Air Exposure to Cerium Oxide Particles at an Air–Liquid Interface

There is a need for representative in vitro models to assess the effects of airborne particles on lung health. The ob-jective of this study was to assess the cellular effects of cerium oxide (Ce02) particles exposed via an air—liquid interface in three relevant cell models in parallel. BEAS-2B, A549, and MucilAirTM cells were exposed for 1 hour to Ce02 particles comprising a range of doses (0.04-3.0 pg/cm2) and sizes (0.75 pm and 13.8 nm primary particle size). MucilAir cells are complex 3D cell systems with intact mucocilairy system and are cultured at air—liquid interface, in contrast to the simple cell lines A549 and BEAS 2B, which are essentially immersion models. Cell responses varied according to cell type used. BEAS-2B and A549 cells (normally cultured in liquid media) were sensitive to air exposure alone and exposure to Ce02 particles in terms of cytotoxicity, infiammation, and genotoxicity. MucilAir cells normally cultured at an air—liquid interface were insensitive to the air stream alone and only exhibited oxidative stress response after exposure to Ce02 particles. Minimal or no effects on gene ex-pression were detected in all cell types. Variations according to different sizes and doses of Ce02 were apparent but did not result in any definitive patterns. The minimal effects, except for the oxidative stress response, ob-served in the MucilAir cells are likely because of the presence of extracellular defensive mechanisms, such as intact mucocilairy system, that were not present in the other cell types. Further studies with MucilAir cells and other compounds are warranted to understand wider applicability in inhalation toxicology research

Modular glovebox connector and associated good practices for control of radioactive and chemically toxic materials.

Design and associated good practices are described for a modular glovebox connector to improve control of radioactive and chemically toxic materials. The connector consists of an anodized aluminum circular port with a mating spacer, gaskets, and retaining rings for joining two parallel ends of commercially available or custom-manufactured glovebox enclosures. Use of the connector allows multiple gloveboxes to be quickly assembled or reconfigured in functional units. Connector dimensions can be scaled to meet operational requirements for access between gloveboxes. Options for construction materials are discussed, along with recommendations for installation of the connector in new or retrofitted systems. Associated good practices include application of surface coatings and caulking, use of disposable glovebags, and proper selection and protection of gasket and glove materials. Use of the connector at an inhalation toxicology research facility has reduced the time and expense required to reconfigure equipment for changing operational requirements, the dispersion of contamination during reconfigurations, and the need for decommissioning and disposal of contaminated enclosures.

Statistical Modeling of Carcinogenic Risks in Dogs That Inhaled 238 PuO 2

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.

Biological Effects of 137 CsCl Injected in Beagle Dogs of Different Ages

The toxicity of 137Cs in the beagle dog was investigated at the Inhalation Toxicology Research Institute (ITRI) and Argonne National Laboratory (ANL) as part of programs to evaluate the biological effects of both radionuclides in atomic bomb fallout and internally deposited fission-product radionuclides. In the ITRI study, young adult dogs were exposed once by intravenous injection to a range of 137Cs concentrations; the results have recently been published (Nikula et al., Radiat. Res. 142, 347-361, 1995). The purpose of the present report is to summarize the ANL study and to compare the results of the two studies. At ANL, 63 dogs in three age groups (15 juveniles, 142-151 days old; 38 young adults, 388-427 days old; and 10 middle-aged dogs, 1387-2060 days old) were given 137Cs intravenously at levels (61-162 MBq/kg) near those expected to be lethal within 30 days after injection. There were 17 control dogs from the same colony. Twenty-three of the dogs injected with 137Cs, including all middle-aged dogs, died within 52 days after injection due to hematopoietic cell damage resulting in severe pancytopenia that led to fatal hemorrhage and/or septicemia. The other significant early effect was damage to the germinal epithelium of the seminiferous tubules of all male dogs. These early effects are the same as those reported for the dogs injected with 137Cs at ITRI. In addition, the design of the ANL study revealed an age- and gender-related differential radiosensitivity for early effects: The middle-aged dogs died significantly earlier due to complications of hematological dyscrasia compared to the juvenile and young adult dogs, and the middle-aged females died significantly earlier than the middle-aged males. The most significant non-neoplastic late effects in the 137Cs-injected dogs from ANL and ITRI were atrophy of the germinal epithelium of seminiferous tubules with azoospermia, and a significant dose-dependent decrease in survival. However, the survival of the ANL dogs was decreased more than that of the ITRI dogs at similar radiation doses from 137Cs. Numerous neoplasms occurred at many different sites in the dogs injected with 137Cs at ANL and ITRI. Two differences in the findings of the two studies were that (1) there was an increased risk for malignant thyroid neoplasms in the ANL male dogs injected with 137Cs, but not the ITRI dogs of either gender, and (2) there was an increased relative risk for benign neoplasms excluding mammary neoplasms in the ITRI dogs injected with 137Cs, but not the ANL dogs. In both groups, there were dose-related increased incidences of malignant neoplasms, malignant neoplasms excluding mammary neoplasms, all sarcomas considered as a group, all non-mammary carcinomas considered as a group and malignant liver neoplasms. In summary, the similarity of the findings between the two studies and the dose-response relationships for survival and for large groupings of neoplasms suggests that these results are consistent findings in 137Cs-injected dogs and might be dose-related late effects in humans exposed to sufficient amounts of internally deposited 137Cs.

Animal models of beryllium-induced lung disease.

The inhalation Toxicology Research Institute (ITRI) is conducting research to improve the understanding of chronic beryllium disease (CBD) and beryllium-induced lung cancer. Initial animal studies examined beagle dogs that inhaled BeO calcined at either 500 or 1000 degrees C. At similar lung burdens, the 500 degrees C BeO induced more severe and extensive granulomatous pneumonia, lymphocytic infiltration into the lung, and positive Be-specific lymphocyte proliferative responses in vitro than the 1000 degrees C BeO. However, the progressive nature of human CBD was not duplicated. More recently, Strains A/J and C3H/Hej mice were exposed to Be metal by inhalation. This produced a marked granulomatous pneumonia, diffuse infiltrates, and multifocal aggregates of interstitial lymphocytes with a pronounced T helper component and pulmonary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 micrograms Be/g lung, inhaled Be metal induced benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving > or = 1 year on study. Substantial tumor multiplicity was found, but K-ras and p53 gene mutations were virtually absent. In mice, however, a lung burden of approximately 60 micrograms (-300 micrograms Be/g lung) caused only a slight increase in crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models.

Biological Effects of 137 CsCl Injected in Beagle Dogs

The toxicity of intravenously administered 137CsCl in the beagle dog was investigated as part of a program to evaluate the biological effects of internally deposited fission-product radionuclides. The intravenous route of exposure was chosen for simplicity and accuracy because it was known that after intravenous injection, inhalation or ingestion, internally deposited 137CsCl is rapidly absorbed and distributed throughout the body, exposing the whole body to beta-particle and gamma radiations. Fifty-four dogs were injected intravenously with 137Cs to provide one group of six dogs with mean initial body burdens of 141 MBq 137Cs/kg body mass and four groups of 12 dogs each with mean initial body burdens of 104, 72, 52 and 36 MBq 137Cs/kg. Twelve dogs were injected with isotonic saline as study controls. Because the number of study control dogs was small, data from an additional 49 control dogs from other studies at the Inhalation Toxicology Research Institute that were performed over a similar span of years were also used. There was a significant, dose-dependent decrease in survival of the 137Cs-injected dogs. Eleven 137Cs-injected dogs, including all six in the highest initial body burden group, died within 81 days after injection, primarily due to hematopoietic cell damage resulting in severe pancytopenia. An additional 25 dogs had transient hematological dyscrasia but survived for long times. All 137Cs-injected male dogs had marked damage to the germinal epithelium of the testicular seminiferous tubules with azoospermia in the long-term survivors. Benign and malignant neoplasms occurred in a variety of organs in 137Cs-injected dogs, rather than in a single target organ. When individual organs were considered, the incidence of malignant neoplasms was increased in the liver and in the nasal cavity and paranasal sinuses of the 137Cs-injected dogs. There was a 137Cs treatment effect in the incidence of malignant neoplasms (P < 0.001) in male dogs but no 137Cs-related treatment effect in female dogs. However, when malignant mammary neoplasms were excluded from the analysis, there was no gender difference, and there was a dose-related response (P < 0.001) in both males and females for the incidence of malignant neoplasms.

Gene dysfunctions in rodent lung tumors : Steven A. Belinsky, Inhalation Toxicology Research Institute, Albuquerque, NM 87112

Gene dysfunctions in rodent lung tumors : Steven A. Belinsky, Inhalation Toxicology Research Institute, Albuquerque, NM 87112

K- ras and p53 mutations in rodent lung tumors : Belinsky SA. Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185

K- ras and p53 mutations in rodent lung tumors : Belinsky SA. Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185

Intercomparison of Activity Size Distributions of Thoron Progeny by Alpha- and Gamma-counting Methods

It is difficult to calibrate sampling devices using radon or thoron progeny or particles measuring 1-4 nm; therefore, an interlaboratory comparison is important to verify the performance of graded diffusion batteries for the activity size distributions of the "unattached" progeny. This paper describes the results of an interlaboratory comparison of 220Rn progeny size distributions using graded diffusion batteries by alpha- and gamma-counting methods with different data inversion schemes. Graded diffusion batteries designed at the Inhalation Toxicology Research Institute and at the Environmental Measurement Laboratory were used in the study. Screens and backup filters from the Environmental Measurement Laboratory-graded diffusion batteries were counted simultaneously in alpha counters for total alpha activities, and those of the Inhalation Toxicology Research Institute-graded diffusion batteries were counted in a gamma detector for gamma activities from 212Pb. Because of the different counting methods and data analysis procedures used, this interlaboratory study of 220Rn progeny allows a more rigorous way of testing instrument performance. 212Pb particles generated in well-controlled environments of oxygen, nitrogen, or oxygen with 1 ppm of nitrogen oxide were measured. In general, good agreement in activity size distributions was obtained from these two methods. Some differences observed in individual size spectra were attributable to the data inversion programs used in each laboratory. When the data were analyzed by the same computer program, most differences disappeared.

Comparison of lung carcinoma incidence in Beagle dogs exposed to 239PuO 3 as young adults or as immature dogs : Griffith WC, Guilmette RA, Muggenburg BA. Inhalation Toxicology Research Inst., PO Box 5890, Albuquerque, NM 87185. Radiat Prot Dosim 1992;41:101

Comparison of lung carcinoma incidence in Beagle dogs exposed to 239PuO 3 as young adults or as immature dogs : Griffith WC, Guilmette RA, Muggenburg BA. Inhalation Toxicology Research Inst., PO Box 5890, Albuquerque, NM 87185. Radiat Prot Dosim 1992;41:101

Assessment of Exposure to Pulmonary Toxicants: Use of Biological Markers

Assessment of Exposure to Pulmonary Toxicants: Use of Biological Markers Get access JAMES A. BOND, JAMES A. BOND *Chemical Industry Institute of ToxicologySix Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar LANCE A. WALLACE, LANCE A. WALLACE †U.S. EPA/EPICBuilding 166, Bicher Road, Vint Hill Farm Station, Warrenton, Virginia 22186 Search for other works by this author on: Oxford Academic PubMed Google Scholar SIV OSTERMAN-GOLKAR, SIV OSTERMAN-GOLKAR ‡Chemical Industry Institute of Toxicology and Department of Radiobiology, University of StockholmS-106 91 Stockholm, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar GEORGE W. LUCIER, GEORGE W. LUCIER §NIEHS, Division of Biometry and Risk AssessmentP.O. Box 12233, Research Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar ALAN BUCKPITT, ALAN BUCKPITT ¶Department of Pharmacology and Toxicology, University of California/Davis, School of Veterinary MedicineDavis, California 95616 Search for other works by this author on: Oxford Academic PubMed Google Scholar ROGENE F. HENDERSEN ROGENE F. HENDERSEN ‖Lovelace Inhalation Toxicology Research InstituteP.O. Box 5890, Albuquerque, New Mexico 87185 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 18, Issue 2, February 1992, Pages 161–174, https://doi.org/10.1093/toxsci/18.2.161 Published: 01 February 1992 Article history Received: 23 September 1991 Accepted: 23 September 1991 Published: 01 February 1992

Comparative Dosimetry of Inhaled Materials: Differences among Animal Species and Extrapolation to Man

Comparative Dosimetry of Inhaled Materials: Differences among Animal Species and Extrapolation to Man ALAN R. DAHL, ALAN R. DAHL **Lovelace Inhalation Toxicology Research InstituteP.O. Box 5890, Albuquerque, New Mexico 87185 Search for other works by this author on: Oxford Academic PubMed Google Scholar RICHARD B. SCHLESINGER, RICHARD B. SCHLESINGER †Institute of Environmental Medicine, New York University Medical Center550 First Avenue, New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar HENRY D' A. HECK, HENRY D' A. HECK ‡Chemical Industry Institute of ToxicologyResearch Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar MLCHELE A. MEDINSKY, MLCHELE A. MEDINSKY ‡Chemical Industry Institute of ToxicologyResearch Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar GEORGE W. LUCIER GEORGE W. LUCIER §National Institute of Environmental Health SciencesResearch Triangle Park, North Carolina 27 709 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 16, Issue 1, January 1991, Pages 1–13, https://doi.org/10.1093/toxsci/16.1.1 Published: 01 January 1991 Article history Received: 31 July 1990 Accepted: 16 August 1990 Published: 01 January 1991

Retention Patterns for Inhaled Particles in the Lung

In the absence of adequate data exclusively from studies of inhaled particles in people, the results of inhalation studies using laboratory animals are necessary to estimate particle retention in exposed people. To make accurate projections from animal studies and the limited human data, it is necessary to consider species similarities and differences in lung retention and accumulation patterns for inhaled materials. This paper reviews species similarities and differences in pulmonary retention and clearance for inhaled particles, with emphasis on animal species most commonly used in inhalation toxicology research (rats, guinea pigs, dogs, and nonhuman primates). Simulation models for these four species and for humans were used to compare projected lung burdens which would be accumulated during chronic inhalation exposures. These simulation models project an eightfold difference among these species in the lung concentration of particles per gram of lung after a 2-y chronic inhalation exposure to the same aerosol for 8 h d-1, 5 d wk-1. The largest lung accumulation would occur in guinea pigs, the smallest in rats. To reach the same target lung concentration of particles in the lungs of both animals would therefore require about an eightfold difference in air concentration of the exposure material. These comparisons are useful for selecting appropriate laboratory animal species to study as surrogates for humans, for setting aerosol concentrations to use in inhalation studies, and for making approximations of lung burdens that would result from defined exposure scenarios.

Modeling for scaling to humans: time to get serious.

The subject matter for this 26th Annual Hanford Life Sciences Symposium evolved from the deliberations of a Task Group on Modeling for Scaling to Humans, which was established in January 1986 through the efforts of the Office of Health and Environmental Research of the Department of Energy (OHER/DOE). Several laboratories that utilize animals in radiobiological research sponsored by the OHER/DOE were extensively reviewed in the spring of 1985, and, as a result, OHER recommended establishment of eight task groups designed for selected purposes. The current membership of the Task Group on Modeling for Scaling to Humans is shown in Table 1; Dr. James A. Mewhinney of the Lovelace Inhalation Toxicology Research Institute has been Chairman since these Task Groups were established. Ms. Judy Mahaffey of Battelle. Pacific Northwest Laboratories served as chairperson for this symposium, and the Task Group membership has served as the Program Committee. The OHER/DOE thanks all of them for their work as members of the Task Group as well as for their arranging such a potentially productive and informative meeting.

Symposium on the Importance of Combined Exposures in Inhalation Toxicology

Symposium on the Importance of Combined Exposures in Inhalation Toxicology Get access ROGENE F HENDERSON, ROGENE F HENDERSON *Lovelance Inhalation Toxicology Research InstituteP.O. Box 5890. Albuquerque, New Mexico 87185 Search for other works by this author on: Oxford Academic PubMed Google Scholar RICHARD B. SCHLESINGER RICHARD B. SCHLESINGER †Institute of Environmental Medicine, New York University Medical Center550 First Avenue. New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 12, Issue 1, January 1989, Pages 1–11, https://doi.org/10.1093/toxsci/12.1.1 Published: 01 January 1989

Symposium on Lung Cancer Risk of Exposure to Radon

Journal Article Symposium on Lung Cancer Risk of Exposure to Radon Get access ROGENE F. HENDERSON ROGENE F. HENDERSON Lovelace Inhalation Toxicology Research InstituteP. O. Box 5890, Albuquerque, New Mexico 87185 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 13, Issue 4, November 1989, Pages 624–634, https://doi.org/10.1093/toxsci/13.4.624 Published: 01 November 1989 Article history Received: 05 July 1989 Accepted: 21 July 1989 Published: 01 November 1989

Regional Deposition of Inhaled Monodisperse Coarse and Fine Aerosol Particles in Small Laboratory Animals

The regional deposition of inhaled monodisperse insoluble particles of about 1,3,5 and 10 μm in activity median aerodynamic diameter was measured in four small rodent species including CF1 mice, golden Syrian hamsters, Fischer 344 rats and Hartley guinea pigs and in New Zealand rabbits. Near monodisperse aerosols of about 0.05 μm activity median diffusive diameter were also studied. The five species are commonly utilized in inhalation toxicology research. Monodisperse aerosols of fused aluminosilicate particles (2.46 g/cm3) labelled with radioactive l69Yb were generated utilizing a modified vibrating liquid stream generator, reduced to Boltzmann charge equilibrium with a 85Kr discharge device, concentrated with a centripeter stage, fused in a 1200°C quartz tube furnace, and delivered to a specially designed nose-only exposure system suitable for use with coarse particles as large as 10 μm. Twenty unanaesthetized animals (eight rabbits) were exposed simultaneously for up to 45 minutes to each aerosol particle size. Half were sacrificed immediately after exposure and the remaining half were sacrificed after 20 hours to measure bronchial clearance. Radioassay of selected tissues included the individual lung lobes, trachea, larynx, head airways, and gastrointestinal tract to determine deposition quantities. The results show enhanced nasal-pharyngeal deposition for particles larger than 3 μm in aerodynamic diameter, with over 90 percent nasal-pharyngeal deposition for particles larger than 5 μm. Conversely, pulmonary (alveolar) deposition approaches nil for the larger particles.

Organs and Cells at Risk after Inhalation of Insoluble Beta-Emitting Radionuclides: Lessons From Experimental Studies

Lifespan studies of Beagle dogs that inhaled beta-emitting radionuclides in a relatively insoluble form have been conducted at the Lovelace Inhalation Toxicology Research Institute. These studies were designed to determine the types and locations of radiation-induced tumors as well as the influence of dose protraction on the incidence of such tumors. Although not all these studies are complete, data on organs and cells at risk are available. Histologic tumor types of the lung indicate that numerous cell types are probably at risk after inhalation of beta-emitting radionuclides. Tumors of blood vessels, connective tissue, and pulmonary epithelium have been seen. The numerous cell types involved in tumors of the pulmonary epithelium make it difficult to designate one cell type at risk. The tumors do originate, however, in the terminal airway and alveolar portions of the lung, not the larger airways. Organs other than lung developed tumors through direct irradiation of the tissues. These are tracheobronchial lymph nodes and heart. Neither of these organs has been considered targets for radionuclide-induced tumors. Results from these studies indicate that attention to dose effect relationships in these non-pulmonary tissues may be warranted.