Pulmonary retention and clearance of inhaled biopersistent aerosol particles: Data-reducing interpolation models and models of physiologically based systems - A review of recent progress and remaining problems

Critical Reviews in Toxicology

Volumn 27, Issue 6, 1997, Pages 539-598

  Stöber, Werner ^a   McClellan, Roger O ^a  

^a CIIT CENTERS FOR HEALTH RESEARCH   (United States)

Author keywords

Biopersistent particles; Extrapolation bias; Insoluble particles; Multicompartmental pulmonary modeling; Overload carcinogenesis; Rat lung

Indexed keywords

CARCINOGEN; CYTOTOXIC AGENT;

AEROSOL; COMPARTMENT MODEL; ENVIRONMENTAL EXPOSURE; HUMAN; HYPOTHESIS; LONG TERM EXPOSURE; LUNG CANCER; LUNG TOXICITY; MATHEMATICAL ANALYSIS; MATHEMATICAL MODEL; NONHUMAN; REVIEW; RISK ASSESSMENT;

ANIMALIA;

EID: 0031463997     PISSN: 10408444     EISSN: None     Source Type: Journal    
DOI: 10.3109/10408449709084404     Document Type: Review

References (93)

1. Findeisen, W., Über das Absetzen kleiner, in der Luft suspendierter Teilchen in der menschlichen Lunge bei der Atmung. Pflüger's Arch. gesamte Physiol. 236:367-379, 1935.
2. Landahl, H.D., T.N. Tracewell, and W.H. Lassen, Retention of Airborne Particulates in the Human Lung: III. Arch. Ind. Hyg. 6:508-511, 1952.
3. Wilson, I.B. and V.K. LaMer, The Retention of Aerosol Particles in the Human Respiratory Tract as a Function of Particle Radius. J. Ind. Hyg. Toxicol. 30:265-280, 1948.
4. McClellan, R.O, R.F. Henderson (eds.), Concepts in Inhalation Toxicology, 2nd edition, Taylor & Francis, Washington DC, 648 pp., 1995.
5. Stöber, W., R.O. McClellan, and P.E. Morrow, Approaches to Modeling Disposition of Inhaled Particles and Fibers in the Lung. In: Toxicology of the Lung. D.E. Gardner, J.D. Crapo, and R.O. McClellan (eds.), Raven Press, New York, NY. 527-601, 1993.
6. Heyder, J., J. Gebhart, C. Roth, W. Stahlhofen, B. Stuck, G. Tarroni, T. Dezaiacomo, M. Formignani, C. Melandri, and V. Prodi, Intercomparison of Lung Deposition Data for Aerosol Particles. J. Aerosol Sci. 9:147-155, 1978.
7. Guyton, A.C., Measurement of the Respiratory Volumes of Laboratory Animals. Am. J. Physiol. 150:70-77, 1947.
8. Stahl, W.R., Scaling of Respiratory Variables in Mammals. J. Appl. Physiol. 22:453-460, 1967.
9. Andersen, M.E., Tissue Dosimetry in Risk Assessment, or What's the Problem Here Anyway ? In: Pharmacokinetics in Risk Assessment - Drinking Water and Health. Volume 8. National Research Council/National Academy Press, Washington, DC. 8-23, 1987.
10. LaBelle, C.W. and H. Brieger, Synergistic Effects of Aerosols - II. Effects on Rate of Clearance from the Lung. Arch. Ind. Health 20:100-105, 1959.
11. Kanapilly, G.M., O.G. Raabe, C.H.T. Goh, and R.A. Chimenti, Measurement of in vitro Dissolution of Aerosol Particles for Comparison to in vivo Dissolution in the Lower Respiratory Tract after Inhalation. Health Phys. 24:497-507, 1973.
12. Albert, R.E. and L.C. Arnett, Clearance of Radioactive Dust from the Human Lung. Arch. Ind. Health 12:99-106, 1955.
13. Bellmann, B., H. Muhle, O. Creutzenberg, C. Dasenbrock, R. Kilpper, J.C. MacKenzie, P. Morrow, and R. Mermelstein, Lung Clearance and Retention of Toner, Utilizing a Tracer Technique, during Chronic Inhalation Exposure in Rats. Fundam. Appl. Toxicol. 17:300-313, 1991.
14. WolfF, R.K., R.F. Henderson, M.B. Snipes, W.C. Griffith, J.L. Mauderly, R.G. Cuddihy, and R.O. McClellan, Alterations in Particle Accumulation and Clearance in Lungs of Rats Chronically Exposed to Diesel Exhaust. Fundam. Appl. Toxicol. 9:154-166, 1987.
15. Oberdörster, G., J. Ferin, and B.E. Lehnert, Correlation between Particle Size, In Vivo Particle Persistence and Lung Injury. Environ. Health Perspect. Suppl. 102 (5):173-179, 1994.
16. Morrow, P.E., The Setting of Particulate Exposure Levels for Chronic Inhalation Toxicity Studies. J. Am. Coll. Toxicol. 5:533-544, 1986.
17. Mauderly, J.L., R.K. Jones, W.C. Griffith, R.F. Henderson, and R.O. McClellan, Diesel Exhaust is a Pulmonary Carcinogen in Rats Exposed Chronically by Inhalation. Fundam. Appl. Toxicol. 9:208-221, 1987.
18. Heinrich, U., R. Fuhst, S. Rittinghausen, O. Creutzenberg, B. Bellmann, W. Koch, and K. Levsen, Chronic Inhalation Exposure of Wistar Rats and Two Different Strains of Mice to Diesel Engine Exhaust, Carbon Black and Titanium Dioxide. Inhalation Toxicol. 7:533-556, 1995.
19. Dungworth, D.L., U. Mohr, U. Heinrich, H. Ernst, and B. Kittel, Pathological Effects of Inhaled Particles in Rat Lungs: Associations between Inflammatory and Neoplastic Processes. In: Toxic and Carcinogenic Effects of Solid Particles in the Respiratory Tract. U. Mohr, D.L. Dungworth, J.L. Mauderly, and G. Oberdörster (eds.), ILSI Press, Washington, DC. 75-98, 1994.
20. Ishinishi, N., A. Koizumi, R.O. McClellan, and W. Stöber (eds.), Carcinogenic and Mutagenic Effects of Diesel Engine Exhaust, Elsevier Science Publ., New York, 539 pp., 1986.
21. IARC, Diesel and Gasoline Exhausts and Some Nitroarenes. IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans 46:1-ff., 1989.
22. Nikula, K.J., M.B. Snipes, E.B. Barr, W.C. Griffith, R.F. Henderson, and J.L. Mauderly, Influence of Particle-Associated Organic Compounds on the Carcinogenicity of Diesel Exhaust. In: Toxic and Carcinogenic Effects of Solid Particles in the Respiratory Tract. U. Mohr (ed.), Springer Verlag, Berlin. 565-568, 1994.
23. Selikoff, I.J., E.C. Hammond, and H. Seidman, Mortality Experience of Insulation Workers in the United States and Canada, 1943 - 1976. Ann. N. Y. Acad. Sci. 330:91-116, 1979.
24. McConnell, E.E., R.W. Mast, T.W. Hesterberg, J. Chevalier, P. Kotin, D.M. Bernstein, P. Thevenaz, L.R. Glass, and R. Anderson, Chronic Inhalation Toxicity of a Kaolin-Based Refractory Ceramic Fiber in Syrian Golden Hamsters. Inhalation Toxicol. 7:503-532, 1995.
25. Heppleston, A.G., Silica, Pneumoconiosis, and Carcinoma of the Lung. Am. J. Ind. Med. 7:285-294, 1985.
26. Martin, J.C., H. Daniel, and L. Le Bouffant, Short- and Long-Term Experimental Study of the Toxicity of Coal-Mine Dust and Some of its Constituents. In: Inhaled Particles IV, Part 1. W.H. Walton and B. McGovern (eds.), Pergamon Press, Oxford. 361-371, 1977.
27. Mauderly, J.L., E.B. Barr, A.F. Eidson, J.R. Harkema, R.F. Henderson, J.A. Pickrell, R.K. Wolff, and M.R. Anver, Pneumoconiosis in Rats Exposed Chronically to Oil Shale Dust and Diesel Exhaust, Alone and in Combination. Ann. Occup. Hyg. 38 (Suppl.1):403-409, 1994.
28. Muhle, H., B. Kittel, H. Ernst, U. Mohr, and R. Mermelstein, Neoplastic Lung Lesions in Rat after Chronic Exposure to Crystalline Silica. Scand. J. Work Environ. Health 21 (Suppl.2):27-29, 1995.
29. 2 Dust Deposition. Environ. Res. 41:144-167, 1986.
30. Schwartz, J. and D.W. Dockery, Particulate Air Pollution and Daily Mortality in Steubenville, Ohio. Am. J. Epidemiol. 135:12-19, 1992.
31. Utell, M.J. and J.M. Samet, Particulate Air Pollution and Health. New Evidence of an Old Problem. Am. Rev. Respir. Dis. 147:1334-1335, 1993.
32. Lippmann, M. and K. Ito, Separating the Effects of Temperature and Season on Daily Mortality from those of Air Pollution in London: 1965-1972. Inhalation Toxicol. 7:85-97, 1995.
33. Oberdörster, G., R.M. Gelein, J. Ferin, and B. Weiss, Association of Particulate Air Pollution and Acute Mortality: Involvement of Ultrafine Particles ? Inhalation Toxicol. 7:111-124, 1995.
34. Pope, C.A.,III, D.W. Dockery, and J. Schwartz, Review of Epidemiological Evidence of Health Effects of Particulate Air Pollution. Inhalation Toxicol. 7:1-18, 1995.
35. Moolgavkar, S.H., E.G. Luebeck, T.A. Hall, and E.L. Anderson, Particulate Air Pollution, Sulfur Dioxide, and Daily Mortality : A Reanalysis of the Steubenville Data. Inhalation Toxicol. 7:35-44, 1995.
36. Stöber, W., Interpretation of Carcinogenicity and Effective Dose in Chronic Exposures of Rats to High Diesel Exhaust Concentrations. In: Nitroarenes, Occurence, Metabolism and Biological Impact. P.C. Howard, S.S. Hecht, and F.A. Beland (eds.), Plenum Press, New York. 15-27, 1990.
37. Hart, G.A., L.M. Kathman, and T.W. Hesterberg, In vitro Cytotoxicity of Asbestos and Man-Made Vitreous Fibers: Roles of Fiber Length, Diameter and Composition. Carcinogenesis 15:971-977, 1994.
38. Stöber, W. and J.L. Mauderly, A Model-Inferred Hypothesis of a Critical Dose for Overload Tumor Induction by Diesel Soot and Carbon Black. Inhalation Toxicol. 6:427-457, 1994.
39. ICRP, Human Respiratory Tract Model for Radiological Protection. Ann. ICRP 24(1-3) ICRP Publ.66:1-482, 1994.
40. Stöber, W., Dynamic Shape Factors of Nonspherical Aerosol Particles. In: Assessment of Airborne Particles. T.T. Mercer, P.E. Morrow, and W. Stöber (eds.), Charles C. Thomas, Publisher, Springfield, Illinois. 249-289, 1972.
41. Morgan, A., Fiber Dimensions: Their Significance in the Deposition and Clearance of Inhaled Fibrous Dusts. In: Dust and Disease. R. Lemen and J.M. Dement (eds.), Pathtox Publishers Inc., Park Forest South, IL. 87-96, 1979.
42. Bernstein, D.M., C. Morscheidt, H. Tiesler, H.-G. Grimm, P. Thevenaz, and U. Teichert, Evaluation of the Biopersistence of Commercial and Experimental Fibers Following Inhalation. Inhalation Toxicol. 7:1029-1056, 1995.
43. ICRP, Recommendations of the International Commission on Radiological Protection, Report of Committee II on Permissible Doses for Internal Radiation. ICRP Publication 2:1-40, 1959; see also Health Phys. 3:103-207, 1960.
44. ICRP, Recommendations of the International Commission on Radiological Protection, Report of Committee II on Permissible Doses for Internal Radiation. ICRP Publication 2:1-40, 1959; see also Health Phys. 3:103-207, 1960.
45. Yu, C.P., J.P. Hu, G. Leikauf, D. Spektor, and M. Lippmann, Mucociliary Transport and Particle Clearance in the Human Tracheobronchial Tree. In: Aerosols in the Mining and Industrial Work Environment. V.A. Marple and B.Y.H. Liu, (eds.), Proceed.Internat.Symp., Minneapolis, MN. 177-184, 1983.
46. Yu, C.P., J.P. Hu, B.M. Yen, D.M. Spektor, and M. Lippmann, Models for Mucociliary Particle Clearance in Lung Airways. In: Aerosols: Research, Risk Assessment and Control Strategies. S.D. Lee, T. Schneider, L.D. Grant, and P.J. Verkerk, (eds.), Lewis Publishers Inc., Chelsea, Michigan. 569-578, 1986.
47. DiStefano III, J.J. and E.M. Landaw, Multiexponential, Multicompartmental, and Noncompartmental Modeling. I. Methodological Limitations and Physiological Interpretations. Am. J. Physiol. (Regul. Integrat. Comp. Physiol. 15) 246:R651-R664, 1984.
48. Task Group on Lung Dynamics, P.E. Morrow, D.V. Bates, B.R. Fish, T.F. Hatch, and T.T. Mercer, Deposition and Retention Models for Internal Dosimetry of the Human Respiratory Tract. Health Phys. 12:173-207, 1966.
49. Phalen, R.F., R.G. Cuddihy, G.L. Fisher, O.R. Moss, R.B. Schlesinger, D.L. Swift, and H.C. Yeh, Main Features of the Proposed NCRP Respiratory Tract Model. Radiat. Prot. Dosim. 38:159-184, 1991.
50. Snipes, M.B., B.B. Boecker, and R.O. McClellan, Retention of Monodisperse or Polydisperse Alumosilicate Particles Inhaled by Dogs, Rats and Mice. Toxicol. Appl. Pharmacol. 69:345-362, 1983.
51. Yu, C.P., P.E. Morrow, T.L. Chan, K.A. Strom, and K.J. Yoon, A Nonlinear Model of Alveolar Clearance of Insoluble Particles from the Lung. Inhalation Toxicol. Premier Issue:97-107, 1988.
52. Strom, K.A., T.L. Chan, and J.T. Johnson, Pulmonary Retention of Inhaled Submicron Particles in Rats: Diesel Exhaust Exposures and Lung Retention Model. Ann. Occup. Hyg. 32, Supplement 1:645-657, 1988.
53. Pepelko, W.E. and C. Chen, Quantitative Assessment of Cancer Risk from Exposure to Diesel Emissions. Regul. Toxicol. Pharmacol. 17:52-65, 1993.
54. Yu, C.P. and K.J. Yoon, Retention Modeling of Diesel Exhaust Particles in Rats and Humans. HEI Health Effects Institute Research Report No. 40:1-24, 1990.
55. Vincent, J.H., A.M. Johnston, A.D. Jones, R.E. Bolton, and J. Addison, Kinetics of Deposition and Clearance of Inhaled Mineral Dusts during Chronic Exposure. Br. J. Ind. Med. 42:707-715, 1985.
56. Soderholm, S.C., Compartmental Analysis of Diesel Particle Kinetics in the Respiratory System of Exposed Animals, GM Research Publication No. GMR-3808, Warren, MI. 1-20, 1981.
57. Bellmann, B., H. Muhle, O. Creutzenberg, C. Dasenbrock, R. Kilpper, J.C. MacKenzie, P. Morrow, and R. Mermelstein, Lung Clearance and Retention of Toner, Utilizing a Tracer Technique, during Chronic Inhalation Exposure in Rats. Fundam. Appl. Toxicol. 17:300-313, 1991.
58. Bellmann, B., O. Creutzenberg, H. Muhle, and R. Mermelstein, Models for Deposition, Retention and Clearance of Particles after Dust Overloading of Lungs in Rats. Ann. Occup. Hyg. 38 (Suppl.1):303-311, 1994.
59. Bellmann, B., H. Muhle, O. Creutzenberg, and R. Mermelstein, Recovery Behaviour after Dust Overloading of Lungs in Rats. J. Aerosol Sci. 21:377-380, 1990.
60. Smith, T.J., Development and Application of a Model for Estimating Alveolar and Interstitial Dust Levels. Ann. Occup. Hyg. 29:495-516, 1985.
61. Klosterkötter, W. and F. Gono, Long-Term Storage, Migration and Elimination of Dust in the Lungs of Animals, with Special Respect to the Influence of Polyvinyl-Pyridine-N-Oxide. In: Inhaled Particles III, Volume I. W.H. Walton (ed.), Unwin Brothers Ltd., Old Woking, Surrey, England. 273-280, 1971.
62. Bohning, D.E., H.L. Atkins, and S.H. Cohn, Long-Term Particle Clearance in Man: Normal and Impaired. Ann. Occup. Hyg. 26:259-271 1982.
63. Peters, J.M., T.J. Smith, L. Bernstein, W.E. Wright, and S.K. Hammond, Pulmonary Effects of Exposures in Silicon Carbide Manufacturing. Br. J. Ind. Med. 41:109-115, 1984.
64. Smith, T.J., S.K. Hammond, F. Laidlaw, and S. Fine, Respiratory Exposures Associated with Silicon Carbide Production : Estimation of Cumulative Exposures for an Epidemiological Study. Br. J. Ind. Med. 41:100-108, 1984.
65. Bloom, S.B., J.D. Brain, and P. Gehr, Progression of Phagocytosis of Magnetic Particles by Hamster Pulmonary Macrophages. J. Leukoc. Biol. 36:401, 1984.
66. Brody, A.R., M.W. Roe, J.N. Evans, and G.S. Davis, Deposition and Translocation of Inhaled Silica in Rats - Quantification of Particle Distribution, Macrophage Participation, and Function. Lab. Invest. 47:533-542, 1982.
67. Parkes, W.R., Occupational Lung Disorders, 2nd edition, Butterworth, London, 1982.
68. van Lier, J.A., P.L. de Bruyn, and J.Th.G. Overbeek. The Solubility of Quartz. J. Physical Chem. 64:1675-1682, 1960.
69. Verma, D.K., D.C.F. Muir, M.L. Stewart, J.A. Julian, A.C. Ritchie, The Dust Content of the Lungs of Hard-Rock Miners and Its Relationship to Occupational Exposure, Pathological and Radiological Findings. Ann. occup. Hyg. 26, 401-409, 1982.
70. Katsnelson, B.A., L.K. Konysheva, L.I. Privalova, and K.I. Morosova, Development of a Multicompartmental Model of the Kinetics of Quartz Dust in the Pulmonary Region of the Lung During Chronic Inhalation Exposures of Rats. Br. J. Ind. Med. 49:172-181, 1992.
71. Katsnelson, B.A., L.K. Konysheva, N.Y. Sharapova, and L.I. Privalova, Prediction of the Comparative Intensity of Pneumoconiotic Changes by Chronic Inhalation Exposure to Dusts of Different Cytotoxicity by Means of a Mathematical Model. Occup. Environ. Med. 51:173-180, 1994.
72. Privalova, L.I., B.A. Katsnelson, and L.N. Yelnichnykh, Some Peculiarities of the Pulmonary Phagocytic Response: Dust Retention Kinetics and Silicosis Development During Long Term Exposure of Rats to High Quartz Dust Levels. Br. J. Ind. Med. 44:228-235, 1987.
73. Morrow, P.E., Possible Mechanisms to Explain Dust Overloading of the Lungs. Fundam. Appl. Toxicol. 10:369-384, 1988.
74. Stöber, W., P.E. Morrow, and M.D. Hoover, Compartmental Modeling of the Long-Term Retention of Insoluble Particles Deposited in the Alveolar Region of the Lung. Fundam. Appl. Toxicol. 13:823-842, 1989.
75. Stöber, W., P.E. Morrow, and G. Morawietz, Alveolar Retention and Clearance of Insoluble Particles in Rats Simulated by a New Physiology-Oriented Compartmental Kinetics Model. Fundam. Appl. Toxicol. 15:329-349, 1990.
76. Strom, K.A., J.T. Johnson, and T.L. Chan, Retention and Clearance of Inhaled Submicron Carbon Black Particles. J. Toxicol. Environ. Health 26:183-202, 1989.
77. 2 and Quartz During a Long-Term Study in Rats. Toxicologist 8, Abstract 272:69, 1988.
78. Muhle, H., R. Mermelstein, C. Dasenbrock, S. Takenaka, U. Mohr, R. Kilpper, J. MacKenzie, and P. Morrow, Lung Response to Test Toner upon 2-Year Inhalation Exposure in Rats. Exp. Pathol. 37:239-242, 1989.
79. Stöber, W., P.E. Morrow, G. Morawietz, W. Koch, and M.D. Hoover, Developments in Modeling Alveolar Retention of Insoluble Particles in Rats. J. Aerosol Med. 3, Supplement 1:S129-S154, 1990.
80. Snipes, M.B., E.B. Barr, I.-Y. Chang, R.F. Henderson, K.J. Nikula, and L.J. Mauderly, Particle Clearance and Sequestration in Lungs of Rats Exposed Chronically to Diesel Exhaust or Carbon Black. In: 9th Health Effect Institute Annual Conference, Monterey CA, Abstracts for Poster Sessions, p. 20, 1992.
81. Heinrich, U., R. Fuhst, S. Rittinghausen, O. Creutzenberg, B. Bellmann, W. Koch, and K. Levsen, Chronic Inhalation Exposure of Wistar Rats and Two Different Strains of Mice to Diesel Engine Exhaust, Carbon Black and Titanium Dioxide. Inhalation Toxicol. 7:533-556, 1995.
82. 2) Aerosols and Lung Tumor Induction in Rats Simulated by a Physiology-Oriented Model. Inhalation Toxicol. 7:1059-1074, 1995.
83. Stöber, W., P.E. Morrow, W. Koch, and G. Morawietz, Alveolar Clearance and Retention of Inhaled Insoluble Particles in Rats Simulated by a Model Inferring Macrophage Particle Load Distributions. J. Aerosol Sci. 25:975-1002, 1994.
84. Crapo, J.D., B.E. Barry, H.A. Foscue, and J. Shelburne, Structural and Biochemical Changes in Rat Lungs Occurring During Exposures to Lethal and Adaptive Doses of Oxygen. Am. Rev. Respir. Dis. 122:123-143, 1980.
85. 59Iron Oxide with Alveolar Macrophages during Alveolar Clearance. Exp. Lung. Res. 9:1-16, 1985.
86. Tran, C.-L., A.D. Jones, and K. Donaldson, Mathematical Model of Phagocytosis and Inflammation After the Inhalation of Quartz at Different Concentrations. Scand. J. Work Environ. Health 21 (Suppl.2):50-54, 1995.
87. Tran, C.L., A.D. Jones, and K. Donaldson, Development of a Dosimetric Model for Assessing the Health Risks Associated with Inhaling Coal Mine Dusts, Report No. TM/94/01, Institute of Occupational Medicine, Edinburgh, UK. 1-59, 1994.
88. Stöber, W. and W. Koch, Steady-State Load Distribution of Insoluble Particles in Alveolar Macrophages. Inhalation Toxicol. 3:181-193, 1991.
89. Vincent, J.H., A.D. Jones, A.M. Johnston, C. McMillan, R.E. Bolton, and H. Cowie, Accumulation of Inhaled Mineral Dust in the Lung and Associated Lymph Nodes: Implications for Exposure and Dose in Occupational Lung Disease. Ann. Occup. Hyg. 31:375-393, 1987.
90. Jones, A.D., J.H. Vincent, C.H. McMillan, A.M. Johnston, J. Addison, C. McIntosh, M.S. Whittington, H. Cowie, I. Parker, K. Donaldson, and R.E. Bolton, Animal Studies to Investigate the Deposition and Clearance of Inhaled Mineral Dusts, Report No. TM/88/05, Institute of Occupational Medicine, 8 Roxburgh Place, Edinburgh, Scotland. 1-159, 1988.
91. Kuschner, M., Animal Models in the Assessment of Fiber Carcinogenesis. In: Relevance of Animal Studies to Evaluate Human Cancer Risk. D. D'Amato (ed.), Wiley-Liss, Inc., 71-77, 1992.
92. Katsnelson, B.A. and L.I. Privalova, Recruitment of Phagocytizing Cells into the Respiratory Tract as a Response to the Cytotoxic Action of Deposited Particles. Environ. Health Perspect. 55:313-325, 1984.
93. Mauderly, J.L., M.B. Snipes, E.B. Barr, S.A. Belinsky, J.A. Bond, A.L. Brooks, I-Y. Chang, Y.S. Cheng, N.A. Gillett, W.C. Griffith, R.F. Henderson, C.E. Mitchell, K.J. Nikula, and D.G. Thomassen, Pulmonary Toxicity of Inhaled Diesel Exhaust and Carbon Black in Chronically Exposed Rats - Part I: Neoplastic and Nonneoplastic Lung Lesions. HEI Health Effects Institute Research Report No. 68:1-96, 1994.