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Disposition of inhaled radionuclides
BIOLOGICAL
EFFECTS
OF INHALED
RADIONUCLIDES
B. DISPOSITION OF INHALED RADIONUCLIDES
The nature and magnitude of biological effects that may occur following inhalation of radionuclides will depend upon many factors including the disposition of the particles inhaled, the fraction deposited in the respiratory tract, the sites of deposition among the several components of the respiratory tract, the retention time at sites of deposition, the translocation to other tissues, and the rate of excretion from the body. While a detailed description of the disposition of inhaled radionuclides is not an objective of this report, a brief treatment of the topic may be a helpful introduction to a description of biological responses and discussion of tissues at risk. Details on the disposition of specific inhaled radionuclides in the body precede an enumeration of biological responses in Section C . Deposition in the Respiratory Tract The most comprehensive compilation of information on the initial deposition of inhaled particles in the respiratory tract was published by the ICRP Task Group on Lung Dynamics in 1966 (ICRP, 1966a). Their report includes an anatomical description of the respiratory tract, characteristics of particle size distribution, and physiological parameters describing the inhalation process. Based on these variables, a quantitative model for initial respiratory tract deposition was developed. That Task Group separated the respiratory tract into four major compartments: (1) the nasopharyngeal region (NP); (2) the tracheobronchial region (TB); (3) the pulmonary region or the nonciliated portion of the lungs (P), and (4) lymph nodes (L).
The NP region begins with the anterior nares and extends to the level of the larynx. The TB region comprises the trachea and bronchial tree through the terminal bronchioles. The P region consists of the remainder of the respiratory tract, including the alveoli. The thoracic lymph nodes are the L region. The Task Group calculated the amount of inhaled aerosol particles of different sizes that would be deposited in each region, assuming a respiratory rate of I5 breaths per minute and using tidal volumes of 750,1450, and 2 150 cm3/1, respectively. From these calculations, a model for the deposition of particle distributions in the human respiratory tract was developed (ICRP ,1966a).
Clearance from the Lungs The major factors in determining the clearance of a compound from the lungs are real particle size, cytotoxicity of the particle, solubility of the compound in body fluids, and cell reactivity. Other properties, such as radioactivity, may also be involved. An initial rapid clearance phase occurs within the first few days after deposition of material in the respiratory tract. This is attributable primarily to rapid absorption of readily soluble material into the blood and to transport of material deposited on the ciliated epithelium of the respiratory tract to the esophagus. This latter material is swallowed and either absorbed from the gastrointestinal tract or excreted in the feces. The initial clearance phase is usually followed by a slower second phase and, depending upon the material inhaled, an even slower third clearance phase involving material deposited deep within the pulmonary region of the lungs. Although it appears inevitable that some
4
REPORT OF COMMITTEE
fraction of the aerosol deposited deep in the lungs must leave via the ciliated escalator epithelia of the bronchioles and bronchi, dissolution has gained more recognition as an important mode of long-term clearance (Mercer, 1967). In addition to these two routes of clearance from the pulmonary region (mucociliary action and dissolution), there is also a route to bronchial and tracheobronchial lymph nodes which may transport a large portion of the total insoluble material deposited in the lungs (Thomas, 1972). Although it is not certain in what form materials are transported from the lungs to the lymph nodes, it is presumed that particles themselves are involved. Whether the particle is translocated as such and/or by a macrophage has not been determined precisely. The Task Group on Lung Dynamics (1966a) also developed a clearance model that was more comprehensive than those used previously. It was based on extensive studies with laboratory animals and results of human contamination cases; it also incorporated the major clearance processes. With the lungs compartmentalized as described previously, and considering lymph nodes, blood and gastrointestinal tract, the Task Group calculated rate constants for transfer of particles between compartments. various retention this With model, characteristics were described for compounds of all the elements in the periodic table. The ICRP Task Group lung model was slightly modified in ICRP Publication 19 and further revised in ICRP Publication 30. Compounds were separated into three broad classes according to lung retention: avid lung retention (cleared slowly over periods of a year or more); moderate retention (cleared within weeks); or minimal retention (cleared within hours or days). Constants for compartments in the three regions of the respiratory tract were estimated. In the two compartments of the NP region two retention half-times were described, 0.01 and 0.4 day. The TB region was separated into two compartments, one having a retention half-time of 0.01 day and the other a half-time of 0.2 day. The fractions of compounds leaving these four compartments to
1
enter the blood or gastrointestinal tract are highly dependent upon the class of compound involved. The pulmonary region was represented as having four compartments, each of which might be associated with a different clearance process. Removal half-times assigned to D, W, and Y class compounds are 0.5,50, and 500 days, respectively. The lymph nodes were considered separately because they accumulate a sizable quantity of relatively insoluble particles; they were assigned retention halftimes of 0.5,50 and 1000 days for D, W, and Y classes, respectively. It is important to recognize that this model was developed for radiation protection purposes and, therefore, it was not necessary to reflect the nuances of behavior of all inhaled radioactive compounds. Experimental data may suggest that some compounds do not fit any of the three categories; however, to avoid having the model become unduly complex, three broad categories were chosen rather than many narrow ones. Thus, the oxides of all the actinides were considered class Y compounds, clearing very slowly from the pulmonary region even though clearance half-times ranging from 50 to 1000 days have been observed experimentally for oxides of americium, curium and plutonium. Conversely, certain of the soluble forms of the actinides were considered to have moderate retention kinetics in the P region (clearance half-time of 50 days), although lower rates of clearance have been observed experimentally. Therefore, it should be remembered that the first consideration in developing the ICRP lung model was protection against the harmful effects of radiation and not necessarily an accurate, detailed description of the behavior of inhaled radionuclides. Qualitatively, the biological effects that are described in this report reflect the behavior of inhaled radionuclides as described by the ICRP lung model. However, the radiation doses ascribed to these effects were calculated for specific materials inhaled by specific animals in which the behavior of the particular inhaled radionuclide may have differed somewhat from that described by the ICRP model developed for human beings.
EFFECTS
OF INHALED
RADIONUCLIDES
B. DISPOSITION OF INHALED RADIONUCLIDES
The nature and magnitude of biological effects that may occur following inhalation of radionuclides will depend upon many factors including the disposition of the particles inhaled, the fraction deposited in the respiratory tract, the sites of deposition among the several components of the respiratory tract, the retention time at sites of deposition, the translocation to other tissues, and the rate of excretion from the body. While a detailed description of the disposition of inhaled radionuclides is not an objective of this report, a brief treatment of the topic may be a helpful introduction to a description of biological responses and discussion of tissues at risk. Details on the disposition of specific inhaled radionuclides in the body precede an enumeration of biological responses in Section C . Deposition in the Respiratory Tract The most comprehensive compilation of information on the initial deposition of inhaled particles in the respiratory tract was published by the ICRP Task Group on Lung Dynamics in 1966 (ICRP, 1966a). Their report includes an anatomical description of the respiratory tract, characteristics of particle size distribution, and physiological parameters describing the inhalation process. Based on these variables, a quantitative model for initial respiratory tract deposition was developed. That Task Group separated the respiratory tract into four major compartments: (1) the nasopharyngeal region (NP); (2) the tracheobronchial region (TB); (3) the pulmonary region or the nonciliated portion of the lungs (P), and (4) lymph nodes (L).
The NP region begins with the anterior nares and extends to the level of the larynx. The TB region comprises the trachea and bronchial tree through the terminal bronchioles. The P region consists of the remainder of the respiratory tract, including the alveoli. The thoracic lymph nodes are the L region. The Task Group calculated the amount of inhaled aerosol particles of different sizes that would be deposited in each region, assuming a respiratory rate of I5 breaths per minute and using tidal volumes of 750,1450, and 2 150 cm3/1, respectively. From these calculations, a model for the deposition of particle distributions in the human respiratory tract was developed (ICRP ,1966a).
Clearance from the Lungs The major factors in determining the clearance of a compound from the lungs are real particle size, cytotoxicity of the particle, solubility of the compound in body fluids, and cell reactivity. Other properties, such as radioactivity, may also be involved. An initial rapid clearance phase occurs within the first few days after deposition of material in the respiratory tract. This is attributable primarily to rapid absorption of readily soluble material into the blood and to transport of material deposited on the ciliated epithelium of the respiratory tract to the esophagus. This latter material is swallowed and either absorbed from the gastrointestinal tract or excreted in the feces. The initial clearance phase is usually followed by a slower second phase and, depending upon the material inhaled, an even slower third clearance phase involving material deposited deep within the pulmonary region of the lungs. Although it appears inevitable that some
4
REPORT OF COMMITTEE
fraction of the aerosol deposited deep in the lungs must leave via the ciliated escalator epithelia of the bronchioles and bronchi, dissolution has gained more recognition as an important mode of long-term clearance (Mercer, 1967). In addition to these two routes of clearance from the pulmonary region (mucociliary action and dissolution), there is also a route to bronchial and tracheobronchial lymph nodes which may transport a large portion of the total insoluble material deposited in the lungs (Thomas, 1972). Although it is not certain in what form materials are transported from the lungs to the lymph nodes, it is presumed that particles themselves are involved. Whether the particle is translocated as such and/or by a macrophage has not been determined precisely. The Task Group on Lung Dynamics (1966a) also developed a clearance model that was more comprehensive than those used previously. It was based on extensive studies with laboratory animals and results of human contamination cases; it also incorporated the major clearance processes. With the lungs compartmentalized as described previously, and considering lymph nodes, blood and gastrointestinal tract, the Task Group calculated rate constants for transfer of particles between compartments. various retention this With model, characteristics were described for compounds of all the elements in the periodic table. The ICRP Task Group lung model was slightly modified in ICRP Publication 19 and further revised in ICRP Publication 30. Compounds were separated into three broad classes according to lung retention: avid lung retention (cleared slowly over periods of a year or more); moderate retention (cleared within weeks); or minimal retention (cleared within hours or days). Constants for compartments in the three regions of the respiratory tract were estimated. In the two compartments of the NP region two retention half-times were described, 0.01 and 0.4 day. The TB region was separated into two compartments, one having a retention half-time of 0.01 day and the other a half-time of 0.2 day. The fractions of compounds leaving these four compartments to
1
enter the blood or gastrointestinal tract are highly dependent upon the class of compound involved. The pulmonary region was represented as having four compartments, each of which might be associated with a different clearance process. Removal half-times assigned to D, W, and Y class compounds are 0.5,50, and 500 days, respectively. The lymph nodes were considered separately because they accumulate a sizable quantity of relatively insoluble particles; they were assigned retention halftimes of 0.5,50 and 1000 days for D, W, and Y classes, respectively. It is important to recognize that this model was developed for radiation protection purposes and, therefore, it was not necessary to reflect the nuances of behavior of all inhaled radioactive compounds. Experimental data may suggest that some compounds do not fit any of the three categories; however, to avoid having the model become unduly complex, three broad categories were chosen rather than many narrow ones. Thus, the oxides of all the actinides were considered class Y compounds, clearing very slowly from the pulmonary region even though clearance half-times ranging from 50 to 1000 days have been observed experimentally for oxides of americium, curium and plutonium. Conversely, certain of the soluble forms of the actinides were considered to have moderate retention kinetics in the P region (clearance half-time of 50 days), although lower rates of clearance have been observed experimentally. Therefore, it should be remembered that the first consideration in developing the ICRP lung model was protection against the harmful effects of radiation and not necessarily an accurate, detailed description of the behavior of inhaled radionuclides. Qualitatively, the biological effects that are described in this report reflect the behavior of inhaled radionuclides as described by the ICRP lung model. However, the radiation doses ascribed to these effects were calculated for specific materials inhaled by specific animals in which the behavior of the particular inhaled radionuclide may have differed somewhat from that described by the ICRP model developed for human beings.