Abstract  Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Abstract  About 2000 breathing experiments were performed, involving four breathing manoeuvres, four volunteers, a wide range of particle diameters and various breathing patterns. Monodisperse droplets of bis(2-ethylhexyl) sebacate served as aerosol particles. The deposition of particles in the nose was calculated from total deposition of particles in the whole respiratory tract for mouth, nose, mouth-nose and nose-mouth breathing. This method allowed the determination of nasal deposition and nasal efficiency for inspiration and expiration. Total deposition was determined from measurements of the particle concentration and the respiratory volume flow rate. Considerable scatter of nasal deposition in the four subjects was found. At a constant tidal volume it rose rapidly with increasing flow rate. The nasal efficiences were found to be independent of tidal volume. For inspiration as well as expiration the nasal passages removed particles very efficiently by inertial impaction. However, inspiratory and expiratory nasal efficiences were different. The scatter of individual inspiratory efficiency could be considerably reduced by employing a mathematical relationship to describe inspiratory nasal efficiency which makes use of the pressure difference across the nose and nasopharynx during nose breathing.

Abstract  Mucociliary clearance of deposited particles in the conducting airways of the human lung was investigated using various symmetric and stochastically generated asymmetric models of the conducting tree. Mucous velocities in all airways of the conducting airways were calculated from the principle of mass balance for the mucus. These velocities were used to calculate particle residence time in all the airways of the conducting tree. Equations for the transport of particles by the mucous escalator were developed and solved numerically. The retained mass in the tracheobronchial region was calculated for a scenario of 1 h exposure followed by 2 days of post exposure. Initial deposition pattern of particles in the conducting airways was found to be crucial for the analysis of retention curves. Particles deposited in peripheral bronchiolar airways of asymmetric stochastic lungs cleared more slowly than those in more central airways. Consequently, the retention curves of the stochastic lungs with a greater number of bronchial generations exhibited longer tails than those of symmetric lungs. The results indicated that the asymmetric stochastic lung models may predict significant lung burdens even after 24 h. The extent of the difference in inter-subject variability in retained particle mass may partially explain the observation of investigators regarding greater than expected retained mass in the TB region after 24 h, without invoking any additional slow bronchial clearance mechanisms.

Abstract  Models of the human respiratory tract were developed based on detailed morphometric measurements of a silicone rubber cast of the human tracheobronchial airways. Emphasis was placed on the “Typical Path Lung Model” which used one typical pathway to represent a portion of the lung, such as a lobe, or to represent the whole lung. The models contain geometrical parameters, including airway segment diameters, lengths, branching angles and angles of inclination to gravity, which are needed for estimating inhaled particle deposition. Aerosol depositions for various breathing patterns and particle sizes were calculated using these lung models and the modified Findeisen-Landahl computational scheme. The results agree reasonably well with recent experimental data. Regional deposition, including lobar deposition fractions, are also calculated and compared with results based on the ICRP lung deposition model.

Abstract  The respiratory anatomic dead space has been measured by the single breath nitrogen washout method of Fowler in 73 normal subjects ranging from 4 to 42 years of age. The volume of the anatomic dead space correlated closely with height (Vd (ml) = 7.585 x Ht (cm)2.363 x 10-4·ɣ = .917), but also with body weight, surface area, and functional residual capacity. When compared on the basis of any of these parameters there was no significant difference between the anatomic dead space values for males and females. Comparisons with available data for newborn infants suggest that the value of the anatomic dead space has a relatively constant relation to height from birth to adulthood. Dead space appears to increase more rapidly than weight, surface area, and functional residual capacity during, at least, the early period of somatic growth.

Abstract  We recorded maximum expiratory flow-volume curves in 3046 healthy persons, blacks and whites, age 7 and over — a representative population of lifetime nonsmokers except for some black adults males, who were healthy smokers or ex-smokers. We computed regression equations for lung function measurements (FVC, FEV1.0, FEV1.0/FVC, PEF, MEF, 50% and MEF 25%) as a function of age, height and weight terms for eight subgroups (by sex and race, and for children or adults). Objective statistical criteria were used to select the optimal equations. Simple linear regressions on age and height are inaccurate, in particular for young adults and for the elderly. Weight affects most function measurements: lung function first increases with weight (‘muscularity effect’)_ and decreases with further increases in weight (‘obesity effect’). The regression equations allow more accurate prediction of normal lung function. In addition, the lower 95% confidence limits are closer to the predicted values and are valid regardless of height, weight and age within each subgroup.

Abstract  Regional deposition of inhaled particles was studied experimentally in a hollow cast of the human larynx-tracheobronchial tree extending through the first six branching levels, and in twenty-six non-smoker human volunteers in vivo. Results of the hollow cast study indicated a linear dependence of particle deposition efficiency on the Stokes number for aerosols with aerodynamic diameters greater than 2 micrometers. Alveolar and total respiratory tract in vitro deposition in healthy non-smokers was minimal for particles of approximately 0.4 micrometers, and alveolar deposition for mouthpieces inhalations peaked for particles of approximately 3 micrometers. A new anatomic parameter, the bronchial deposition size (BDS), is introduced to permit the classification of various individuals and populations according to their tracheobronchial deposition efficiencies. The average BDS's were 1.20 cm for 26 healthy non-smokers, 1.02 cm for 46 cigarette smokers, 0.90 cm for 19 clinical patients being treated for obstructive lung disease and 0.60 cm for six severely disabled patients.

Abstract  Models of the lung airways of a rat were developed from complete measurements of the tracheobronchial airways. A silicone rubber cast of the tracheobronchial airways of a rat lung was prepared and all individual airway segments down to and including the terminal bronchioles were measured to obtain the segment diameters, lengths, branching angles and angles of inclination to gravity. Models of the rat tracheobronchial airways were constructed based on the original measurements and the subsequent analysis. Some mathematical assumptions about acinar anatomy distal to terminal bronchioles were made to extend the models to include pulmonary regions. Emphasis was placed on the "Typical Path Lung Model" which used one typical pathway to represent either a whole lung or a lobe of the lung. The models are simple and can be applied in calculation of physiologic variables or particle deposition during inhalation in various lobes of the lung.

Abstract  Predicting the amount of particle deposition in the human lung following exposure to airborne particulate matter is the first step toward evaluating risks associated with exposure to airborne pollutants. Realistic deposition models are needed for accurate predictions of deposition in the lung, but a major limitation is the degree to which the lung geometry can be accurately reconstructed. Morphometric data for the entire airway tree of the human lung are not available. So far, idealistic lung structures have been used for deposition calculations. In this study, 10 statistical lung structures based on morphometric measurements of Raabe et al. (1976) were generated for the conducting airways of the human lung. A symmetric, dichotomous branching alveolar airway structure was attached to the end of the conducting airway tree of each lung structure. The total volume of the alveolar region was the same among the lung geometries. Using a mathematical scheme developed previously (Anjilvel and Asgharian 1995), regional, Lobar, and per-generation depositions of particles were calculated in these geometries. The results were compared to deposition predictions using typical-path and five-lobe symmetric lung geometry models. All three lung models showed very similar regional and generation-by-generation deposition results. Lobar deposition was found to strongly depend on the detailed morphometry of the lung structure that was used.

Abstract  The MPPD model is a computational model that can be used for estimating human and rat airway particle dosimetry. The model is applicable to risk assessment, research, and education. The MPPD model calculates the deposition and clearance of monodisperse and polydisperse aerosols in the respiratory tracts of rats and human adults and children (deposition only) for particles ranging in size from ultrafine (0.01 µm) to coarse (20 µm). The models are based on single-path and multiple-path methods for tracking air flow and calculating aerosol deposition in the lung. The single-path method calculates deposition in a typical path per airway generation, while the multiple-path method calculates particle deposition in all airways of the lung and provides lobar-specific and airway-specific information. Within each airway, deposition is calculated using theoretically derived efficiencies for deposition by diffusion, sedimentation, and impaction within the airway or airway bifurcation. Filtration of aerosols by the nose and mouth is determined using empirical efficiency functions. The MPPD model includes calculations of particle clearance in the lung following deposition. Eight tutorials are provided so that the user can learn to interact with the software.

Abstract  A sample of 144 male, and 117 female healthy adults was selected to determine the normal ventilatory functions for Jordanians. Forced vital capacity, FEV1, and FMF 25-75% were determined using a dry bellows spirometer. Linear regression curves and nomograms were constructed for predicted values. Jordanian values for FVC and FEV1 were similar to those of Caucasians living in the western hemisphere.

Abstract  To understand better the factors influencing the relationships among airborne particle exposure, lung burden, and fibrotic lung disease, we developed a biologically based kinetic model to predict the long-term retention of particles in the lungs of coal miners. This model includes alveolar, interstitial, and hilar lymph node compartments. The 131 miners in this study had worked in the Beckley, West Virginia, area and died during the 1960s. The data used to develop this model include exposure to respirable coal mine dust by intensity and duration within each job, lung and lymph node dust burdens at autopsy, pathological classification of fibrotic lung disease, and smoking history. Initial parameter estimates for this model were based on both human and animal data of particle deposition and clearance and on the biological and physical factors influencing these processes. Parameter estimation and model fit to the data were determined using least squares. Results show that the end-of-life lung dust burdens in these coal miners were substantially higher than expected from first-order clearance kinetics, yet lower than expected from the overloading of alveolar clearance predicted from rodent studies. The best-fitting and most parsimonious model includes processes for first-order alveolar-macrophage-mediated clearance and transfer of particles to the lung interstitium. These results are consistent with the particle retention patterns observed previously in the lungs of primates. The findings indicate that rodent models extrapolated to humans, without adjustment for the kinetic differences in particle clearance and retention, would be inadequate for predicting lung dust burdens in humans. Also, this human lung kinetic model predicts greater retained lung dust burdens from occupational exposure than predicted from current human models based on lower exposure data. This model is useful for risk assessment of particle-induced lung diseases, by estimating equivalent internal doses in rodents and humans and predicting lung burdens in humans with occupational dust exposures.

Abstract  New information on particle retention of inhaled insoluble material indicates that the ICRP Human Respiratory Tract Model (HRTM) significantly underestimates long-term retention in the lungs. In a previous paper, the information from three studies was reviewed, and a model developed to predict particle retention in the lungs of coal miners was adapted in order to obtain parameter values for general use to predict particle retention in the alveolar-interstitial (AI) region. The model is physiologically based and simpler than the HRTM, requiring two instead of three compartments to model the AI region. The main difference from the HRTM AI model is that a significant fraction, about 35 %, of the AI deposit of insoluble material remains sequestered in the interstitium. The new model is here applied to the analysis of two well-known contamination cases with several years of follow-up data.

Abstract  The experimental techniques and the results of inhalation studies with radioaerosols on normal non-smokers for mouth-breathing are described and discussed. Monodisperse iron oxide particles tagged with 198Au are produced with a spinning top generator in the aerodynamic size range between 1 to 10 micrometers. An aerosol inhalation apparatus enables the subjects to breathe under standardized conditions with respect to tidal volume and breathing frequency. The calculation of total deposition is based upon measurements of the number of in- and exhaled particles per breath by means of photometric methods and pneumotachography. The retention of the radioactive particles present in the body after aerosol administration is measured with a body counter designed and constructed for these experiments. Retention measurements as functions of time after inhalation are carried out in extrathoracic-, chest- and stomach-position. The body counter consists of four shielded NaF(TI)-detectors. The geometrical arrangement, the collimation and the shielding of the four detectors have been optimized by computer calculations in such a way that the response of the counter is independent of the distribution of activity within the chest. Another characteristic feature of the body counter is its low sensitivity to neighboring organs and to neighboring regions within the respiratory tract. For the evaluation of extrathoracic deposition, the activity measured in the stomach immediately after inhalation is added to extrathoracic activity. The elimination of material from the chest (intrathoracic airways) is found to be much slower for the material deposited in the alveolar region (non-ciliated air spaces) than for the amount deposited in the tracheobronchial tree (ciliated airways). This allows the intrathoracic deposition to be divided into tracheobronchial and alveolar deposition by means of the different slopes of the normalized chest retention function. Different normalized chest retention functions are presented and analysed with respect to their different elimination rates belonging to the tracheobronchial and alveolar region. Total, tracheobronchial, alveolar and extrathoracic deposition data are reported in the aerodynamic diameter range between 1 and 10 micrometers.

Abstract  The effect of particle size on the regional deposition of aerosols inhaled through the mouth was determined in 93 studies on 34 subjects. The test aerosols were spherical monodisperse insoluble iron oxide particles (specific gravity 2.5) containing radioactive tags, ranging in median unit density diameter from 2.1 to 12.5-microns (σ ≅ 1.08). Particles deposited on the bronchial tree were translocated to the stomach by mucociliary clearance which was essentially complete within the first day. The proportion of the initial lung burden of radioactive particles removed during the first 24 hours provided a functional measure of tracheo-bronchial deposition. A portion of the inhaled aerosol was deposited in the head by impaction. As an impactor, the tracheobronchial tree is more efficient. For each individual subject, head and tracheobronchial deposition increased with increasing particle size. Alveolar depositions decreased with size for particles larger than 4-microns.

Abstract  Particulate matter dosimetry provides the critical link between exposures and initial doses reaching various sites in the respiratory tract. To extrapolate findings from animal models to humans, quantitative respiratory-tract anatomical data dosimetry in these animal models is required. The goal of this study was to provide anatomical information for the tracheobronchial and pulmonary region so predictions of particle deposition could be performed for a widely used model of asthma; the sensitized Balb/c mouse. Tracheobronchial airway morphometry of sensitized male Balb/c mice was generated from three in situ prepared lung casts. Distribution of the number of generations to terminal bronchiole for each lung lobe was determined by assigning a unique binary number to each airway. This strategy enabled the median path length to terminal bronchiole to be determined. A total of 25 median length paths to terminal bronchiole were measured (airway length, diameter, and branch angle) in each lung cast. These 25 paths were proportionately distributed among the six lobes based upon the number of median length pathways in each cast. Airway length, diameter, and branch angle were measured for each airway in the 25 median length pathways. Measurements of airway length, diameter, and branch angle for each generation were averaged to create a typical path tracheobronchial anatomy model. A pulmonary airway model was also developed so that particle deposition predictions could be performed for particle diameters of 0.2-10 micrometers. Particle deposition efficiency predictions were consistent with in vivo measured deposition.

Abstract  This report describes an investigation of the respiratory physiology of normal premature and full-term newborn infants. As in previous studies on normals (1-3), minute volumes, rates and tidal volumes have been measured. Additional measurements of CO2 production, plasma CO2 partial pressure, and intraesophageal pressure differences have allowed calculations of effective alveolar ventilation, functional dead space and estimates of the work of respiration. Since certain adaptations were necessary for the study of this age group, the techniques are reported in detail. The data from normal infants are the subject of this report; comparable data for newborns with respiratory distress are reported in a second paper (4).

Abstract  Residual volume (RV), functional residual capacity (TGV) and total lung capacity (TLC) have been measured in 42 adolescents aged 16-22 years (22 young men and 20 young women) and in 60 children aged 12-15 years (29 boys and 31 girls) who were selected as having the same ranges of heights. TLC and TGV were related to height in each age and sex group; the slope of the regression curves did not differ between subgroups. RV was related to height in the boys and girls and not in the adolescents; however the number of subjects in each group was small. Relative to height the residual volumes of boys and girls were similar and in both sexes were larger than those for adolescents. Amongst the latter the values for young women were smaller than those for young men. The possible mechanisms are discussed.

Abstract  This report is the first in a series of reports replacing Publications 30 and 68 to provide revised dose coefficients for occupational intakes of radionuclides by inhalation and ingestion. The revised dose coefficients have been calculated using the Human Alimentary Tract Model (Publication 100) and a revision of the Human Respiratory Tract Model (Publication 66) that takes account of more recent data. In addition, information is provided on absorption into blood following inhalation and ingestion of different chemical forms of elements and their radioisotopes. In selected cases, it is judged that the data are sufficient to make material-specific recommendations. Revisions have been made to many of the models that describe the systemic biokinetics of radionuclides absorbed into blood, making them more physiologically realistic representations of uptake and retention in organs and tissues, and excretion. The reports in this series provide data for the interpretation of bioassay measurements as well as dose coefficients, replacing Publications 54 and 78. In assessing bioassay data such as measurements of whole-body or organ content, or urinary excretion, assumptions have to be made about the exposure scenario, including the pattern and mode of radionuclide intake, physical and chemical characteristics of the material involved, and the elapsed time between the exposure(s) and measurement. This report provides some guidance on monitoring programmes and data interpretation.

Abstract  The aim of this study was to investigate exposure-dose relationships in humans with working lifetime exposures to respirable particulates, by using a bio-mathematical exposure-dose model to predict lung and lymph node dust burdens in coalminers with long-term exposure to respirable dust. To meet this aim, statistical and mathematical modelling techniques were used to analyse data from an autopsy study of UK miners held at the Institute of Occupational Medicine. In this study, we validated an existing lung dosimetry model for consistency with observed human lung and lymph burden data. The results of our test suggested that, for humans, the sequestration of dusts in the interstitial compartment is a more prominent feature than the retention of dust due to overload that is observed in animal studies. Modelling and statistical analyses have shown that quartz is more likely to be retained in the lung and lymph nodes than the non-quartz fraction of lung burden and that the quartz fraction may play an important role in the development of PMF. The results of statistical analyses have also shown that the translocation to the lymph nodes is not simply a linear function of lung burden, but may terminate beyond a threshold in lung burden. Our assessment of the variation in the model parameters yielded a distribution of values for the clearance rate and the translocation rate to the lymph nodes respectively. While other sources of uncertainty (e.g. uncertainty in exposure estimation) were not investigated in this study, the results suggested that variability can be quantified and incorporated in the current modelling framework. This approach may be useful for assessing risk in humans to dust exposure.