Abstract  The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the respiratory tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for respiratory tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Abstract  Different particle types cause excessive lung inflammation that is thought to play a role in the various types of pathology they produce. Recently attention has been focused on nanoparticles due to their presence in environmental particulate air pollution, their use and exposure in occupational settings, and their potential use in nanotechnology and novel therapeutics. We have shown previously that the surface area metric drives the overload response. We have instilled a number of low-toxicity dusts of various particle sizes and assessed neutrophil influx into the lung at 18-24 h postinstillation. The extent of inflammation was demonstrated as being a function not of the mass dose instilled but interestingly of the surface area dose instilled. Since low-toxicity nanoparticles present a "special" case of high surface area, they are relatively inflammogenic. We tested whether we could use this approach to model the reactivity of highly toxic dusts. Rats were instilled with either DQ12 quartz or aluminum lactate-treated DQ12 and, as anticipated, the high specific surface toxicity of DQ12 meant that it was much more inflammogenic (63 times more) than the surface area alone would have predicted. By contrast, aluminum lactate-treated DQ12 fell into the line of "low-toxicity" dusts. In addition, as an in vitro testing alternative to that of in vivo testing, interleukin (IL)-8 production in A549 cells exposed to the panel of various particles clearly demonstrated the ability to also identify a relationship between surface area dose and reactivity. These approaches present the possibility of modelling potential toxicity of nanoparticles and nuisance dusts based on the inflammatory response of a given instilled surface area dose.

Abstract  Background: Studies in monkeys with intranasally instilled gold ultrafine particles (UFPs; < 100 nm) and in rats with inhaled carbon UFPs suggested that solid UFPs deposited in the nose travel along the olfactory nerve to the olfactory bulb. Methods: To determine if olfactory translocation occurs for other solid metal UFPs and assess potential health effects, we exposed groups of rats to manganese (Mn) oxide UFPs (30 nm; ~ 500 μg/m3) with either both nostrils patent or the right nostril occluded. We analyzed Mn in lung, liver, olfactory bulb, and other brain regions, and we performed gene and protein analyses. Results: After 12 days of exposure with both nostrils patent, Mn concentrations in the olfactory bulb increased 3.5-fold, whereas lung Mn concentrations doubled; there were also increases in striatum, frontal cortex, and cerebellum. Lung lavage analysis showed no indications of lung inflammation, whereas increases in olfactory bulb tumor necrosis factor-α mRNA (~ 8-fold) and protein (~ 30-fold) were found after 11 days of exposure and, to a lesser degree, in other brain regions with increased Mn levels. Macrophage inflammatory protein-2, glial fibrillary acidic protein, and neuronal cell adhesion molecule mRNA were also increased in olfactory bulb. With the right nostril occluded for a 2-day exposure, Mn accumulated only in the left olfactory bulb. Solubilization of the Mn oxide UFPs was < 1.5% per day. Conclusions: We conclude that the olfactory neuronal pathway is efficient for translocating inhaled Mn oxide as solid UFPs to the central nervous system and that this can result in inflammatory changes. We suggest that despite differences between human and rodent olfactory systems, this pathway is relevant in humans.

Abstract  Increased production of industrial devices constructed with nanostructured materials raises the possibility of environmental and occupational human exposure with consequent adverse health effects. Ultrafine (nano) particles are suspected of having increased toxicity due to their size characteristics that serve as carrier transports. For this reason, it is critical to refine and improve existing deposition models in the nano-size range. A mathematical model of nanoparticle transport by airflow convection, axial diffusion, and convective mixing (dispersion) was developed in realistic stochastically generated asymmetric human lung geometries. The cross-sectional averaged convective-diffusion equation was solved analytically to find closed-form solutions for particle concentration and losses per lung airway. Airway losses were combined to find lobar, regional, and total lung deposition. Axial transport by diffusion and dispersion was found to have an effect on particle deposition. The primary impact was in the pulmonary region of the lung for particles larger than 10 nm in diameter. Particles below 10 nm in diameter were effectively removed from the inhaled air in the tracheobronchial region with little or no penetration into the pulmonary region. Significant variation in deposition was observed when different asymmetric lung geometries were used. Lobar deposition was found to be highest in the left lower lobe. Good agreement was found between predicted depositions of ultrafine (nano) particles with measurements in the literature. The approach used in the proposed model is recommended for more realistic assessment of regional deposition of diffusion-dominated particles in the lung, as it provides a means to more accurately relate exposure and dose to lung injury and other biological responses.

Abstract  Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2-4 nm (Ir) and 5-10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with (192)Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, (192)Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of (192)Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics--the material and the size of the chain-type aggregates--determine translocation and accumulation in STOs, skeleton, and soft tissue.

Abstract  In vivo experiments have shown that nanoparticles depositing in the rat olfactory region can translocate to the brain via the olfactory nerve. Quantitative predictions of the dose delivered by inhalation to the olfactory region are needed to clarify this route of exposure and to evaluate the dose-response effects of exposure to toxic nanoparticles. Previous in vivo and in vitro studies quantified the percentage of inhaled nanoparticles that deposit in the rat nasal passages, but olfactory dose was not determined. The dose to specific nasal epithelium types is expected to vary with inhalation rate and particle size. The purpose of this investigation, therefore, was to develop estimates of nanoparticle deposition in the nasal and, more specifically, olfactory regions of the rat. A three-dimensional, anatomically accurate, computational fluid dynamics (CFD) model of the rat nasal passages was employed to simulate inhaled airflow and to calculate nasal deposition efficiency. Particle sizes from 1 to 100 nm and airflow rates of 288, 432, and 576 ml/min (1, 1.5, and 2 times the estimated resting minute volume) were simulated. The simulations predicted that olfactory deposition is maximum at 6-9% of inhaled material for 3- to 4-nm particles. The spatial distribution of deposited particles was predicted to change significantly with particle size, with 3-nm particles depositing mostly in the anterior nose, while 30-nm particles were more uniformly distributed throughout the nasal passages.

Abstract  By extrapolation from the rat study, a mathematical model of deposition, clearance, and retention kinetics for inhaled Ni compounds (high-temperature (green) NiO, Ni(3)S(2), and NiSO(4). 6H(2)O) in the alveolar region of the human lung has been developed. For human deposition, an updated version of an earlier model (C. P. Yu and C. K. Diu, 1982, Am. Ind. Hyg. Assoc. J.) was used in this study. Because of the profound differences in physiological and ventilation conditions between humans and rats, humans were found to have a higher alveolar deposition fraction than rats when exposed to the same Ni compounds. However, when normalized to the lung weight, the deposition rate per gram of lung in humans is much smaller than in rats. In the development of a clearance model, a single-compartment model in the lung was used and a general assumption was made that the clearance of the insoluble and moderately soluble nickel compounds (high-temperature (green) NiO and Ni(3)S(2), respectively) depends highly on the volume of retained particles in the lungs. As for the highly soluble nickel compound (NiSO(4). 6H(2)O), the clearance rate coefficient was assumed to depend on the retained particle mass and total alveolar surface. These clearance rate coefficients were extrapolated from the rat data. The retention half-times for high temperature (green) NiO and Ni(3)S(2) particles in humans were found to be much longer than in rats, whereas the retention half-time for NiSO(4). 6H(2)O particles was about the same for both species. The lung burden results in humans for various exposure conditions are predicted and the equivalent exposure concentrations for humans which lead to the same lung burdens found in rats were calculated.

Abstract  Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental 13C particles (CMD = 36 nm; GSD = 1.66) from [13C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m3. Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. 13C concentrations were determined by isotope ratio mass spectroscopy and compared to background 13C levels of sham-exposed controls (day 0). The background corrected pulmonary 13C added as ultrafine 13C particles on day 1 postexposure was 1.34 microg/lung. Lung 13C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added 13C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 13C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that ~20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.

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 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  Direct calculation of delivered dose in the species of interest potentially affects the magnitude of an uncertainty factor needed to address extrapolation of laboratory animal data to equivalent human exposure scenarios, thereby improving the accuracy of human health risk estimates. Development of an inhalation reference concentration (RfC) typically involves extrapolation of an effect level observed in a laboratory animal exposure study to a level of exposure in humans that is not expected to result in an appreciable health risk. The default dose metric used for respiratory effects is the average deposited dose normalized by regional surface area. However, the most relevant dose metric is generally one that is most closely associated with the mode of action leading to the response. Critical factors in determining the best dose metric to characterize the dose-response relationship include the following: the nature of the biological response being examined; the magnitude, duration, and frequency of the intended exposure scenario; and the mechanisms by which the toxicants exert their effects. Dosimetry models provide mechanistic descriptions of these critical factors and can compute species-specific dose metrics. In this article, various dose metrics are postulated based on potential modes of action for poorly soluble particles (PSP). Dosimetry models are used to extrapolate the internal dose metric across species and to estimate the human equivalent concentration (HEC). Dosimetry models for the lower respiratory tract (LRT) of humans and rats are used to calculate deposition and retention using the principle of particle mass balance in the lower respiratory tract. Realistic asymmetric lung geometries using detailed morphometric measurements of the tracheobronchial (TB) airways in rats and humans are employed in model calculations. Various dose metrics are considered for the TB and pulmonary (P) regions. Because time is an explicit parameter incorporated in species-specific constants such as mucociliary clearance rates used in the models, the impact of the application of optimal model structures to refine adjustments and assumptions used in default risk assessment approaches to address exposure duration are discussed. HEC estimates were found for particles ranging in sizes that corresponded to existing toxicity studies of PSP (0.3 to 5 microm). A dose metric expressed as number of particles per biologically motivated normalization factors (e.g., number of ventilatory units, number of alveoli, and number of macrophages) was lower than the current default of mass normalized to regional surface area for either deposited or retained dose estimates. Retained dose estimates were lower than deposited dose estimates across all particle sizes evaluated. Dose metrics based on the deposited mass per unit area in small and large airways of the TB region indicate HECs of 1 to 5 times those of rats: that is, an equivalent exposure to humans which would achieve the same internal dose as in the rat would be 1 to 5 times greater. HEC estimates in the TB region increase with an increase in particle size for particles from 0.3 to 2 microm in the small airways and >3 microm in the large airways. The HEC decreases with increase in particle size in the P region across all particle sizes studied, and the decrease has a more significant slope for those particles >2 microm due to the limited inhalability of particles this size in rats relative to humans. Our modeling results elucidate a number of important issues to be considered in assessing current default approaches to dosimetry adjustment for inhaled PSP. Simulation of realistic, polydisperse particle distributions for the human exposure scenario results in reduced HEC estimates compared to estimates derived with the experimental particle distribution used in the laboratory animal study. Consideration should be given also to replacing the default dose metric of normalized deposited dose in the P region with normalized retained dose. Chronic effects are more likely due to retained dose and estimates calculated using retained versus deposited mass are shown to be lower across all particle sizes. Because dose metrics based on normalized particle number rather than normalized mass result in lower HEC estimates, use of inhaled mass as the default should also be revisited, if the pathogenesis suggests particle number determines the mode of action. Based on demonstrated age differences, future work should pursue the construction of "lifetime" estimates calculated by sequentially appending simulations for each specific age span.

Abstract  National Institute of Environmental Health Sciences.Dosimetry parameters such as deposition, clearance, retention, and translocation and dissolution of inhaled particles in and to different lung compartments may be important for the persistence of particles in the lung and may correlate with adverse pulmonary effects. We investigated such correlations using a model involving TiO2 particles of two particle sizes (20 nm diameter, ultrafine; 250 nm diameter, fine) of the same crystalline structure (anatase). A 12-week inhalation experiment in rats resulted in a similar mass deposition of the two particle types in the lower respiratory tract. The ultrafine particles elicited a persistently high inflammatory reaction in the lungs of the animals compared to the larger-sized particles. In the postexposure period (up to 1 year) retention in the alveolar space per se was not different between fine and ultrafine TiO2. However, the following differences between the particle types were noted: a significantly different total pulmonary retention, both quantitatively (significantly prolonged retention of the ultrafine TiO2) and qualitatively (increased translocation to the pulmonary interstitium and persistence there of the ultrafine TiO2); greater epithelial effects (Type II cell proliferation; occlusion of pores of Kohn) and the beginning of interstitial fibrotic foci with ultrafine TiO2; significant sustained impairment of alveolar macrophage function after ultrafine TiO2 exposure as measured by the clearance of test particles. A correlation between particle surface area and effects was observed. A comparison of the adverse reactions with dosimetric parameters of TiO2 in different lung compartments in the postexposure period showed a correlation of the persistence of effects in both the alveolar and interstitial space with the persistence of particles in the respective compartment.

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  Dust overloading of lungs was reported in various studies (Ferin and Feldstein, 1978; Vostal et al., 1982; Vincent et al., 1985). We investigated this effect in a variety of subchronic and chronic inhalation studies after exposure to benign or slightly toxic insoluble materials. The characteristic findings were accumulation of large quantities of insoluble material in the lung, impairment of the alveolar clearance and an inflammatory response.

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  National Science Foundation; Whitaker Foundation. #Airflow patterns within the human upper airways, including nasal airway, oral airway, laryngeal airway, and the first two generations of tracheobronchial airway, are investigated by numerically solving the corresponding full Navier-Stokes equations using the flow simulation software CFX-F3D. A body-fitted three-dimensional curvilinear grid system and a multiblock method have been employed to mimic the complex head airway geometry and to match the computational domain with the outline of a semirealistic nasal sagittal cross-section geometry. Effects of human breath patterns, i.e., nasal breath, oral breath and simultaneous nasal and oral breath, on airflow and ultrafine particle deposition are investigated. Results of ultrafine particle deposition generated by computer simulation show reasonable agreements with the experimental measurements.

Abstract  There is increasing evidence that inspiratory airflow patterns play a major role in determining the location of nasal lesions induced in rats by reactive, water-soluble gases such as formaldehyde and chlorine. Characteristic lesion patterns have also been seen in inhalation toxicity studies conducted in rhesus monkeys, the nasal anatomy of which resembles that of humans. To examine the hypothesis that regions of high airflow-dependent uptake and lesions occur in similar nasal locations in the primate, airflow and gas uptake patterns were simulated in an anatomically accurate computer model of the right nasal airway of a rhesus monkey. The results of finite-element simulations of steady-state inspiratory nasal airflow for the full range of resting physiological flow rates are reported. Simulated airflow patterns agreed well with experimental observations, exhibiting secondary flows in the anterior nose and streamlined flow posteriorly. Simulated airflow results were used to predict gas transport to the nasal passage walls using formaldehyde as an example compound. Results from the uptake simulations were compared with published observations of formaldehyde-induced nasal lesions in rhesus monkeys and indicated a strong correspondence between airflow-dependent transport patterns and local lesion sites. This rhesus computer model will provide a means for confirming the extrapolation of toxicity data between species by extrapolating rat simulation results to monkeys and comparing these predictions with primate lesion data.

Abstract  In laboratory studies of rodents, the inhalation of organic vapors often results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a corresponding nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a mathematical model based on a combination of computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The nasal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks containing mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airway regions were determined by a solution of the Navier-Stokes and convection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transport through the 16 tissue stacks. The model was validated by using overall uptake data from rodent inhalation studies for three "unreactive" vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensitivity analysis revealed that accurate values of the mass transfer coefficient were not necessary to simulate regional concentrations and uptake of unreactive vapors in the rat nose, but reliable estimates of diffusion coefficients in tissue were crucial for accurate simulations.

Abstract  A stochastic model for the calculation of aerosol deposition in human lungs has been developed. In this model the geometry of the airways along the path of an inhaled particle is selected randomly, whereas deposition probabilities are computed by deterministic formulae. The philosophy of the airway geometry selection, the random walk of particles through this geometry and the methods of aerosol deposition calculation in conductive and respiratory airways during a full breathing cycle are presented. The main features of the Monte Carlo code IDEAL-2, written for the simulation of random walks of particles in a stochastic lung model, are briefly outlined.

Abstract  A new method for recording the respirograms of laboratory animals has been devised. Animals breathe into a headpiece connected by large tubing to a system of chambers which provide a constant flow of fresh air through the headpiece. As the animal breathes, the pressure within the chambers varies, minutely displacing the leaves of an electrical condenser, and by means of a special electrical apparatus a wave is made to rise and fall on the screen of an oscilloscope. The respirogram is then recorded by a continuous camera. Respiratory vols. measured by this method and by valve methods were found to be (in ml./min): mouse 24.5, cotton rat 39.6, hamster 60.9, white rat 72.9, guinea pig 155.6, rabbit 800.0, monkey 863.5, man 8732. It was found that the respiratory vol./min. varies from mice to men approx. with the 3/4 power of the wt.