Werner Stöber

Alveolar Retention and Clearance of Insoluble Particles in Rats Simulated by a New Physiology-Oriented Compartmental Kinetics Model

A physiology-oriented compartmental kinetics model of alveolar retention of inhaled insoluble particulate matter in rat lungs was proposed in a recent paper, (W. Stöber, P.E. Morrow, and M.D. However, 1989, Fundam. App. Toxicol. 13, 823-843), and the retention patterns obtained with the model for a hypothetical set of input data appeared to simulate phenomena which were observed in inhalation studies with Fischer 344 rats. The present paper represents the results of applying the new model for simulations of the actual experimental retention data of five different inhalation studies with Fischer 344 rats exposed to three different materials. The experimental data showed that model adjustments had to be made in order to account for clearance effects that appeared to be influenced by the age of the animals. After these adjustments were made and an appropriate set of values for the model parameters describing the respective exposure conditions was used, the model was constrained to represent the empirical data of all of the studies by one unique set of parameter values. Changes in particular values of this set were considered to be acceptable only if they reflected changes of relevant properties of the inhaled particulate matter. The final simulations did not completely comply with this self-imposed criterion. However, the degree of compliance and the simulation quality achieved with a minimum of parameter variations seem to be unprecedented in retention modeling. The results of the study encourage attempts for further refining the present model.

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

During the last 40 years, most models of long-term clearance and retention of biopersistent particles in the pulmonary region of the lung were phenomenologically oriented and accounted for only a small portion of the growing insight into lung dynamics by pulmologists, histologists, and biochemists. In this review, theoretical developments of modeling pulmonary dynamics for biopersistent particles during or after inhalation exposure are discussed. Several characteristic examples are given of the present state of the art. Most of the models presently in use are pragmatical compartmental models with a single compartment for the pulmonary region. They relate to observed data and facilitate an interpolation within the range covered by observation. Occasionally, these models are unjustifiably used for extrapolations in efforts to derive hypothetical risk assessments. Modeling efforts aiming at models of physiologically based pulmonary systems with a potential for extrapolations are not common and were published only during the last decade. Of this kind of approach, the review covers four examples. Promising progress has been made, but scarcity of supporting experimental data slows validation and extension. The two most recent model developments are based on a hypothesis by P.E. Morrow. According to Morrow, alveolar clearance is accomplished by mobile alveolar macrophages after phagocytosis of particles on the alveolar surface. The macrophage mobility, however, and thus the efficiency of the transport to the mucociliary escalator of the tracheobronchial tract will eventually decline towards total loss of mobility after the particle burden of the macrophages exceeds a critical value. The POCK model has been evaluated for a variety of chronic and subchronic rat exposure studies with noncytotoxic aerosols and gave good simulation results. The model by Tran et al. appears to be still in the developing stage of facilitating simulations for cytotoxic aerosols, but the combination of both model approaches seems to be a sound route of future efforts.

A note on the aerodynamic diameter and the mobility of non-spherical aerosol particles

Abstract The aerodynamic diameter of a non-spherical aerosol particle is primarily related to the final settling velocity of the particle. The aerodynamic diameter is not obtained directly from mobility measurements by formally calculating a sphere diameter from the mobility equation for a spherical particle. Instead, a correction factor involving the dynamic shape factor of the non-spherical particle must be applied.

Alveolar clearance and retention of inhaled insoluble particles in rats simulated by a model inferring macrophage particle load distributions

Abstract This paper presents the description of a revised, physiology-oriented compartmental kinetics (“POCK”) model of alveolar clearance and retention of biologically insoluble, respirable particles. By postulating a deposit-activated maximum macrophage recruitment rate leading to a quasi-steady state of the alveolar macrophage population on the alveolar epithelial surface, the model uses a theoretical derivation of an exposure-dependent distribution of particles in the alveolar macrophage population to determine the total load in mobile and immobilized macrophages. For this, the model assumes an invariant maximum volume capacity of the macrophages for particle uptake and a material-dependent critical load of the macrophages that causes total loss of their inherent mobility. Prior to a gradual onset of mobility decrease, there is a material-dependent range of low macrophage burdens without mobility impairment. Using independently determined physiological data for classical clearance rate coefficients, as well as for the lifetime of the alveolar macrophages and their particle turnover by phagocytosis, the model seems to be applicable to experimental results obtained for rats. A constant set of model parameters and a minimum of three material-dependent, physiologically meaningful model variables were sufficient to simulate the alveolar lung burden and available lymph node load data of 15 different subchronic or chronic exposures of Fischer 344 rats to diesel soot, carbon black or xerographic toner. For constant deposition rates, the model predicts the establishment of quasi-steady states for the total load of the alveolar macrophage pool. The final load would increase with increasing deposition rate and, particularly under overload conditions, i.e. at high deposition rates, the number of immobilized macrophages would grow significantly. According to the model, overload does not cause an excessive growth of the total burden of the macrophage pool, but leads to a tremendous increase of the particulate burden of the interstitial space. This compartmental burden is not available for macrophage-mediated classical clearance. Except for partial removal to the lymph nodes, the interstitial burden will persist even when exposures are discontinued and the alveolar macrophage population recovers to full mobility. Subchronic exposure studies seem to bear this out, but due to lack of experimental data for the burdens in most of the alveolar subcompartments of the model, the corresponding predictions cannot be validated at the present time.

Model-Inferred Hypothesis of A Critical Dose for Overload Tumor Induction by Diesel Soot and Carbon Black

AbstractThe application of the POCK model of pulmonary clearance and retention to new experimental results of chronic inhalation studies with rats exposed for 2 yr to diesel exhaust or carbon black is reported. For the first time in lifetime studies with these carbonaceous aerosols, experimental data became available for paniculate mass burdens in the lung-associated lymph nodes. Furthermore, seven out of eight lifetime runs used exposure rate indices causing lung overload and lung tumors. The simulations of the POCK model were consistent with previous POCK representations of diesel soot and carbon black exposure studies. The new data on lifetime patterns of lymph node loads, however, required an adjustment of the interstitial kinetics in order to account for the apparent lymph-node load stagnation after about 1 yr of chronic exposures leading to lung overload. The consistently observed coincidence of lymph-node load stagnation and tumor induction in the new exposure studies occurred always in a situation...

REVISITING EPIDEMIOLOGICAL KEY STUDIES ON OCCUPATIONAL DIESEL EXHAUST EXPOSURE AND LUNG CANCER IN TRUCK DRIVERS

Over the last 25 years, railroad workers and truck drivers occupationally probably exposed to diesel exhaust were investigated in numerous epidemiological studies for prevalence of lung cancer. A recent assessment of 21 of these studies, including 11 truck driver studies by the Health Effects Institute (HEI, 1995), claimed that the studies showed consistently a lung cancer risk increase of 20 to 40% for the study subjects. The supposedly most reliable study of railroad workers in the United States is presently under serious dispute. With regard to the assessed truck driver studies, uncontemplated, incomplete, or incorrect reporting on more than half of the 11 truck driver investigations warranted a reanalysis of the original study results. The quality and power of the truck driver studies varied widely. Two older studies - one of them showing significant risk increases - were already rejected in 1981 by the National Research Council in the United States as being inadequate. Of 7 studies reporting nonsigni...

Pulmonary Retention of Inhaled Anatase (Tio2) Aerosols and Lung Tumor Induction in Rats Simulated by a Physiology-Oriented Model

AbstractA physiology-oriented compartmental kinetics (POCK) model of alveolar retention of respirable, insoluble particles in rats was used to simulate the results of two subchronic inhalation tests with male Fischer rats exposed to submicron anatase TiO2 particles of either 250 or 20 nm average size (Oberdorster et al., 1994). Earlier, the ultrafine variety had been used in a lifetime study with female Wistar rats (Heinrich & Fuhst, 1992) and the results were also subjected to POCK simulations. The database on anatase was not as extensive as in case of previous studies that used submicrometer carbonaceous aerosols. However, besides the usual results for the patterns of total lung burden and lymph node load, the new subchronic tests provided, for the first time, some data on anatase burdens of both the macrophage pool and the interstitium. Due to the scarcity of the data, the POCK simulation was not entirely unique, but good data representation was achieved with plausible model parameters. The substantial...

A SIMPLE PULMONARY RETENTION MODEL ACCOUNTING FOR DISSOLUTION AND MACROPHAGE-MEDIATED REMOVAL OF DEPOSITED POLYDISPERSE PARTICLES

This article describes a mechanistic two-compartmental model to simulate the disposition by dissolution and particulate clearance of particles deposited in the pulmonary region of the lung. The model provides a general solution for the size distribution of particles in the surfactant layer of the alveolar surface and in the cell plasma of alveolar macrophages. Thus it allows for different dissolution rates in the two compartments and accounts for potentially different kinetics and/or biological effects of particles and their solute in surrounding fluids. The input parameters are, among others, the size distribution density function of the deposited particles and the time constants characterizing the dissolution process as well as phagocytosis rate and particle transport by macrophages to the tracheobronchial tract. Relevant dose parameters such as retained and dissolved mass can be calculated from the temporally retained size distributions. For the first time, this theoretical presentation considers the polydispersity of aerosol particles deposited in the lung and thus provides an indispensable mathematical basis for a multicompartmental retention model that may combine particulate removal from the pulmonary region and the lymph nodes by a competition of the rates of dissolution and particulate clearance in all relevant lung model compartments.

Vergleichende Untersuchung über die Bestimmung der Korngrößenverteilung fester Stäube mit Hilfe eines Hochspannungsabscheiders und des Elektronenmikroskops

ZusammenfassungDie vorliegende Arbeit beschreibt die theoretischen Grundlagen und den Aufbau eines elektrostatischen Hochspannungsabscheiders zur Herstellung und Auswertung von Staubniederschlägen mit repräsentativer Korngrößenverteilung im elektronenmikroskopischen Bereich.Die Ergebnisse vergleichender Messungen werden wiedergegeben und die Brauchbarkeit und die Vorteile des neuen Verfahrens diskutiert.SummaryThis paper deals with the theoretical principles and the construction of an electrostatic precipitator run by high voltage. The device described herein is intended for preparing dust precipitations which might be used to attain a particle-size-distribution in the range of electron microscopy.The results of comparative studies, the usefulness, and advantages of this technic are discussed.RésuméDans cette étude les principes théoriques et la construction d’un précipitateur électrostatique de haute tension sont décrites à l’aide duquel on peut produire des précipités de poudre à une distribution représentative pour le microscope électronique.Les résultats des comptes comparants sont démontrés, l’utilité et les avantages de cette méthode nouvelle sont discutés.

POCK model simulations of pulmonary quartz dust retention data in extended inhalation exposures of rats.

In recent years, a physiology-oriented multicompartmental kinetics (POCK) model was developed to simulate pulmonary retention data of biopersistent, noncytotoxic aerosols in long-term inhalation exposures of rats. Experimental data were successfully simulated for submicrometer-sized aerosols like carbon black, diesel soot, and titanium dioxide and for a micrometer-sized xerographic toner aerosol (Stöber et al., 1994, 1995). This article describes for various rat strains successful POCK model simulations of experimental pulmonary retention data of micrometer-sized aerosols of biopersistent cytotoxic SiO2 modifications like quartz and quartzite. In the past, the POCK model was not applied to cytotoxic aerosols and dusts. Cytotoxicity was considered incompatible with the model assumption of a constant macrophage lifetime independent of the macrophage aerosol load. The few relevant experimental retention studies with biopersistent silica found in the open literature showed particulate lung burdens up to some 15 mg per rat lung. Apparently, at these loads, pulmonary burdens could be simulated because the fraction of alveolar macrophages killed by the cytotoxic particles was possibly still small compared to the total number of viable macrophages. Of necessity, however, the classical alveolar clearance in these studies was exclusively performed by alveolar macrophages that were burdened with cytotoxic particles, and the cells appeared to suffer from a substantial initial decrease of their inherent mobility. Thus a sizeable reduction of the alveolar clearance rate coefficient in comparison to nontoxic aerosol was found. The results for the model parameters of several different exposure studies are shown and interpreted in comparison to nontoxic titanium dioxide retention parameters.