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.

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.

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.

Germany's competent authority initiatives.

A decentralised approach on the enforcement's' responsibility of the medical devices act, which includes the directives and the guidelines for the vigilance system, has been adopted in Germany. DIMDI under this act, had been nominated to set up a database-supported information system, that would ensure secure usage of medical devices in Germany. The necessary measures taken in order to fulfil the German legislation as well as DIMDI's points of view for the international data exchange on medical devices are being discussed in this paper.

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.

Compartmental modeling of the long-term retention of insoluble particles deposited in the alveolar region of the lung.

The state of the art for modeling the retention of inhaled insoluble particles deposited in the alveolar region of the lung is briefly reviewed, and a new compartmental model of long-term retention is proposed. Wherever possible, this new model favors the replacement of simple first-order kinetics of particle transport processes in the lung by quantified mechanisms derived from or suggested by experimental data of published studies in lung physiology and histopathology. In particular, all macrophage-mediated transport processes, including classical alveolar clearance onto the mucociliary escalator, are modeled as dependent on actual macrophage mobility and are assumed to be influenced by the finite macrophage life time. The mobility is predicted to decrease with increasing particle burden of the macrophage, and there is a limit to the macrophage capacity for accumulating burdens of insoluble particles by phagocytosis. Furthermore, at high particle burdens, macrophages will be progressivity sequestered by irreversible aggregation and immobilization. Using published data on Fischer 344 rats for a quantitative demonstration of the patterns of the new model under chronic exposures, a basic set of model parameters predicts that, at moderate particle deposition rates, retention is limiting itself by establishing a steady state, and the alveolar burden is almost completely eliminated during the postexposure period. However, at high particle deposition rates, the alveolar particle burden increases continuously during the exposure period, and only a small fraction of the deposit is subject to clearance after termination of exposure. In qualitative terms, these are typical features of the "overload" effect which has been observed in a number of recent chronic aerosol inhalation exposure studies with animals.

Chronic effects on the respiratory tract of hamsters, mice and rats after long-term inhalation of high concentrations of filtered and unfiltered diesel engine emissions.

A long-term exposure study with hamsters, mice and rats inhaling filtered and unfiltered diesel engine exhaust was carried out to investigate effects of chronic toxicity and, predominantly, carcinogenicity in the respiratory tract. The level of diesel exhaust in the exposure chambers corresponded to a concentration close to 4 mg m-3 in the unfiltered diesel exhaust. Satellite groups of animals were additionally treated with BaP, DBahA or nitrosamines in order to check for syncarcinogenic effects. In hamsters and rats, alveolar lung clearance and mechanical lung function tests as well as biochemical and cytological measurements in lung lavage fluids showed significant changes only after exposure to unfiltered diesel exhaust and, predominantly, in rats. No lung tumors were found in hamsters. Spontaneous tumor rates occurred in mice and both types of diesel exhaust increased the incidence of adenocarcinomas in the lungs. In rats, only the unfiltered diesel exhaust caused a lung tumor incidence. It amounted to 16% with no tumors in the controls. The heavy load of particulate matter in the lungs of rats was caused by an exposure-related impairment of the alveolar lung clearance and may have been instrumental in the induction of squamous cell tumors. However, an effect of particle-associated PAH cannot be excluded. Syncarcinogenic effects of diesel exhaust after initial carcinogen treatment were found only in the respiratory tract of rats.

Aerosols of smoke, respiratory physiology and deposition.

Tobacco smoke is discussed as a multi-component droplet aerosol system of finite airborne life time which changes rapidly right after formation near the combustion zone of the tobacco and continues to change gradually when aging and approaching a multiphase steady state between vaporized smoke constituents mixed into the air and the dispersed particulate phase which will eventually vanish because of physical mechanisms removing the smoke particles from the airborne state. Data on chemical composition and physical characteristics of mainstream and sidestream cigarette smoke are compared and the dynamic models of aerosol particle behavior and deposition in the respiratory tract under different physiological conditions are discussed. While differences in chemical composition between mainstream and sidestream smoke aerosol systems are reported in the literature at least for the gas phase, there seems to be no reliable body of evidence confirming that mainstream and sidestream cigarette smokes have sufficiently different physical characteristics which would cause substantially different deposition patterns and different relative deposition in the respiratory tract. However, there are scanty experimental data in the literature on cigarette smoke deposition in the lung which seem to indicate that mainstream smoke deposition may exceed theoretical expectations while sidestream smoke may not. Further experimental results are needed before firm conclusions can be drawn. An ongoing experimental effort is described where deposition of sidestream cigarette smoke will be measured on mouth breathing test panels.

Lung dynamics and uptake of smoke constituents by nonsmokers--a survey.

Models of smoke kinetics and lung dynamics of inhaled particles are discussed and compared with the available literature on mainstream and sidestream smoke particles. The literature search reveals a dearth of reliable information on the deposition of inhaled particulate tobacco smoke components in the human lung. Scanty results on mainstream smoke range from unexpectedly high deposits to values in line with predictions of conventional mathematical deposition models confirmed in tests with stable aerosols. For sidestream smoke, only one well-described experimental result is available. It is in agreement with established deposition probabilities. Experimental and theoretical estimates of relative particle deposition in the human lung range from some 10% for sidestream smoke particles to more than 80% for mainstream aerosol. This indicates a need for more, and better, experimental data.

Inventory and biological impact of polycyclic carcinogens in the environment.

The rapid development of the natural sciences and the technical progress during the last century have significantly changed our society and environment. During this period the average life expectancy for people in industrialized countries has doubled. A prolongation of life expectancy to this extent, due to for example, understanding of the relationship between various diseases and their corresponding causative agents, had never before occurred in mankind's history. It resulted in specific hygiene precautions. The recognition of such causal relationship was facilitated by the fact that infection diseases generally become apparent after a short incubation time, i.e. that an environmental situation causes health damage. At present, we are searching for origins of diseases of which the causal correlations with environmental influences are far more difficult to recognize than those of infection diseases, since long-term effects have to be observed. Do we have a situation similar to that which we had for infections at the end of the last century ? For diseases such as lung and larynx cancer, there are significant indications of carcinogenic compounds in the environment. Since both types of cancer are about 10 times more common among cigarette smokers who inhale than among non-smokers, a correlation to the risk factor "smoking" is beyond doubt. Living and working in larger cities or highly populated areas are additional factors which many enhance the lung cancer incidence ("urbanisation factor"). The air quality of these areas is supposed to be the reason for this effect. However, the present "bad air quality" at most doubles the disease incidence. A large number of epidemiological studies report on local differences of the incidence rates as well as significant increases or decreases of the mortality rates for some cancer diseases during comparatively short periods. A summary recently has been published by Misfeld (1). As an example, the mortality rate due to lung cancer for males in the F.R.G. has almost doubled during 1955-1975 from 36.5 per 100,000 to 65.9 per 100,000. This holds true for cancer of the rectum which increased from 8.8 per 100,000 to 18.9 per 100,000 during the same period. In contrast, mortality due to stomach cancer decreased from 59.3 to 36.6 per 100,000 and uterine cancer in females decreased from 16.6. to 8.5 per 100,000 (2). The pronounced changes in mortality rates cannot be explained by alterations of the genetic disposition during such a short period. Improved diagnostic and therapeutic techniques might explain decreases but not increases of mortality rates.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is characterized by an inhalation of the substance under investigation. In an experiment with mice, the inhalation of a mixture of SO2 and NO2 seemed to increase the basic tumor rate induced by dibenz(a,h)anthracene. In a similar two-phase experiment conducted with hamsters, the inhalation of diesel exhaust (total exhaust as well as exhaust without particles) increased a basic tumor rate induced by diethyl nitrosamine. These experiments deserve confirmation before a detailed interpretation is attempted.

Some aspects of analysis of single fibers in environmental and biological samples.

Nuclepore filters were used for sampling and evaluation of fibrous particles in ambient air, in liquids and in biological materials. The fiber counting and fiber size measurements were done by means of SEM-methods. The number of fibers and the distributions of fiber lengths and diameters were plotted. The specific identifications of asbestos, glass and other mineral fibrous particles were made by electron microprobe analysis. Certain elements proved to be approximative identification factors for different fibrous minerals in ambient air, in liquids, on material surfaces, or in biological materials. For ambient air, asbestos, glass, and many other inorganic fibrous particles were found in the urban atmosphere as well as in the atmosphere of remote regions. Fibrous gypsum, fibrous ammonium sulfates, fibrous silicates, fibrous mica, and quartz were identified among these particles. Even in remote ambient air, relatively high concentrations of inorganic fibrous particles could be measured.