Abstract  According to the 1983 NAS paradigm that serves as the basis for current health risk assessment procedures, risk characterization requires the comparison of an exposure estimate against a dose-response estimate. The types of exposure scenarios required under various regulations can be categorized as acute, subchronic, and chronic. Toxicity testing studies can also be so categorized, but such categories are defined by the exposure duration and not the underlying mechanism of action or its appropriate dose metric. Considerations of underlying mechanisms and temporal relationships of toxicity challenge current default assumptions and extrapolation approaches for derivation of dose-response estimates. This article discusses the duration adjustments used in current health risk assessment procedures and highlights the attendant assumptions. Comprehensive dosimetry model structures integrate mechanistic and temporal determinants of the exposure-dose-response continuum. Analysis of dosimetry model structures is proposed as a way to identify key parameters for development of alternative default duration adjustment procedures.

Abstract  The International Commission on Radiological Protection's human respiratory tract dosimetry model was used to predict average particle deposition and retention patterns for two example trimodal (fine, intermodal, and coarse modes) environmental aerosols (Phoenix, Arizona, and Philadelphia, Pennsylvania). Deposited dose metrics are presented as mass (and number) of particles normalized to either respiratory tract region surface area (square centimeters) or mass (grams) of epithelium. Deposition metrics ranged over several orders of magnitude, with extrathoracic > tracheobronchial > alveolar- interstitial. Dissolution-absorption half-times for tine, intermodal, and coarse particles were defined as I (I, 100, and 1000 days, respectively, to allow modeling of chronic exposures. Default values for particle physical clearance parameters were used. Retained dose for the alveolar-interstitial region is presented as the steady-state mass of particles (micrograms)/gram epithelium. Modeling results indicated similar retention patterns for the fine particles. but substantially different patterns for the intermodal and coarse particles. Intermodal and coarse particles dominated the Phoenix aerosol, resulting in predictions that long-term retained lung burdens would be about four times higher in individuals chronically exposed in Phoenix versus Philadelphia. This modeling approach improves the understanding of relationships between exposures to environmental aerosols and deposition/retention patterns in the human respiratory tract. Modeling demonstrated significant thoracic deposition of environmental aerosol particles larger than those collected in a PM25 sampler. This result supports the conclusion that using the PM10 aerosol fraction as an exposure index should be a good indicator of potential health effects. Therefore, aerosol sampling should retain PM141 sampling in order to include the entire respirable size range and provide adequate information for predicting deposition and retained dose metrics for environmental aerosols. Ventilatory activity patterns are also necessary to characterize total personal exposure, and the dissolution-absorption of environmental aerosol particles must be determined to allow accurate modeling of their long-term retention in the lung.

Abstract  A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO2) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.0, or 10 mg/m3 uf-TiO2 particles for 6 h/day, 5 days/week, for 13 weeks. Following the exposure period, animals were held for recovery periods of 4, 13, 26, or 52 weeks (49 weeks for the uf-TiO2–exposed hamsters) and, at each time point, uf-TiO2 burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathological alterations. Retained lung burdens increased in a dose-dependent manner in all three species and were at a maximum at the end of exposures. Mice and rats had similar retained lung burdens at the end of the exposures when expressed as mg uf-TiO2/mg dry lung, whereas hamsters had retained lung burdens that were significantly lower. Lung burdens in all three species decreased with time after exposure, and, at the end of the recovery period, the percentage of the lung particle burden remaining in the 10 mg/m3 group was 57, 45, and 3% for rat, mouse, and hamster, respectively. The retardation of particle clearance from the lungs in mice and rats of the 10 mg/m3 group indicated that pulmonary particle overload had been achieved in these animals. Pulmonary inflammation in rats and mice exposed to 10 mg/m3 was evidenced by increased numbers of macrophages and neutrophils and increased concentrations of soluble markers in bronchoalveolar lavage fluid (BALF). The initial neutrophil response in rats was greater than in mice, whereas the relative increase of macrophages was less than in mice. The neutrophilic response of rats, but not mice, declined in a time-dependent manner correlating with declining lung burdens; however, the fraction of recovered neutrophils at 52 weeks postexposure was equivalent in the two species. Consistent increases in soluble indicators of toxicity in the BALF (LDH and protein) occurred principally in rats and mice exposed to 10 mg/m3 and diminished with time postexposure. There were no significant changes in cellular response or with markers indicating toxicity in hamsters, reflecting the capacity of these animals to rapidly clear particles from the lung. Progressive epithelial and fibroproliferative changes were observed in rats of the 10 mg/m3 group. These lesions consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (so-called alveolar bronchiolization) circumscribing aggregated foci of heavily particle-laden macrophages. The observed epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. These lesions became more pronounced with increasing time postexposure. Epithelial, metaplastic, and fibroproliferative changes were not noted in either mice or hamsters. In summary, there were significant species differences in the pulmonary responses to inhaled uf-TiO2 particles. Under conditions where the lung uf-TiO2 burdens were equivalent, rats developed a more severe inflammatory response than mice and, subsequently, developed progressive epithelial and fibroproliferative changes. Clearance of particles from the lung was markedly impaired in mice and rats exposed to 10 mg/m3 uf-TiO2, whereas clearance in hamsters did not appear to be affected at any of the administered doses. These data are consistent with the results of a companion study using inhaled pigmentary (fine mode) TiO2 (Bermudez et al., 2002) and demonstrate that the pulmonary responses of rats exposed to ultrafine particulate concentrations likely to induce pulmonary overload are different from similarly exposed mice and hamsters. These differences can be explained both by pulmonary response and by particle dosimetry differences among these rodent species.

Abstract  An anatomically correct finite element mesh of the right human nasal cavity was constructed from CAT scans of a healthy adult nose. The steady-state Navier-Stokes and continuity equations were solved numerically to determine the laminar airflow patterns in the nasal cavity at quiet breathing flow rates. In the main nasal passages, the highest inspiratory air speed occurred along the nasal floor (below the inferior turbinate), and a second lower peak occurred in the middle of the airway (between the inferior and middle turbinates and the septum). Nearly 30 percent of the inspired volumetric pow passed below the inferior turbinate and about 10 percent passed through the olfactory airway. Secondary flows were induced by curvature and rapid changes in cross-sectional area of the airways, but the secondary velocities were small in comparison with the axial velocity through most of the main nasal passages. The pow patterns changed very little as total half-nasal flow rate varied between resting breathing rates of 125 m/s and 200 ml/s. During expiration, the peaks in velocity were smaller than inspiration, and the flow was more uniform in the turbinate region. Inspiratory streamline patterns in the model were determined by introducing neutrally buoyant point particles at various locations on the external naris plane, and tracking their path based on the computed flow field Only the stream from the ventral tip of the naris reached the olfactory airway. The numerically computed velocity field was compared with the experimentally measured velocity field in a large scale (20X) physical model, which was built by scaling up from the same CAT scans. The numerical results showed good agreement with the experimental measurements at different locations in the airways, and confirmed that at resting breathing flow rates, airflow through the nasal cavity is laminar.

Abstract  U.S. Environmental Protection Agency. An increasing number of epidemiological studies have reported excess mortality and morbidity thought to be associated with elevated levels of particulate matter air pollution. These studies call into question the adequacy of the current National Ambient Air Quality Standard for Particulate Matter as being protective of human health. The lack of data from the animal toxicology literature supportive of the types of effects seen in the epidemiology studies has raised issues of biological plausibility, adequacy of animal models, and relevance of endpoints measured in these models. We focused on various aspects of interspecies differences (rat vs. human) in the dosimetry of particles that may help explain the apparent lack of consistency between the toxicological and epidemiological findings. We adjusted the predicted thoracic deposition fractions in rats for the probability of inhaling particles up to 10 Ám in diameter. While deposition of particles on a mass per unit alveolar surface area is not different between these species, dose metrics based upon particle number per various anatomical parameters (ventilatory unit, alveolus, or alveolar macrophage) exhibit some striking differences between rats and humans. This is particularly the case for particles 0.1 Ám to 0.3 Ám in size (i.e., those in the condensation mode of atmospheric aerosol fine particles). Particle deposition studies in smokers and in subjects with lung diseases, such as asthma and chronic obstructive pulmonary disease, show that these subpopulations are likely to be at increased risk from exposure to particulate air pollution. For dose metrics based upon particle number per anatomical parameter, we found that the trend of differences between rats and humans was even more pronounced for these "compromised lung" individuals compared to "normal" subjects. We hypothesize that "localized overload" of particulate clearance mechanisms in individuals with compromised lung status may be part of the biological plausibility story, and we examine various dosimetry model predictions and dose metrics that point in this direction. While our analyses and conclusions should be currently viewed as preliminary and speculative in nature, they underscore the need for additional research to identify and understand the role of factors leading to acute mortality and morbidity associated with episodic particulate air pollution excursions.

Abstract  Formaldehyde (HCHO), which has been shown to be a nasal carcinogen in rats and mice, is used widely and extensively in various manufacturing processes. Studies in rhesus monkeys suggest that the lower respiratory tract may be at risk and some epidemiologic studies have reported an increase in lung cancer associated with HCHO; other studies have not. Thus, an assessment of possible human risk to HCHO exposure based on dosimetry information throughout the respiratory tract (RT) is desirable. To obtain dosimetry estimates for a risk assessment, two types of models were used. The first model (which is the subject of another investigation) used computational fluid dynamics (CFD) to estimate local fluxes in a 3-dimensional model of the nasal region. The subject of the present investigation (the second model) applied a 1-dimensional equation of mass transport to each generation of an adult human symmetric, bifurcating Weibel-type RT anatomical model, augmented by an upper respiratory tract. The two types of modeling approaches were made consistent by requiring that the 1-dimensional version of the nasal passages have the same inspiratory air-flow rate and uptake during inspiration as the CFD simulations for 4 daily human activity levels. Results obtained include the following: (1) More than 95% of the inhaled HCHO is predicted to be retained by the RT. (2) The CFD predictions for inspiration, modified to account for the difference in inspiration and complete breath times, are a good approximation to uptake in the nasal airways during a single breath. (3) In the lower respiratory tract, flux is predicted to increase for several generations and then decrease rapidly. (4) Compared to first pulmonary region generation fluxes, the first few tracheobronchial generations fluxes are over 1000 times larger. Further, there is essentially no flux in the alveolar sacs. (5) Predicted fluxes based on the 1-dimensional model are presented that can be used in a biologically based dose-response model for human carcinogenesis. Use of these fluxes will reduce uncertainty in a risk assessment for formaldehyde carcinogenicity.

Abstract  National Institutes of Health. #In aerosol research, particle size has been mainly considered in the context of the role it plays in particle deposition along the respiratory tract. The possibility that the primary particle size may affect the fate of particles after they are deposited was explored in this study. Rats were exposed for 12 wk to aerosolized ultrafine (~21 nm diameter) or fine (~250 nm diameter) titanium dioxide (TiO2) particles. Other rats were exposed to TiO2 particles of various sizes (12, 21, 230, and 250 nm) by intratracheal instillation. After the rat lungs were extensively lavaged, analysis of particle content in the lavaged lungs, lavage fluid, and of lymphatic nodes was performed. Electron and light microscopy was also performed using unlavaged lungs. Both acute instillation and subchronic inhalation studies showed that ultrafine particles (~20 nm) at equivalent masses access the pulmonary interstitium to a larger extent than fine particles (~250 nm). An increasing dose in terms of particle numbers and a decreasing particle size promoted particle access into the interstitium. The translocation of particles into the interstitium appeared to be a function of the number of particles, and the process appeared to be related to the particle size, the delivered dose, and the delivered dose rate. A net effect of the preferential translocation of the smaller particles into the interstitium was a prolongation in their lung retention. After the 12-wk inhalation exposure, pulmonary clearance of ultrafine particles was slower (t1/2 = 501 days) than of larger particles (t1/2 = 174 days). Particles not phagocytized by alveolar macrophages in the alveoli were taken up by alveolar type I epithelial cells, which was probably the first step for interstitial access of particles. The two distinct pathways for alveolar clearance of highly insoluble particles -via the airways and via the interstitial-lymphatic route - seem to be interconnected by bronchus-associated lymphoid tissue in rats. TiO2 particle translocation into the Interstitium was accompanied by an acute inflammatory response, as indicated by polymorphonuclear leukocyte (PMN) increases among lavaged cells. In the postexposure period, although the lung burdens were still substantially elevated, the lavaged PMN numbers decreased to almost control values. This suggests that inflammation was affected by the processes occurring during exposure and less by the lung burden or by particle redistribution after exposure.

Abstract  Young adult rats were exposed via inhalation or intratracheal instillation to oxides of arsenic, beryllium, cadmium, cobalt, lead, selenium, vanadium, and ytterbium. Serial necropsies were performed to assess the metal content in organs at times up to several weeks after exposure. The lung clearance varied widely for these compounds, and the times to remove 50% of the initial burden ranged from 18 min for vanadium to 400 days for beryllium. Arsenic, cadmium, lead, selenium, and vanadium were initially soluble in lung, but a small fraction (1-20%) remained there over the long term. Extrapulmonary tissues often accumulated substantial amounts of the soluble oxides, and whole-body retention was often greater for compounds that were more soluble in lung. Arsenic, selenium, and vanadium translocated to carcass and bone. Arsenic, cadmium, lead, and selenium accumulated in the liver, and the kidney retained cadmium and lead. Beryllium, cobalt and ytterbium did not deposit at any extrapulmonary site in significant amounts. In general, the aqueous solubility of these compounds was a poor predictor for behavior in vivo because of their interaction with metabolic processes. Of the metal oxides tested for acute lethality following pulmonary deposition, cadmium was most toxic, followed by selenium, vanadium, and arsenic.

Abstract  Particulate size-selective sampling is an important consideration in determining ambient air quality standards and threshold limit values for workplace exposures. Hazard evaluations, as well as risk analyses, can benefit from an improved understanding of factors affecting regional respiratory tract deposition of particles in man. Here, thoracic deposition and its component parts are examined, as a function of particulate size, for ventilation rates ranging from normal respiration to heavy exercise in individuals who are habitual mouth breathers and in those who normally employ oronasal breathing when minute ventilations exceed approximately 35 Lmin(-1). Nonlinear regression techniques were used to fit logistic models of the form Y = [1 + e("small alpha" + "small beta"log X) ](-1) to data from tests measuring extrathoracic (ET) and tracheobronchial (TB) deposition. X was defined as an impaction parameter ("small rho" d(2)Q) and as the aerodynamic diameter of the particle (D(ae)) for ET and TB deposition, respectively. The logistic models yielded significantly improved fits of the experimental data compared with previously used linear regression models. Our analyses demonstrate that the activity level of the exposed population should be taken into account to assess the potential health consequences from ambient or workplace exposures.

Abstract  To determine if clearance from ciliated airways is complete in 24 hrs, we measured whole lung and regional clearance of radiolabeled aerosols over 24 hrs in a large number of normal and diseased individuals. Using a gamma camera and computer analysis, we found small but significant amounts of aerosol in the central airways of normal subjects, and greater central retention in some patients with obstructive lung disease. In patients, a significant factor related to the central retention of aerosol was the presence of chronic flow limitation during tidal breathing. Whole lung retention in normal lungs correlated with the initial pattern of aerosol deposition, but not in disease. We conclude that the 24 hr image often contains a significant amount of deposited aerosol in central airways and not just alveoli. In addition, the presence of flow limiting segments in central airways is associated with prolonged retention of aerosol in patients with obstructive lung disease.

Abstract  Chemical Industry Institute of Toxicology; U.S. Environmental Protection Agency. A multiple-path model of particle deposition in the entire rat lower respiratory tract was developed. Deposition in every branch of an asymmetric lung model was calculated using published analytic formulas for efficiencies of deposition by sedimentation, diffusion, and impaction. The conducting airway tree of the model included the entire set of airway measurements for the Long-Evans rat collected by Raabe et al. (1976). A model acinus defined by Yeh et al. (1979) was attached to each terminal bronchiole. Deposition was calculated for each acinus. Substantial variations in acinar deposition were predicted. These depended on inhaled particle size and tidal volume. The standard deviation in acinar dose was on the order of 0.2 times the average dose. Dose to some pulmonary acini was nearly twice the average acinar dose, suggesting that the geometry of the conducting airway tree of the rat lung may cause a fraction of pulmonary sites to sustain damage from inhaled particles at levels of exposure which cause no effect in the majority of the lung. The results represent a first step toward a complete model of inhaled particle deposition which assesses the effect of heterogeneity of lung structure on deposition at the level of individual airways.

Abstract  The identification, recording, and interpretation of nasal lesions can be a difficult task in toxicology studies. The objective of this article is to provide some guidelines for approaches to nasal toxicologic pathology, based on the author's experience and information available in the published literature. Identification of treatment-induced nasal lesions requires adequate in-life and post-mortem observation, and thorough histopathology. Histopathologic assessment is dependent upon high quality and consistent histologic preparations, adequate knowledge of nasal anatomy and histology, and experience with the range of aging, background, and treatment-induced lesions that may be encountered. In recent years there has been a marked increase in the number of articles reporting nasal pathology in studies for which materials were delivered by inhalation and by non-inhalation routes. Because of the increasing size of this database, it is recommended that standardized and systematic nomenclature be developed for these changes. The following points are considered to be particularly important: 1) alert animal care staff to clinical changes that may indicate nasal lesions; 2) screen animals for nasal disease, such as nasal nematodes in non-human primates; 3) record gross lesions during trimming of decalcified nasal tissues; 4) save spare tissue in fixative; 5) remember that the normal bilateral symmetry of the nose can be a valuable diagnostic aid; 6) avoid excessive lumping or splitting of diagnoses; 7) develop a logical order for recording of lesions (the approach preferred by the author is degenerative, inflammatory, regenerative, proliferative, for each of the epithelial types in a logical anatomical order, such as squamous, transitional, respiratory, and olfactory); 8) accurately determine the site of toxic responses; 9) keep a notebook of interesting or important observations and ideas if you are using a computerized data acquisition system; 10) consider the role of factors that may account for lesion distribution (regional dose and tissue susceptibility) during interpretation of tissue responses; and 11) during preparation of the descriptive narrative, clearly define what occurred, where and when it occurred, and consider the use of simple anatomical diagrams as an adjunct to the text. Adequate lesion detection and characterization by the toxicologic pathologist is often a critical feature of toxicology studies, and can play an important role in determination of human risks associated with exposure to xenobiotics. A systematic but flexible approach is recommended.

Abstract  Chronic rat inhalation studies have shown that a number of different particle types can induce significant adverse effects, including impaired lung clearance, chronic pulmonary inflammation, pulmonary fibrosis, and lung tumors. These effects occurred when highly insoluble particles of low solubility and low cytotoxicity were inhaled in long-term studies. Inhaled concentrations ranged from a few milligrams per cubic meter up to 250 mg/m3. This wide range of inhaled concentrations may indicate that the particulate compounds have differed largely in their toxicity. This view appears to be supported by the fact that cytotoxic crystalline SiO2 shows very similar effects after much lower inhaled concentrations. However, although administered doses are customarily expressed in units of mass, this may not be the appropriate dose-metric for a correlation with observed effects. For example, effects on alveolar macrophage (AM) mediated clearance of particles could best be correlated with the volumetric lung burden of different particle types, suggesting that the particle volume phagocytized by AM is an appropriate dose parameter for this endpoint. On the other hand, the inflammatory response induced by a number of different particle types could best be correlated with the surface area of the particles retained in the alveolar space. In addition, total surface area of retained particles was the best dose parameter (or a correlation when the endpoint was lung tumors. In all of these studies crystalline SiO2 did not fit into the overall exposure-response or dose-response relationship, clearly demonstrating that SiO2 is a very different (more cytotoxic) particle type. Particle size and surface area can play important roles in the response to inhaled particles, which is especially relevant for ultrafine particles. Inhalation studies with rats exposed to aggregated ultrafine TiO2 and carbon black showed that both compounds induced lung tumors in rats at considerably lower gravimetric lung burdens than larger sized TiO2. However, the different ultrafine particle types did also show differences in the strength of response that cannot be explained by differences in surface area only. Analyses of inhalation studies with ultra fine particles show that the movement of particles from alveolar spaces into interstitial sites appears to reflect the ability of inhaled ultrafine particle aggregates (TiO2; carbon black) to break down into smaller units, or even singlet particles. Further data are needed to evaluate the importance of interstitial cell-particle interactions for the long-term effects. The lung tumor response in rats after chronic high-dose particle inhalation has been suggested to be a rat-specific response that may not be relevant to humans. However, lacking an understanding about mechanistic events, the rat model should not be dismissed prematurely. What should be questioned instead is the relevance of using excessively high exposure concentrations of particles in a rat study. Exposure-response and dose-response relationships for different endpoints indicate the existence of a threshold below which no adverse effects may occur. Such a threshold could be explained by overwhelming specific defense mechanisms in the respiratory tract, such as particle loading of macrophages (prolongation of particle clearance), or limitations of pulmonary antioxidant capacities (inflammatory response). It appears, however, that duration of exposure plays a significant role that can result in a shift of exposure-dose-response relationships and a shift of a threshold when these relationships are compared at the end of a subchronic study versus the end of a chronic study. This shift will cause difficulties for defining a threshold as well as a maximum tolerated dose from results of a subchronic particle inhalation study.

Abstract  In this article the volumetric overload hypothesis, which predicts the impairment of clearance of particles deposited in the lung in terms of particle volume, is reevaluated. The degree to which simple expressions of retained lung burden explain pulmonary responses to overload was investigated using data from a series of chronic inhalation experiments on rats with two poorly soluble dusts, titanium dioxide and barium sulfate. The results indicated that the difference between the dusts in the level of inflammation and translocation to the lymph nodes could be explained most simply when the lung burden was expressed as total particle surface area. The shape of the statistical relationship for both lung responses indicated the presence of a threshold at approximately 200-300 cm2 of lung burden. On the basis of this and other similar results, a hypothesis regarding a generic mechanism for the impairment of clearance and associated lung responses is proposed for such 'low-toxicity' dusts.

Abstract  Animal studies frequently are used in assessing potential human health effects from exposure to inhaled toxicants. Such studies also are used to investigate sensitive subpopulations such as children. Among other factors that influence the degree to which animal models are predictive of human effects in the delivered dose of the toxicant to the various regions of the respiratory tract. Because the rat is an obligatory nose breather, an understanding of the rat nasal-pharyngeal airway geometry is needed to relate exposures to delivered doses. In this study, the growth and development of the rat nasal-pharyngeal airway was studied at one-week intervals in male Fischer-344 rats from one to five weeks. Casts of an adult (60 day) and an aging (441 day) rat were included for comparison. Replica casts of the nasal-pharyngeal airway were made by injecting silicone rubber through the trachea, and sections in anterior-posterior positions were made for morphometric study. A simple structure of the nasal-pharyngeal airway was found in the young rats. While the percentage of the airway composed of turbinates was similar at all ages, the surface area of the turbinates increased 7.7-fold between 7 and 60 days. Because of the simpler structure and smaller surface area in the young rat, extrathoracic clearance is probably less efficient, resulting in a higher delivered dose to the lung of a young rat than to that of an adult rat exposed to the same toxicant concentration.

Abstract  Nasal filter efficiency for particles has been described by several authors as showing large individual variations, probably somehow related to airflow resistance. Twelve children, aged 5.5-11.5 yrs and 8 aged 12-15 yrs were compared to a group of ten adults. Deposition of polystyrene beads (1, 2.05, 2.8 "mu"m mass median aerodynamic diameter (MMAD)) was measured by comparing inhaled aerosols and exhaled air concentrations, for both nose and mouth breathing. Ventilation was controlled to scale breathing patterns appropriate for each age either at rest or during moderate exercise to allow comparison between subjects In similar physiological conditions. Anterior nasal resistance (as a function of flow rate) and standard lung function were measured for each subject. For the same inhalation flow rate of 0.300 l-s-1, children had much higher nasal resistances than the adults, 0.425 +/- 0.208 kPa-l-1-s under 12 yrs, 0.243 +/- 0.080 kPa+l-1+s over 12 yrs and 0.145 +/- 0.047 kPa-1-1-s in adults. Individually, nasal deposition Increased with particle size, ventilation flow rate and nasal resistance, from rest to exercise. The average nasal deposition percentages were lower in children than in adults, In similar conditions: at rest, 12.9 and 11.7 versus 15.6 for 1 "mu"m; 13.3 and 15.9 versus 21.6 for 2.05 "mu"m, 11 and 17.7 versus 20 for 2.8 "mu"m. This was even more significant during exercise, 17.8 and 15.9 versus 29.2 for 1 "mu"m; 21.3 and 18.4 versus 34.7 for 2.05 "mu"m; 16 and 16.1 versus 36.8 for 2.8 "mu"m. At rest and during moderate exercise, for these particle sizes, the average nasal deposition percentages in children and in adults were better correlated with inspiratory airfiows (r=0.357, 0.473 and 0.435 for 1, 2.05 and 2.8 "mu"m, respectively) than with resistances (r=0.066, -0.148 and .0.254) or pressure drops (r=0.156, 0.199 and 0.107).

Abstract  Intakes and doses are assessed for seven workers who accidentally inhaled particles containing Co in the same incident. Comprehensive whole body data to 15 y, and some early urine and fecal data, are available for each individual. The biokinetic and dosimetric models currently recommended by ICRP have been used to assess these cases. It was not possible to obtain good fits to the data using the ICRP models with their default parameter values. However, good fits to all the measurement data were obtained by varying parameter values following a procedure similar to that recommended in recently developed guidelines for assessment of internal doses from monitoring data. It was found that retention in the lungs was much longer than predicted by the ICRP Human Respiratory Tract Model, and so for each case it was necessary to reduce the particle transport clearance of material from the deep lungs. This reduction in lung clearance rates, and the use of specific AMAD values, were the dominating factors in changing assessed doses from those calculated using ICRP default values.

Abstract  A panel of experts in physiologically based pharmacokinetic (PBPK) modeling and relevant quantitative methods was convened to describe and discuss model evaluation criteria, issues, and choices that arise in model application and computational tools for improving model quality for use in human health risk assessments (HHRAs). Although publication of a PBPK model in a peer-reviewed journal is a mark of good science, subsequent evaluation of published models and the supporting computer code is necessary for their consideration for use in HHRAs. Standardized model evaluation criteria and a thorough and efficient review process can reduce the number of review and revision iterations and hence the time needed to prepare a model for application. Efficient and consistent review also allows for rapid identification of needed model modifications to address HHRA-specific issues. This manuscript reports on the workshop where a process and criteria that were created for PBPK model review were discussed along with other issues related to model review and application in HHRA. Other issues include (1) model code availability, portability, and validity; (2) probabilistic (e.g., population-based) PBPK models and critical choices in parameter values to fully characterize population variability; and (3) approaches to integrating PBPK model outputs with other HHRA tools, including benchmark dose modeling. Two specific case study examples are provided to illustrate challenges that were encountered during the review and application process. By considering the frequent challenges encountered in the review and application of PBPK models during the model development phase, scientists may be better able to prepare their models for use in HHRAs.

Abstract  The procedures recommended in Publications 30 and 66 by ICRP for calculating radiation doses from inhaled or ingested radionuclides include classification of material on the basis of different parameters, among which transportability plays a major role, The allocation of transportable Classes or absorption Types should, whenever possible, be based on animal or human data. However, when such in vivo data are unavailable, it becomes appropriate to consider the use of other approaches, among which in vitro dissolution techniques are reasonable alternatives. This paper reviews and critically analyzes in vitro dissolution techniques that have been described historically and recommends methods shown to be useful in estimating the in vivo solubility of radioactive particles.

Abstract  It is generally believed that the reduction in plasma [HCO3] characteristic of chronic hypocapnia results from renal homeostatic mechanisms designed to minimize the alkalemia produced by.the hypocapneic state. To test this hypothesis, we have induced chronic hypocapnia in dogs in which plasma [HCO3] had previously been markedly reduced (from 21 to 15 meq/liter) by the prolonged feeding of HCl. The PaCO2 of chronically acid-fed animals was reduced from 32 to 15 mm Hg by placing the animials in a large environmental chamber containing 9% oxygen. In response to this reduction in PaCO2, mean plasma [HCO3] fell by 8.6 meq/liter, reaching a new steady-state level of 6.4 meq/liter. This decrement in plasma [HCO3] is almost identical to the 8.1 meq/liter decrement previously observed in normal (nonacid-fed) animals in which the same degree of chronic hypocapnia had been induced. Thus, in both normal and HCl-fed animals, the renal response to chronic hypocapnia causes plasma [HCO3] to fall by approximately 0.5 meq/liter for each millimeter of Hg reduction in CO2 tension. By contrast, the response of plasma [H+] in the two groups was markedly different. Instead of the fall in [H+] which is seen during chronic hypocapnia in normal animals, [H+] in HCl-fed animals rose significantly from 53 to 59 neq/liter (pH 7.28-7.23). This seemingly paradoxical response is, of course, an expression of the constraints imposed by the Henderson equation and reflects the fact that the percent fall in [HCO3] in the HCl-fed animals was greater than the percent fall in PaCO2. These findings clearly indicate that in chronic hypocapnia the kidney cannot be regarded as the effector limb in a homeostatic feedback system geared to the defense of systemic acidity.

Abstract  Inhaled vapors may be absorbed at the alveolar-capillary membrane and enter arterial blood flow to be carried to other organs of the body. Thus, the biological effects of inhaled vapors depend on vapor uptake in the lung and distribution to the rest of the body. A mechanistic model of vapor uptake in the human lung and surrounding tissues was developed for soluble and reactive vapors during a single breath. Lung uptake and tissue disposition of inhaled formaldehyde, acrolein, and acetaldehyde were simulated for different solubilities and reactivities. Formaldehyde, a highly reactive and soluble vapor, was estimated to be taken up by the tissues in the upper tracheobronchial airways with shallow penetration into the lung. Vapors with moderate solubility such as acrolein and acetaldehyde were estimated to penetrate deeper into the lung, reaching the alveolar region where absorbed vapors had a much higher probability of passing through the thin alveolar-capillary membrane to reach the blood. For all vapors, tissue concentration reached its maximum at the end of inhalation at the air-tissue interface. The depth of peak concentration moved within the tissue layer due to vapor desorption during exhalation. The proposed vapor uptake model offers a mechanistic approach for calculations of lung vapor uptake, air:tissue flux, and tissue concentration profiles within the respiratory tract that can be correlated to local biological response in the lung. In addition, the uptake model provides the necessary input for pharmacokinetic models of inhaled chemicals in the body, thus reducing the need for estimating requisite parameters.

Abstract  The problem of steady state mass diffusion of acrosols without axial diffusion in a long cylindrical channel and for small diffusion parameter, Δ, is presented. Results are obtained when the laminar fluid flow is Poiseuille, plug and a combination of Poiseuille and plug, such that an allowance for slip velocity of the fluid at the wall can be taken into account. The asymptotic solution for large Δ, that has been obtained by several previous authors, is matched to asymptotic solutions that have been obtained in this paper for small Δ. A solution for the complete range of values of the parameter Δ is thus presented.

Abstract  Both epidemiological and toxicological studies indicate that inhalation and subsequent deposition of air borne particles into the lungs have adverse health effects. Recently, the ultrafine particle (UfP) fraction (diameter < 100nm) has received particular attention, as their small size may lead to more toxic proper ties. In this study we summarize the current knowledge on the dosimetry of inhaled particles (including UfPs) with a focus on recent data on translocation of UfPs into secondary target organs (such as brain and heart) suggesting that the lifetime dose of ambient UfPs in secondary target organs is about 1011 particles. Furthermore, we highlight the main pathways of particle induced toxicity and the reasons for the potentially higher toxicity of UfPs. Finally, we discuss recent evidence indicating that (BET) surface area is the single most relevant dose metric for the toxicity of UfPs, which has important implications for regulatory measures on the toxicity of ambient and engineered particles.