James S. Ultman

Modeling Approaches for Estimating the Dosimetry of Inhaled Toxicants in Children

Risk assessment of inhaled toxicants has typically focused upon adults, with modeling used to extrapolate dosimetry and risks from lab animals to humans. However, behavioral factors such as time spent playing outdoors may lead to more exposure to inhaled toxicants in children. Depending on the inhaled agent and the age and size of the child, children may receive a greater internal dose than adults because of greater ventilation rate per body weight or lung surface area, or metabolic differences may result in different tissue burdens. Thus, modeling techniques need to be adapted to children in order to estimate inhaled dose and risk in this potentially susceptible life stage. This paper summarizes a series of inhalation dosimetry presentations from the U.S. EPAs Workshop on Inhalation Risk Assessment in Children held on June 8–9, 2006 in Washington, DC. These presentations demonstrate how existing default models for particles and gases may be adapted for children, and how more advanced modeling of toxicant deposition and interaction in respiratory airways takes into account childrens anatomy and physiology. These modeling efforts identify child-adult dosimetry differences in respiratory tract regions that may have implications for childrens vulnerability to inhaled toxicants. A decision framework is discussed that considers these different approaches and modeling structures including assessment of parameter values, supporting data, reliability, and selection of dose metrics.

Alveolar epithelial cell injuries by subchronic exposure to low concentrations of ozone correlate with cumulative exposure

Electron microscopy morphometry has been used to study the effects of cumulative exposure of low levels of inhaled O3 on lung proximal alveolar tissue. Six-week-old Fisher 344 rats were exposed to O3 in two different subchronic low-level exposure patterns. The first was a 12 hr/day exposure for 6 weeks and included two O3 concentrations, 0.12 and 0.25 ppm. The second consisted of an exposure profile having a background level of 0.06 ppm with an exposure peak 5 days each week that went from 0.12 to 0.25 ppm and back to 0.12 ppm over a 9-hr period. Rats given the second exposure pattern were exposed for either 3 or 13 weeks. Changes in the volumes of alveolar epithelium were found to be consistent and reproducible markers for cell injury and/or response. Results from the first study indicated that the relative volume of the type I epithelium increased 13 and 23% over the control value (p less than 0.05) following exposures for 6 weeks to 0.12 and 0.25 ppm, respectively. The magnitude of the increases were clearly concentration related. Similarly, when a fixed exposure concentration was employed the relative volume of type I epithelium was found to increase in proportion to the exposure time. In the second exposure, increases of 9 and 33% in relative volume of type I epithelium were found respectively after 3 and 13 weeks of exposure. If the total exposure determined by the product of O3 concentration (including background) and exposure time is plotted against the relative volume of type I epithelium from both the 0.12 ppm (60.5 ppm-hr) and 0.25 ppm (126 ppm-hr) exposures and the 3-week (45.3 ppm-hrs) and 13-week (196.2 ppm-hr) exposures, a linear relationship between increases in type I cell volume and the concentration X time product is observed. The coefficient of correlation (r2) for the linear regression of the animal means is 0.72. Changes in the volume of Type II epithelial cell also correlate with the concentration X time product (r2 = 0.66). This suggests that epithelial cell reactions to low-level subchronic exposure of O3 are directly related to the cumulative oxidant concentration. The pattern of exposure did not appear to affect the resulting degree of injury. Furthermore, a low level of background exposure may contribute to the epithelial cell injuries.

Simulation of ozone uptake distribution in the human airways by orthogonal collocation on finite elements

Ozone transport in a rigid single-pathway anatomic model of the lung was analyzed by a stable convergent numerical algorithm, the method of orthogonal collocation on finite elements. The simulations predicted the dynamic behavior of gas phase concentration profiles for both ozone and an insoluble inert gas. An internal quasi-stationary diffusion front was observed during early inspiration for both gases. In addition, the absorptive distribution of ozone in lung airways was computed as a total dose as well as a tissue dose. The total dose of ozone decreased along the airway path from the mouth. However, the tissue dose of ozone increased along the conducting airways, reached a maximal dose in the terminal bronchioles, and decreased sharply in the respiratory airways.

Thermal head wrap for infants

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Small intrapulmonary artery lung prototypes: design, construction, and in vitro water testing.

Blind-ended, hollow fibers mounted on a pulmonary artery catheter may allow O2 and CO2 transfer in the vena cava, right ventricle, and pulmonary artery. The effects of fiber length, manifold number, and gas oscillation on mass and momentum transfer with water perfusate using mass spectrometry and mass flow controllers were studied. Manifolds with 112-196 microporous polypropylene fibers were mounted on 8 Fr multiple lumen, commercially available pulmonary artery catheters. Fiber lengths varied from 0.5 to 16 cm and surface areas from 7 to 220 cm2. Prototypes with 2 cm long fibers were constructed with 1-15 manifolds. A two manifold prototype with 8 cm long fibers and a surface area of 378 cm2 was also studied. The transfer failed to scale with manifold number because the steady gas flow was maldistributed to the manifolds. Oscillating gas pressures from 780 to 76 mmHg absolute at a rate of 40 cycles/min increased CO2 transfer up to 15-fold and O2 transfer up to 2.5-fold. Oscillation also corrected the maldistribution. Optimal fiber lengths of 3 and 1 cm for O2 and CO2, respectively, were seen with steady gas flow, and 8 cm for both with oscillatory gas flow.

Three-Dimensional Simulations of Reactive Gas Uptake in Single Airway Bifurcations

The pattern of lung injury induced by the inhalation of ozone (O3) depends on the dose delivered to different tissues in the airways. This study examined the distribution of O3 uptake in a single, symmetrically branched airway bifurcation. Reaction in the epithelial lining fluid was assumed to be so rapid that O3 concentration was negligible along the entire surface of the bifurcation wall. Three-dimensional numerical solutions of the continuity, Navier–Stokes and convection–diffusion equations were obtained for steady inspiratory and expiratory flows at Reynolds numbers ranging from 100 to 500. The total rate of O3 uptake was found to increase with increasing flow rate during both inspiration and expiration. Hot spots of O3 flux appeared at the carina of the bifurcation for virtually all inspiratory and expiratory Reynolds numbers considered in the simulations. At the lowest expiratory Reynolds number, however, the location of the maximum flux was shifted to the outer wall of the daughter branch. For expiratory flow, additional hot spots of flux were found on the parent branch wall just downstream of the branching region. In all cases, O3 uptake in the single bifurcation was larger than that in a straight tube of equal inlet radius and wall surface area. This study provides insight into the effect of flow conditions on O3 uptake and dose distribution in individual bifurcations.

Improvements in a chemiluminescent ozone analyzer for respiratory applications

The performance characteristics of a previously developed analyzer utilizing the homogeneous chemiluminescent reaction of ozone (O3) with a stoichiometric excess of 2‐methyl‐2‐butene were improved with the eventual goal of measuring the distribution of O3 in a single human breath. By increasing the sampling flow from 200 to 400 ml/min and utilizing a combination of analog and digital filtering, it was possible to improve the signal‐to‐noise ratio at 0.5 ppm O3 from 5.5 to 28, the minimum detection limit from 0.02 to 0.01 ppm, the sensitivity from 1.5 to 2.3 na/ppm, and the 10%–90% step‐response time from 200 to 100 ms. Humidity, temperature, and inlet gas composition interferences were also evaluated. While temperature and humidity have no influence on the analyzer output, the substitution of carbon dioxide for oxygen increased the analyzer sensitivity by 3.8% for each percent of CO2 that was present. Thus, provided that an appropriate correction for carbon dioxide is made, these improvements allow the instrument to monitor inhaled and exhaled O3 concentrations with a rapid dynamic response and over a broad range of physiologically relevant values.

Longitudinal distribution of ozone absorption in the lung: Effects of nitrogen dioxide, sulfur dioxide, and ozone exposures

Investigators used an ozone bolus inhalation method to study the effects of continuous exposure to ozone, nitrogen dioxide, and sulfur dioxide on ozone absorption in the conducting airways of human lungs. Healthy, young nonsmokers (6 males, 6 females) were exposed on separate days for 2 h to air containing 0.36 ppm nitrogen dioxide, 0.75 ppm nitrogen dioxide, 0.36 ppm sulfur dioxide, or 0.36 ppm ozone. Every 30 min, the subject interrupted exposure for approximately 5 min, during which he or she orally inhaled five ozone boluses-each in a separate breath. Investigators targeted penetration of the boluses distal to the lips in the 70-130-ml range, which corresponded to the lower conducting airways. The authors computed the change in absorption resulting from exposure (delta lambda) by comparing the amount of each ozone bolus that was absorbed with a corresponding value obtained prior to exposure. Results indicated that ozone exposure caused delta lambda to decrease relative to air exposure (p < .01), whereas both nitrogen dioxide and sulfur dioxide exposures caused an increase in delta lambda that was not significantly different from air exposure. This resulted, at least in part, to an artifact caused by preexposure to ozone boluses. The authors concluded that exposure of the lower conducting airways to nitrogen dioxide or sulfur dioxide increased their capacity to absorb ozone because more of the biochemical substrates that are normally oxidized by ozone were made available. During continuous ozone exposure, this excess of substrate is depleted and the absorption of ozone boluses decreases.

Longitudinal mixing by the human larynx

Both the characteristics of the velocity field and the longitudinal dispersion of helium, oxygen and sulfur hexafluoride in air flowing through a cast of a cadaveric human larynx have been studied. The larynx cast was mounted in the center of a 5 m long, 1.6 cm diameter tube through which air was admitted at 206, 425 or 775 ml/s, corresponding to fully-developed laminar (Reynolds number = 1110), transitional (2310), and fully-developed turbulent (4210) flow conditions, respectively. A significant enhancement of longitudinal mixing was detected immediately downstream of the glottis, presumably because of the jetting of air in the vicinity of the constriction. This enhancement did not depend upon the flow rate of air but was inversely related to the molecular diffusivity of the tracer gas; this indicates the importance of Taylor dispersion in the jet. The glottis also generated intense local turbulence which propagated as far as 110 cm from the constriction. This turbulence caused a flattening of the velocity profiles resulting in a reduction in the rate of downstream longitudinal mixing. The reduction was so great that, in spite of mixing enhancement in the jet, the overall mixing was less with the larynx in place than in the empty tube.

Monte carlo simulation of simulateous gas flow and diffusion in an asymmetric distal pulmonary airway model

In order to evaluate the effect of anatomic asymmetries on the gas concentration distribution in the pulmonary airways, a Monte Carlo simulation of combined bulk flow and molecular diffusion was carried out in a realistic distal airway model (Parkeret al., 1971). This airway model, composed of branches distal to the 0.5-ram diameter airways, contained an upper symmetric segment consisting of four generations of conducting airways and a lower asymmetric segment of alveolar ducts and sacs arranged in five transport paths of varying lengths. In accounting for the volume increases of these ducts and sacs occurring during normal respiration, uniform alveolar filling rates and a fixed length-to-diameter ratio of all airways were assumed. For a pulse injection of inert tracer gas, the simulation was employed to determine the longitudinal concentration profiles in the conducting airways. In the alveolated airways, not only were the longitudinal profiles determined along each path, but radial transport from the core to the periphery of the airways was considered.