Annie M. Jarabek

Dosimetric Adjustments for Interspecies Extrapolation of Inhaled Poorly Soluble Particles (PSP)

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 5μm). 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 ≤ 2μm, then decrease with an increase in particle size for particles >2 μm in the small airways and >3 μm 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 μm 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.

Focusing on Children's Inhalation Dosimetry and Health Effects for Risk Assessment: An Introduction

Substantial effort has been invested in improving childrens health risk assessment in recent years. However, the body of scientific evidence in support of childrens health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Childrens inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within childrens health, key issues for consideration include (1) epidemiological evidence of adverse effects following childrens exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of childrens inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand childrens inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved childrens health risk assessment.

Nasal Contribution to Breathing and Fine Particle Deposition in Children Versus Adults

Both the route of breathing, nasal versus oral, and the effectiveness of the nose to filter inhaled, fine particles may differ between children and adults. This study compared (1) the nasal contribution to breathing at rest and during mild to moderate exercise in children (age 6–10 yr) versus young adults and (2) the nasal deposition efficiency (NDE) of fine particles (1 and 2 μm MMAD, GSD < 1.2) under resting and light exercise breathing conditions in the same children and adults. Nasal contribution to breathing was assessed by respiratory inductance plethysmography and a nasal mask with flow meter during incremental exercise on a bicycle ergometer. Fine particle deposition fractions for nasal and oral breathing were assessed by inhalation of monodisperse carnauba wax particles and laser photometry to determine inhaled/exhaled concentrations. There was a trend for children to have a lesser nasal contribution to breathing at rest and during exercise, but the differences from adults were not statistically significant. Children did, however, have significantly decreased NDE for 2-μm particles under light exercise breathing conditions compared to adults, suggesting less efficient nasal filtering for larger particles and higher flow conditions. These results suggest that the lungs of children may be exposed to higher concentrations of inhaled, ambient particles than adults.

UPPER RESPIRATORY TRACT SURFACE AREAS AND VOLUMES OF LABORATORY ANIMALS AND HUMANS: CONSIDERATIONS FOR DOSIMETRY MODELS

To facilitate the development of regional respiratory tract dosimetry comparisons between laboratory animal species and humans, published surface area (SA) and volume (VOL) data for the upper respiratory tract (URT) were reviewed. The review of the literature revealed that (1) different studies used different techniques to prepare specimens and make measurements, (2) different areas of the URT were measured, and (3) URT surface areas and volumes have been reported for a limited number of individual subjects within a species but for a relatively wide range of species. The published data are summarized in tables in this article. New measurements made in an F344 rat and in a female human subject are also presented. Despite the differences in experimental protocols, it was possible to fit allometric scaling equations to the data: In(SA, cm2) = -0.34 + 0.52 In(body weight, g) and In(VOL, cm3) = 1.70 + 0.78 In(body weight, g). Separate scaling equations were also fitted for rats alone. To illustrate the use of these scaling equations in quantitative human health risk assessment, two dose metrics (fractional absorption/cm2 URT SA and fractional absorption/g body weight) for predicted URT uptake in laboratory animals and humans were calculated for acrolein and epichlorohydrin. Expressed as an animal-to-human ratio, the 95% confidence interval for URT SA could change the predicted dose ratio by up to a factor of 2. Additional studies are needed to describe the entire URT (from the nares through the larynx) quantitatively and to decrease variability in scaling equation predictions as well as to develop additional species-specific scaling equations. Three-dimensional imaging techniques provide a noninvasive method to obtain URT surface areas and volumes in humans and the larger laboratory animals. Comparisons of magnetic resonance image (MRI) and computed tomography (CT) scans made as part of this study suggest that the greater clarity of the mucosal-air interface in the CT image provides better resolution for the study of anatomic features. Because there is no radiation exposure associated with MRI imaging, however, it is more safely used than CT scans in making repeated measurements in a subject to elucidate changes in URT geometry associated with normal nasal cycling or other physiological changes.

A PBPK Model for Evaluating the Impact of Aldehyde Dehydrogenase Polymorphisms on Comparative Rat and Human Nasal Tissue Acetaldehyde Dosimetry

Acetaldehyde is an important intermediate in the chemical synthesis and normal oxidative metabolism of several industrially important compounds, including ethanol, ethyl acetate, and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneration of the olfactory and respiratory epithelium in rats at concentrations > 50 ppm (90 day exposure) and respiratory and olfactory nasal tumors at concentrations ≥ 750 ppm, the lowest concentration tested in the 2-yr chronic bioassay. Differences in the anatomy and biochemistry of the rodent and human nose, including polymorphisms in human high-affinity acetaldehyde dehydrogenase (ALDH2), are important considerations for interspecies extrapolations in the risk assessment of acetaldehyde. A physiologically based pharmacokinetic model of rat and human nasal tissues was constructed for acetaldehyde to support a dosimetry-based risk assessment for acetaldehyde (Dorman et al., 2008). The rodent model was developed using published metabolic constants and calibrated using upper-respiratory-tract acetaldehyde extraction data. The human nasal model incorporates previously published tissue volumes, blood flows, and acetaldehyde metabolic constants. ALDH2 polymorphisms were represented in the human model as reduced rates of acetaldehyde metabolism. Steady-state dorsal olfactory epithelial tissue acetaldehyde concentrations in the rat were predicted to be 409, 6287, and 12,634 μM at noncytotoxic (50 ppm), and cytotoxic/tumorigenic exposure concentrations (750 and 1500 ppm), respectively. The human equivalent concentration (HEC) of the rat no-observed-adverse-effect level (NOAEL) of 50 ppm, based on steady-state acetaldehyde concentrations from continual exposures, was 67 ppm. Respiratory and olfactory epithelial tissue acetaldehyde and H+ (pH) concentrations were largely linear functions of exposure in both species. The impact of presumed ALDH2 polymorphisms on human olfactory tissue concentrations was negligible; the high-affinity, low-capacity ALDH2 does not contribute significantly to acetaldehyde metabolism in the nasal tissues. The human equivalent acetaldehyde concentration for homozygous low activity was 66 ppm, 1.5% lower than for the homozygous full activity phenotype. The rat and human acetaldehyde PBPK models developed here can also be used as a bridge between acetaldehyde dose-response and mode-of-action data as well as between similar databases for other acetaldehyde-producing nasal toxicants.

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.

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation.

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

Reexamination of Respiratory Tract Responses in Rats, Mice, and Rhesus Monkeys Chronically Exposed to Inhaled Chlorine

AbstractImportant data for human risk assessment of inhaled chlorine are provided by a recent rodent cancer bioassay (Wolf et al., 1995) and a chronic inhalation toxicity study in rhesus monkeys (Klonne et al., 1987). To improve interspecies comparisons based upon these data sets, the tissues from these studies were reexamined to (a) map the location of responses to assess the potential role of local chlorine dosimetry, (b) generate quantitative data on selected endpoints to compliment subjective scores, and (c) further characterize the responses in relation to interspecies differences and potential human health risks. Chlorine-induced lesions, which were confined to the respiratory tract, exhibited both similarities and differences among rodents and primates. At equivalent airborne concentrations (∼2.5 ppm), chlorine-induced responses were less severe in rhesus monkeys, but extended more distally in the respiratory tract to involve the trachea, while treatment-induced lesions were confined to the nose in...

NASAL TISSUE DOSIMETRY?ISSUES AND APPROACHES FOR "CATEGORY 1" GASES: A Report on a Meeting Held in Research Triangle Park, NC, February 11?12, 1998

Three organizations, the Basic Acrylic Monomer Manufacturers (BAMM), Methacrylate Producers Association (MPA), and Vinyl Acetate Toxicology Group (VATG), have sponsored development of physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry with, respectively, acrylic acid (AA), methyl methacrylate (MMA), and vinyl acetate (VA). These compounds cause lesions in nasal epithelial tissues and are classified as Category 1 gases within the U.S. EPA (1994) classification scheme. The National Center for Environmental Assessment in the U.S. EPA Office of Research and Development also has continuing interests in refining its methods for dosimetry adjustments when data on mode of action are available for Category 1 gases. A round-table discussion was held in Research Triangle Park, NC, on 11-12 February 1998, to develop a broader appreciation of the key processes and parameters required in developing nasal tissue dosimetry models. The discussions at the round table drew on these three case studies and several background presentations to assess the manner in which chemical-specific and mode-of-action data can be incorporated into nasal dosimetry models. The round table had representation from the U.S. EPA, academia, and industry. This article outlines the presentations and topical areas discussed at the round table and notes recommendations made by participants to extend models for nasal dosimetry and to develop improved data for modeling. The contributions of several disciplines ? toxicology, engineering, and physiologically based pharmacokinetic (PBPK) modeling ? were evident in the discussions. The integration of these disciplines in creating opportunities for dosimetry model applications in risk assessments has several advantages in the breadth of skills upon which to draw in model development. A disadvantage is in the need to provide venues and develop cross-discipline dialogue necessary to ensure the understanding of cultural attitudes, terminology, and methods. The round-table discussions were fruitful in achieving such enhanced understanding and communication. Subsequent elaboration of these models will benefit from the interactions of these groups at the round table. The round-table discussions have already led to model improvements ? as noted in several recently published articles. Participants emphasized several generic data needs in relation to nasal vapor uptake studies in human subjects, to broader discussion of tissue diffusion models, and to extensions to other classes of gases. The round-table articles that are published separately in this issue and the discussions, captured in this overview, provide a glimpse of the state of the science in nasal dosimetry modeling and a clear indication of the growth of and continuing opportunities in this important research area.Three organizations, the Basic Acrylic Monomer Manufacturers (BAMM), Methacrylate Producers Association (MPA), and Vinyl Acetate Toxicology Group (VATG), have sponsored development of physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry with, respectively, acrylic acid (AA), methyl methacrylate (MMA), and vinyl acetate (VA). These compounds cause lesions in nasal epithelial tissues and are classified as Category 1 gases within the U.S. EPA (1994) classification scheme. The National Center for Environmental Assessment in the U.S. EPA Office of Research and Development also has continuing interests in refining its methods for dosimetry adjustments when data on mode of action are available for Category 1 gases. A round-table discussion was held in Research Triangle Park, NC, on 11-12 February 1998, to develop a broader appreciation of the key processes and parameters required in developing nasal tissue dosimetry models. The discussions at the round table drew on these three case studies and several background presentations to assess the manner in which chemical-specific and mode-of-action data can be incorporated into nasal dosimetry models. The round table had representation from the U.S. EPA, academia, and industry. This article outlines the presentations and topical areas discussed at the round table and notes recommendations made by participants to extend models for nasal dosimetry and to develop improved data for modeling. The contributions of several disciplines-toxicology, engineering, and physiologically based pharmacokinetic (PBPK) modeling-were evident in the discussions. The integration of these disciplines in creating opportunities for dosimetry model applications in risk assessments has several advantages in the breadth of skills upon which to draw in model development. A disadvantage is in the need to provide venues and develop cross-discipline dialogue necessary to ensure the understanding of cultural attitudes, terminology, and methods. The round-table discussions were fruitful in achieving such enhanced understanding and communication. Subsequent elaboration of these models will benefit from the interactions of these groups at the round table. The round-table discussions have already led to model improvements-as noted in several recently published articles. Participants emphasized several generic data needs in relation to nasal vapor uptake studies in human subjects, to broader discussion of tissue diffusion models, and to extensions to other classes of gases. The round-table articles that are published separately in this issue and the discussions, captured in this overview, provide a glimpse of the state of the science in nasal dosimetry modeling and a clear indication of the growth of and continuing opportunities in this important research area.