Abstract  In vivo experiments have shown that nanoparticles depositing in the rat olfactory region can translocate to the brain via the olfactory nerve. Quantitative predictions of the dose delivered by inhalation to the olfactory region are needed to clarify this route of exposure and to evaluate the dose-response effects of exposure to toxic nanoparticles. Previous in vivo and in vitro studies quantified the percentage of inhaled nanoparticles that deposit in the rat nasal passages, but olfactory dose was not determined. The dose to specific nasal epithelium types is expected to vary with inhalation rate and particle size. The purpose of this investigation, therefore, was to develop estimates of nanoparticle deposition in the nasal and, more specifically, olfactory regions of the rat. A three-dimensional, anatomically accurate, computational fluid dynamics (CFD) model of the rat nasal passages was employed to simulate inhaled airflow and to calculate nasal deposition efficiency. Particle sizes from 1 to 100 nm and airflow rates of 288, 432, and 576 ml/min (1, 1.5, and 2 times the estimated resting minute volume) were simulated. The simulations predicted that olfactory deposition is maximum at 6-9% of inhaled material for 3- to 4-nm particles. The spatial distribution of deposited particles was predicted to change significantly with particle size, with 3-nm particles depositing mostly in the anterior nose, while 30-nm particles were more uniformly distributed throughout the nasal passages.

Abstract  Nanoparticles have unique physico-chemical properties compared to larger particles that have the potential to provide promising new possibilities for biomedical applications. Considerable research is currently exploring these potentials of nanotechnology. In contrast, airborne particles as components of indoor air, ambient air pollution associated with traffic-related pollution, industry, power plants, and other combustion sources have the potential to harm children's health. However, a similar research effort into the potential health effects of exposure to nanoparticles is lacking. Children differ markedly from adults in their developmental biology rendering young children the most vulnerable group with regard to potentially harmful effects induced by particulate exposure. This review discusses the differences between children and adults in regard to nanoparticle exposure highlighting the uniqueness and vulnerability of children.

Abstract  The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the respiratory tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for respiratory tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Abstract  This model calculates the deposition and clearance of monodisperse and polydisperse aerosols in the respiratory tract of rats, human adults and children (deposition only) for particles ranging from ultrafine (0.01 microns) to coarse (20 microns) sizes. The models are based upon single-path and multiple-path methods for tracking air flow and calculating aerosol deposition in the lung. The single-path method calculates deposition in a typical path per airway generation, while the multiple-path method calculates particle deposition in all airways of the lung and provides lobar-specific and airway-specific information. Within each airway, deposition is calculated using theoretically derived efficiencies for deposition by diffusion, sedimentation and impaction within the airway or airway bifurcation. Filtration of aerosols by the head (nose and mouth) is determined using empirical efficiency functions.

Abstract  The sites of uptake and retention of inhalants within the respiratory tract influence which tissues are susceptible to damage. Physical and chemical properties of inhalants, including size, water:air and oil:water partition coefficients, and reactivity or susceptibility to metabolism are the major factors that affect deposition and retention. The high metabolic capacity of the cells of the olfactory tissue and bronchiolar Clara cells contributes to their susceptibility to damage from both inhaled and bloodborne toxicants. The major enzymes that metabolize pesticides and many other potential toxicants are the cytochrome P450 and flavin-containing monooxygenases and the carboxylesterases.

Abstract  Different particle types cause excessive lung inflammation that is thought to play a role in the various types of pathology they produce. Recently attention has been focused on nanoparticles due to their presence in environmental particulate air pollution, their use and exposure in occupational settings, and their potential use in nanotechnology and novel therapeutics. We have shown previously that the surface area metric drives the overload response. We have instilled a number of low-toxicity dusts of various particle sizes and assessed neutrophil influx into the lung at 18-24 h postinstillation. The extent of inflammation was demonstrated as being a function not of the mass dose instilled but interestingly of the surface area dose instilled. Since low-toxicity nanoparticles present a "special" case of high surface area, they are relatively inflammogenic. We tested whether we could use this approach to model the reactivity of highly toxic dusts. Rats were instilled with either DQ12 quartz or aluminum lactate-treated DQ12 and, as anticipated, the high specific surface toxicity of DQ12 meant that it was much more inflammogenic (63 times more) than the surface area alone would have predicted. By contrast, aluminum lactate-treated DQ12 fell into the line of "low-toxicity" dusts. In addition, as an in vitro testing alternative to that of in vivo testing, interleukin (IL)-8 production in A549 cells exposed to the panel of various particles clearly demonstrated the ability to also identify a relationship between surface area dose and reactivity. These approaches present the possibility of modelling potential toxicity of nanoparticles and nuisance dusts based on the inflammatory response of a given instilled surface area dose.

Abstract  The deposition of 0.20, 0.15, and 0.04 Ám diameter particles was measured in a human central airway cast using a variable larynx with cyclic inspiratory flow. Data were compared with theoretical predictions for deposition from laminar flow for the first seven airway generations. With the exception of tracheal deposition, which on average exceeded predictions by a factor of 9, the measured deposition was about twice that predicted. The enhanced deposition is attributable to secondary swirling flows. Less enhancement is observed at higher inspiratory flow rates as turbulence increases. The surface density of particles deposited at bifurcations was approximately 20% greater than along the airway lengths. This increased deposition at bifurcations should be considered when calculating tissue dose for particles which act before the initial deposit is removed by clearance processes.

Abstract  #Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

Abstract  Predicting the amount of particle deposition in the human lung following exposure to airborne particulate matter is the first step toward evaluating risks associated with exposure to airborne pollutants. Realistic deposition models are needed for accurate predictions of deposition in the lung, but a major limitation is the degree to which the lung geometry can be accurately reconstructed. Morphometric data for the entire airway tree of the human lung are not available. So far, idealistic lung structures have been used for deposition calculations. In this study, 10 statistical lung structures based on morphometric measurements of Raabe et al. (1976) were generated for the conducting airways of the human lung. A symmetric, dichotomous branching alveolar airway structure was attached to the end of the conducting airway tree of each lung structure. The total volume of the alveolar region was the same among the lung geometries. Using a mathematical scheme developed previously (Anjilvel and Asgharian 1995), regional, Lobar, and per-generation depositions of particles were calculated in these geometries. The results were compared to deposition predictions using typical-path and five-lobe symmetric lung geometry models. All three lung models showed very similar regional and generation-by-generation deposition results. Lobar deposition was found to strongly depend on the detailed morphometry of the lung structure that was used.

Abstract  A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose-response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application to multiple chemicals, may be sufficient to justify the cost for some applications in regulatory decision-making.

Abstract  Dissolution and transport of particles deposited in the lower respiratory tract (LRT) are important factors when estimating clearance and the long-term hazard associated with inhaled radioactive aerosols. Three methods for the in uitro determination of rates of dissolution in simulated biological fluids of respirable particles are described. Short term an vitro dissolution patterns of 144CeCl3 aerosol particles and various samples of 95Zr-95Nb aerosol particles were determined and compared with data on the in vivo dissolution of similar particles in the LRT of experimental animals. General agreement between the in vitro and in vivo dissolution patterns was observed. The long-term (weeks) in vitro rates of dissolution of narrow size group 90Sr-fused clay particles were measured in static and parallel flow systems. The rate constants of dissolution of 90Sr-fused clay particles in the two systems were calculated as 3.1 × 10−8 g/cm2/day and 3.3 × 10-s g/cm2/day, respectively. The estimated rate constant of dissolution of 90Sr-fused clay particles in the LRT of a Beagle dog, 3.4 × 10−8 g/cm2/day, was in good agreement with the in vitro rate constant of dissolution.

Abstract  The MPPD model is a computational model that can be used for estimating human and rat airway particle dosimetry. The model is applicable to risk assessment, research, and education. The MPPD model calculates the deposition and clearance of monodisperse and polydisperse aerosols in the respiratory tracts of rats and human adults and children (deposition only) for particles ranging in size from ultrafine (0.01 µm) to coarse (20 µm). The models are based on single-path and multiple-path methods for tracking air flow and calculating aerosol deposition in the lung. The single-path method calculates deposition in a typical path per airway generation, while the multiple-path method calculates particle deposition in all airways of the lung and provides lobar-specific and airway-specific information. Within each airway, deposition is calculated using theoretically derived efficiencies for deposition by diffusion, sedimentation, and impaction within the airway or airway bifurcation. Filtration of aerosols by the nose and mouth is determined using empirical efficiency functions. The MPPD model includes calculations of particle clearance in the lung following deposition. Eight tutorials are provided so that the user can learn to interact with the software.

Abstract  Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e.g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F(G)). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F(a)) and F(G) via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (Km) for CYP3A4 and P-gp (C(Lint-CYP3A4) and K(m-CYP3A4), CL(int-P-gp) and K(m-P-gp)). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F(G) whereas an increase in C(Lint-P-gp) resulted in a reduced F(a), but interestingly decreased F(G) too. The reduction in FG was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e.g. P(app), C(Lint-P-gp,) and K(m-P-gp)) and gut wall metabolism (e.g. C(Lint-CYP3A4,) K(m-CYP3A4)) resulted in disproportionate changes in F(G) compared to the magnitude of singular effects. The results suggest that P-gp efflux decreases enterocytic drug concentration for drugs given at reasonably high dose which possess adequate passive permeability (high P(app)), by de-saturating CYP3A4 in the gut resulting in a lower F(G). However, these findings were observed only in a very limited area of the parameters space matching very few therapeutic drugs (a group with very high metabolism, high turn-over by efflux transporters and low F(a)). The systematic approach in this study enabled us to recognise the combination of parameters values where the potential interplay between metabolising enzymes and efflux transporters is expected to be highest, using a realistic range of parameter values taken from an intensive literature search.

Abstract  Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.

Abstract  New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.

Abstract  These guidelines revise and replace the U.S. Environmental Protection Agency’s (EPA’s, or the Agency’s) Guidelines for Carcinogen Risk Assessment, published in 51 FR 33992, September 24, 1986 (U.S. EPA, 1986a) and the 1999 interim final guidelines (U.S. EPA, 1999a; see U.S. EPA 2001b). They provide EPA staff with guidance for developing and using risk assessments. They also provide basic information to the public about the Agency's risk assessment methods.

Abstract  In this unit, the need for laboratory-based inhalation toxicology studies, the historical background on adverse health effects of airborne toxicants, and the benefits of advance planning for the building of analytic options into the study design to maximize the scientific gains to be derived from the investments in the study are outlined. The following methods are described: (1) the generation and characterization of exposure atmospheres for inhalation exposures in humans and laboratory animals; (2) the delivery and distribution into and within whole-body exposure chambers, head-only exposure chambers, face-masks, and mouthpieces or nasal catheters; (3) options for on-line functional assays during and between exposures; and (4) options for serial non-invasive assays of response. In doing so, a description beyond exposures to single agents and simple mixtures is presented, and included are methods for evaluating biological responses to complex environmental mixtures. It is also emphasized that great care should be taken in the design and execution of such studies so that the scientific returns can be maximized both initially, and in follow-up utilization of archived samples of the exposure atmospheres, excreta, and tissues collected for histology. © 2015 by John Wiley & Sons, Inc.

Abstract  Introduction: The evaluation of pulmonary physiological measurements in laboratory animals is an essential tool in many biomedical and toxicological research areas. Recently, an unrestrained single chambered whole-body plethysmograph that utilizes a barometric analysis technique to quantify pulmonary physiological values has gained widespread use. However, results generated with the single chamber plethysmograph have come under increased scrutiny because airflow in the lung is indirectly measured. The purpose of the present study was to use mice with known interstrain differences in pulmonary physiology (A/J, BALB/c, CD-1, and B6C3F1) and compare the physiological data generated with a single chamber plethysmograph to data obtained in the widely accepted double chamber noninvasive airway mechanics (NAM) plethysmograph in which the animals are restrained. Methods: Animals were placed into the plethysmographs and baseline physiological data acquired. The mice were then subjected to challenge with aerosols generated from isotonic saline (control) and methacholine solutions of increasing concentration (2.5-320 mg/ml) for 3 min for determination of the concentration of methacholine that induced a 200% increase in airway resistance (PC,R-200). Results: Repeated physiological measurements on the same animals in both the single and double chamber plethysmographs demonstrated that each instrument generated reproducible baseline physiological data. However, comparison of physiological data generated with the double-chambered instrument to that generated with the single chamber plethysmograph revealed several significant differences. While the single chamber plethysmograph appeared to give inaccurate measurements of tidal volume, it provided much better analysis of airway reactivity based on PC200R results. In contrast, the double chamber plethysmograph provided accurate physiological data such as tidal volume and respiratory rate, but provided inaccurate and irreproducible airway reactivity results based on PC200R. Discussion: Our results indicate that the choice of single or double chamber plethysmograph for physiological measurements should be linked to the study objectives and the type of data required.

Abstract  This review covers the following topics: anatomical and functional characteristics of the olfactory system; electric responses to odorous stimuli from different levels of the olfactory pathways; anatomical and functional attributes of the taste system; taste qualities and gustatory psychophysics; electric responses to taste stimuli from the different levels of gustatory pathways; electric taste; normal and pathological states of smell and taste perception.

Abstract  In this report, the ICRP provides a new biokinetic and dosimetric model of the human alimentary tract to replace the Publication 30 (ICRP, 1979) model. The new human alimentary tract model (HATM) will be used together with the human respiratory tract model (HRTM; ICRP, 1994a,b) in future ICRP publications on doses from ingested and inhaled radionuclides. The HATM is applicable to all situations of radionuclide intake by children and adults. It provides age-dependent parameter values for the dimensions of the alimentary tract regions, and associated transit times for the movement of materials through these regions. For adults, gender-dependent parameter values are given for dimensions and transit times. The default assumption is that radionuclide absorption takes place in the small intestine, but the model allows for absorption in other regions and for retention in or on tissues within the alimentary tract when information is available. Doses are calculated to target cells for cancer induction in the oral cavity, oesophagus, stomach, small intestine, and colon. This report provides reviews of information on the transit of materials through the alimentary tract and on radionuclide retention and absorption. It considers data on health effects, principally in order to specify the target cells for cancer induction within the mucosal lining of the tract and to justify approaches taken to dose averaging within regions. Comparisons are made between doses calculated using the HATM and the Publication 30 model for examples of radionuclide ingestion for which absorption is assumed to occur in the small intestine alone. Examples are also given of the effects on doses of considering absorption from other regions and the effect of possible retention in the alimentary tract. This report also considers uncertainties in model assumptions and their effect on doses, including alimentary tract dimensions, transit times, radionuclide absorption values, and the location of targets for cancer induction.

Abstract  Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and mu CT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species specific anatomy and physiology for deposition.

Abstract  Olfactory receptor neuron (ORN) axon diameters and the conduction velocity of the compound action potential along ORN axons were studied in olfactory marker protein (OMP)-null mice and genotypically matched controls. The compound action potential was distinguished from postsynaptic field potentials by its shorter latency, its persistence following application of cobalt or kynurenic acid that blocked postsynaptic responses, and its ability to follow paired-pulse stimulation at 300 Hz. Blockade of the postsynaptic field responses by kynurenic acid indicates that in the mouse, as in the rat, glutamate is the olfactory nerve transmitter. The mean conduction velocity of ORNs in wild-type control mice was 0. 47+/-0.19 (S.E.M.) m/s (n=5), similar to the conduction velocity reported for other mammals. The mean diameter of ORN axons in control mice was 0.202+/-0.005 and 0.261+/-0.006 microm in the OMP-null mice. This increase in fiber diameter in the OMP-nulls predicts an increase in impulse conduction velocity. However, the mean conduction velocity of OMP-null mice, 0.38+/-0.03 m/s (n=6), was not significantly different from control (P>0.1). The conduction velocity predicted by the increase in fiber diameter in OMP-null mice was within the 95% confidence interval of the measured value. Thus, OMP-null ORNs are normal with respect to the conduction velocity of their axons. The number of axodendritic synapses in the glomeruli of OMP-null mice is higher than in congenic wild-type mice.

Abstract  The availability of molecular and genetic tools has made the mouse the most common animal model for a variety of human diseases in toxicology studies. However, little is known about the factors that will influence the dose delivery to murine lungs during an inhalation study. Among these factors are the respiratory tract anatomy, lung physiology, and clearance characteristics. Therefore, the objective of this paper is to briefly review the current knowledge on the aforementioned factors in mice and their implications to the dose delivered to mouse models during inhalation studies. Representative scientific publications were chosen from searches using the NCBI PubMed and ISI Web of Knowledge databases. Relevant respiratory physiological differences have been widely reported for different mouse strains and sexes. The limited data on anatomical morphometry that is available for the murine respiratory tract indicates significant differences between mouse strains. These differences have implications to the dose delivered and the biological outcomes of inhalation studies.