Abstract  A morphologic description of the airways of the guinea pig was developed from measurements of casts of the lungs and nasal cavity and from measurements of frozen sections of the lungs. The lengths, diameters, branching pattern, and numbers of elements of the respiratory tract formed the basis for a representative model of the system. The brainching pattern is irregular to the pulmonary region but regularly dichotomous thereafter. The nasopharyngeal-tracheobronchial region contributes 2.64 cm3 of the total respiratory volume of 21.62 cm3. The alveoli contribute 16.31 cm3 of the 18.98 cm3 pulmonary region. The nasal region consist of convoluted and irregular airways with a functional volume of 0.48 cm3.

Abstract  For highly water soluble and reactive gases, such as formaldehyde, the reported distribution of nasal lesions in rats and rhesus monkeys following inhalation exposure may be attributable, at least in part, to regional gas uptake patterns that are a consequence of nasal airflow characteristics. Inspiratory nasal airflow was studied at flow rates across the physiologic range using a unidirectional dynamically similar water-dye siphon system in clear acrylic molds of the nasal airways of F344 rats and rhesus monkeys. In both species there were complex inspiratory flow streams, exhibiting regions of simple laminar, complex secondary (vortices, eddies, swirling), and turbulent flows, with only minor effects of the volumetric flow rates studied on these flow patterns. There was a precise association between points of dye intake at the nostril with complex but generally coherent streaklines throughout the nose, indicating the potential for sensitive dependence of nasal airflow on nostril geometry. On the basis of these studies, a classification for the major airways (meatuses) in the nasal passages of rats and rhesus monkeys was proposed. The spiral shape of the anterior nasal airway of the rat was considered to play an important role in local mixing of inspired airstreams. In the rhesus monkey, the complex geometry of the nasal vestibule contributed to the formation of secondary flows and turbulence in the anterior nose, which represents a potentially important difference between rhesus monkeys and humans. There was a good correlation between routes of flow, regional secondary flows, turbulence, and impaction of airstreams on the airway wall, with the reported distribution of formaldehyde-induced nasal lesions in rats and rhesus monkeys. These studies support the proposal that nasal airflow patterns play an important role in the distribution of lesions induced by formaldehyde.

Abstract  Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO2 produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity (PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counter-balance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level (NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers (>20 Ám) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern - fast initial and slow final phase - it is essential that the slow phase of the retention kinetics of fibers longer than 20 Ám is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.

Abstract  Dose calculations for inhaled radon decay products presented in Part I (Ho79) have revealed that the doses to tracheobronchial and pulmonary compartments of the ICRP lung model are significantly dependent on age. From a consideration of the nonuniform dose distribution within the tracheobronchial region, doses are now calculated for the bronchial epithelium basal cells which are commonly regarded as the critical target for the induction of lung cancer. For the simulation of deposition and clearance mechanisms a refined mathematical model for postnatal growth of the human respiratory tract was developed on the basis of the Weibel model A. A reference atmosphere of 1 pCi/l for each nuclide with a mean respiratory minute volume, corresponding to a mean physical activity, was used to determine doses for the basal cells in different generations of the tracheobronchial tree as functions of age. The results obtained show again a strong dependence on age. In general a continuous decrease of dose with increasing age can be seen, with distinct differences between the various generations. If, however, the physical activity distribution and the ratio for the decay products as already defined in Part I are used, maximum dose values appear again in all generations at the age of about six years. Application of data on the relative risk of the induction of various malignancies versus age, taken from the BEIR report, results in even more pronounced dose maxima with a significantly higher radiation risk for children between birth and ten years of life of about one order of magnitude as compared to adults.

Abstract  The geometry and morphometry of intraacinar airways in rat and rabbit lungs were studied from silicone rubber casts. Acini, defined as the complex of alveolated airways distal to the "terminal" bronchiole, were trimmed off the bronchial tree. In both species, the acinar volume followed a log-normal distribution over a range in size of one order of magnitude. At an inflation level of 60% total lung capacity, their mean volume was 1.86 mm3 in the rat and 3.46 mm3 in the rabbit. On a representative sample of acini of different volumes, the branching pattern was characterized as irregular dichotomy, and the segment length and inner and outer diameters were measured. The average acinus had a mean of six generations in the rat and seven in the rabbit. Both showed a decrease in segment length and inner diameter with each generation. The mean longitudinal pathway length--that is, the distance from the initial acinar segment to the terminal sacs--was found to depend on the cube root of the acinar volume in both species. It was calculated at 1.46 and 1.95 mm for rat and rabbit, respectively.

Abstract  Silicone rubber casts were prepared of the nasal, pharyngeal and laryngeal regions of two rats, a rhesus monkey, and three beagle dogs and one for each species selected for detailed measurements. Cross-sections of the casts were made and the area and perimeter of each section measured using an image analyzing computer. Considerable anatomical differences were found between the species. Some of the differences, such as the sharp bend in the nasopharynx of the monkey, could be related to normal posture. One of the main differences was the greater complexity of the turbinate region of the dog as compared to the corresponding area of the monkey.

Abstract  Results from animal studies have indicated some uncertainties over the validity of a single general occupational control limit for all types of 'particulates (insoluble) not otherwise classified' (PNOC). Therefore, to examine the extent to which a given control limit may be valid for nontoxic dusts with different physical characteristics, this study compared the pulmonary effects in rats of inhalation exposure to two poorly soluble dusts of similar density and with relatively low toxicity: titanium dioxide and barium sulfate. The objectives were to compare the dusts in (a) their buildup and clearance in the lungs during inhalation; (b) their transfer to lymph nodes; (c) the changes, with time, in the lavageable cell population; and (d) the pathological change from histology. The exposure aerosol concentrations were selected to achieve similar mass and volume lung burdens for both dusts and to attain 'overload' over the common exposure periods of about 4 mo and 7 mo. Despite obtaining similar lung burdens for both dusts, there was significantly more translocation of TiO2 to the hilar lymph nodes than with BaSO4. It was also found that clearance of TiO2 was retarded whereas clearance of BaSO4 was not. Trends in these data were clarified by the use of a simple model of particle clearance. Retardation of particle clearance and translocation to the lymph nodes are markers of the condition known as 'overload' in which the alveolar macrophage-based clearance of particles from the deep lung is impaired. In addition, bronchoalveolar lavage showed that TiO2 caused significantly more recruitment of inflammatory neutrophils to lungs than BaSO4. These differences between the dusts were not due to differences in toxicity, solubility, or lung deposition. The explanation that the different responses are due to the different particle size distributions of the two dust types is examined in a companion paper (Tran et al., this issue).

Abstract  Inhalation exposure of humans to high concentrations of manganese (Mn) is associated with elevated Mn levels in the basal ganglia and an extrapyramidal movement disorder. In the rat, direct olfactory transport of Mn from the nose to the brain has been demonstrated following intranasal instillation of 54MnCl2. However, the contribution this route makes to brain Mn delivery following inhalation is unknown and was the subject of our study. Male 8-week old CD rats underwent a single 90-min nose-only exposure to a 54MnCl2 aerosol (0.54 mg Mn/m3; MMAD 2.51 Ám). The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 2, 4, and 8 days postexposure. Control rats were exposed to 54MnCl2 with both nostrils patent to evaluate the symmetry of Mn delivery. Another group of rats had the right nostril plugged to prevent nasal deposition of 54MnCl2 on the occluded side. Gamma spectrometry (n = 6 rats/group/time point) and autoradiography (n = 1 rat/group/time point) were used to compare the levels of 54Mn found on the left and right sides of the nose and brain to determine the contribution of olfactory uptake to brain 54Mn levels. Brain and nose samples from the side with the occluded nostril had negligible levels of 54Mn activity, validating the nasal occlusion procedure. High levels of 54Mn were observed in the olfactory bulb and tract/tubercle on the side or sides with an open nostril within 1-2 days following inhalation exposure. These results demonstrated, for the first time, that the olfactory route contributes the majority (up to >90%) of the 54Mn found in the olfactory pathway, but not in the striatum, of the rat brain up to 8 days following a single inhalation exposure. These findings suggest that the olfactory route may make a significant contribution to brain Mn levels following inhalation exposure in the rat.

Abstract  On 23-24 March 1998, the International Life Sciences Institute (ILSI) Risk Science Institute convened a workshop entitled "Relevance of the Rat Lung Response to Particle Overload for Human Risk Assessment." The workshop addressed the numerous study reports of lung tumors in rats resulting from chronic inhalation exposures to poorly soluble, non fibrous particles of low acute toxicity and not directly genotoxic. These poorly soluble particles, indicated by the acronym PSPs (e.g., carbon black, coal dust, diesel soot, nonasbestiform talc, and titanium dioxide), elicit tumors in rats when deposition overwhelms the clearance mechanisms of the lung resulting in a condition referred to as "overload." These PSPs have been shown not to induce tumors in mice and hamsters, and the available data in humans are consistently negative. The objectives were twofold: (1) to provide guidance for risk assessment on the interpretation of neoplastic and nonneoplastic responses of the rat lung to PSPs; and (2) to identify important data gaps in our understanding of the lung responses of rats and other species to PSPs. Utilizing the five critical reviews of relevant literature that follow herein and the combined expertise and experience of the 30 workshop participants, a number of questions were addressed. The consensus views of the workshop participants are presented in this report. Because it is still not known with certainty whether high lung burdens of PSPs can lead to lung cancer in humans via mechanisms similar to those of the rat, in the absence of mechanistic data to the contrary it must be assumed that the rat model can identify potential carcinogenic hazards to humans. Since the apparent responsiveness of the rat model at overload is dependent on coexistent chronic active inflammation and cell proliferation, at lower lung doses where chronic active inflammation and cell proliferation are not present, no lung cancer hazard is anticipated.

Abstract  There are many ways in which the dose can be expressed in inhalation toxicology studies. This can lead to confusion when comparing results from studies performed in different laboratories. A working party of the Association of Inhalation Toxicologists has reviewed this subject in detail and has collected data from 10 inhalation laboratories and used these data to determine a new algorithm for the calculation of Respiratory Minute Volume (RMV), one of the most important factors in the calculation of delivered dose. The recommendations of the working party for regulatory inhalation toxicology studies with pharmaceuticals are as follows: 1. The dose should be reported as the delivered dose calculated according to the formula: DD=C x RMV x D(xIF)/BW where DD = delivered dose (mg/Kg); C = concentration of substance in air (mg/L); RMV = respiratory minute volume or the volume of air inhaled in one minute (L/min); D = duration of exposure (min); IF = proportion by weight of particles that are inhalable by the test species, the inhalable fraction (inclusion of this parameter is not essential provided that the aerosol has reasonable respirability for the intended species. If it is included, the way in which it is determined should be clearly stated); BW = bodyweight (Kg). 2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to the formula: RMV(L/min) = 0.608 x BW(Kg)(0.852) 3. If deposited dose or the amount of material actually retained in the respiratory tract is presented as supplementary information, the way in which it is calculated should be clearly stated. 4. Dose should always be presented in mg/Kg but may also be presented in other ways, such as mg/unit body surface area, as supplementary information.

Abstract  Theoretical impaction and sedimentation deposition of fibers in a model airway have been obtained based upon Jeffery's theory of particle motion. The corresponding expressions for the equivalent diameter of fibers have also been derived. The results are compared with experimental data and other formulas available in the literature for glass fibers. It is shown that for the flow condition existing in the airways, the equivalent diameters of fibers for both impaction and sedimentation are very close to the values obtained when the fibers are oriented parallel to the flow.

Abstract  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. EPA's 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 children's anatomy and physiology. These modeling efforts identify child-adult dosimetry differences in respiratory tract regions that may have implications for children's 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.

Abstract  The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop in Barcelona, Spain, in November 2005 to develop testing strategies to establish the safety of nanomaterials. It brought together about 70 scientific and clinical experts from industry, academia, government agencies, research institutes, and nongovernmental organizations. The primary questions to be addressed were the following: What can we do today, and what do we need tomorrow? The three major themes of the workshop were: (1) the need for enhanced efforts in nanomaterial characterization; (2) methodologies for assessments of airborne and internal exposures to nanomaterials; and (3) evaluation of the hazard potential - primarily focusing on pulmonary or dermal routes of exposures. Some of the summary conclusions of the workshop included the following: For the development of nanoparticle characterization, the working definition of nanoparticles was defined as < 100 nm in one dimension or < 1000 nm to include aggregates and agglomerates. Moreover, it was concluded that although many physical factors can influence toxicity, including nanoparticle composition, it is dissolution, surface area and characteristics, size, size distribution, and shape that largely determine the functional, toxicological and environmental impact of nanomaterials. In addition, most of the information on potential systemic effects has thus far been derived from combustion-generated particles. With respect to the assessment of external exposures and metrics appropriate for nanoparticles, the general view of the meeting was that currently it is not possible or desirable to select one form of dose metric (i.e., mass, surface area, or particle number) as the most appropriate measure source. However, it was clear that the surface area metric was likely to be of interest and requires further development. In addition, there is a clear and immediate need to develop instruments which are smaller, more portable, and less expensive than the currently available state of the art instrumentation. With regard to a general testing approach for human health hazard evaluation of nanoparticles, a first step to determine potency may include a prioritization-related in vitro screening strategy to assess the possible reactivity, biomarkers of inflammation and cellular uptake of nanoparticles; however this process should be validated using in vivo techniques. A Tier 1 in vivo testing strategy could include a short-term inhalation or intratracheal instillation of nanoparticles as the route of exposure in the lungs of rats or mice. The endpoints that should be assessed include indices of lung inflammation, cytotoxicity, and cell proliferation, as well as histopathology of the respiratory tract and the major extrapulmonary organs. For Tier 2 in vivo testing for hazard identification, a longer term inhalation study is recommended, and this would include more substantive mechanistic endpoints such as determination of particle deposition, translocation, and disposition within the body. Additional studies could be designed with specific animal models to mimic sensitive populations. With regard to dermal exposures, currently there is little evidence that nanoparticles at a size exceeding 100 nm penetrate through the skin barrier into the living tissue (i.e., dermal compartment). The penetration of nanoparticles at a size less than 100 nm should be a topic of further investigation. Moreover, considering the impacts of dermal exposures and corresponding hazard potential of nanoparticles, it must be taken into consideration that the dermal uptake of nanoparticles will be an order of magnitude smaller than the uptake via the inhalation or oral routes of exposure. For the evaluation of the health risk of nanoparticles, it has to be determined whether they are harmful to living cells and whether, under real conditions, they penetrate through the skin barrier into the living tissue. For the evaluat

Abstract  Particulate matter dosimetry provides the critical link between exposures and initial doses reaching various sites in the respiratory tract. To extrapolate findings from animal models to humans, quantitative respiratory-tract anatomical data dosimetry in these animal models is required. The goal of this study was to provide anatomical information for the tracheobronchial and pulmonary region so predictions of particle deposition could be performed for a widely used model of asthma; the sensitized Balb/c mouse. Tracheobronchial airway morphometry of sensitized male Balb/c mice was generated from three in situ prepared lung casts. Distribution of the number of generations to terminal bronchiole for each lung lobe was determined by assigning a unique binary number to each airway. This strategy enabled the median path length to terminal bronchiole to be determined. A total of 25 median length paths to terminal bronchiole were measured (airway length, diameter, and branch angle) in each lung cast. These 25 paths were proportionately distributed among the six lobes based upon the number of median length pathways in each cast. Airway length, diameter, and branch angle were measured for each airway in the 25 median length pathways. Measurements of airway length, diameter, and branch angle for each generation were averaged to create a typical path tracheobronchial anatomy model. A pulmonary airway model was also developed so that particle deposition predictions could be performed for particle diameters of 0.2-10 micrometers. Particle deposition efficiency predictions were consistent with in vivo measured deposition.

Abstract  Accurate quantification of the dose delivered by aerosol exposures is essential for estimating the risk of potential adverse health effects. The fraction of airborne particles that can enter the nose or mouth during inhalation is referred to as the inspirable particulate mass fraction. This inhalable fraction is equivalent to delivered dose for particles greater than approximately 25 mu m (aerodynamic particle diameter, d(ae)), which deposit completely and almost exclusively in the extrathoracic airways. Particle inhalability at high wind speeds (1-9 m/s) has been well characterized. However, there is a paucity of data describing the inhalability of particles at low wind speeds (<= 0.3 m/s), which are typical of indoor environments. High-wind-speed criteria poorly describe inhalability at low wind speeds. Based on the aspiration efficiencies of blunt and sharp-edged inlets, a function was developed for oral inhalability, P(I-O), of particles at low wind speeds. This function predicts a slow decline in P(I-O) from 0.95 at d(ae) = 8 mu m, to 0.5 at d(ae) = 74 mu m, and 0.1 at d(ae) = 175 mu m. Data available from the literature for inhalability at relatively low wind speeds during oral breathing are well described by this logistic function (r(2) = 0.69).

Abstract  Nasal efficiency for removing fine particles from inhaled air may be affected by variations in nasal structure associated with race. In 11 African American and 11 Caucasian adults (age 18-31 yr) we measured the fractionaldeposition (DF) of fine particles (1 and 2 μm mass median aerodynamic diameter) (MMAD) for oral and nasal breathing using individual breathing patterns previously measured by respiratory inductance plethysmography during a graded exercise protocol. DF for both nasal and mouth breathing was measured separately by laser photometry at the same tidal volume and breathing rate for resting and light exercise (20% of maximum work load) conditions. From these DF measures, nasal deposition efficiency (NDE) was calculated for each condition. For light exercise conditions, NDE for both 1- and 2-μm particles was less in African Americans versus Caucasians, 0.15 ′ 0.07 (SD) versus 0.24 ′ 0.11 for 1-μm particles (p =.03), and 0.29 ′ 0.13 versus 0.44 ′ 0.11 for 2-μm particles (p = .006). The racial differences in NDE were associated with racial differences in nasal resistance and nostril shape. These race-dependent nasal efficiencies are dosimetric factors that should be considered in modeling and assessing particulate dose from human exposure to air pollutants.

Abstract  The first step in mathematically modeling the mechanics of respiratory deposition of particles is to estimate the ability of a particle to enter the head, either through the mouth or nose. Models of the biological effects from inhaled particles are commonly, albeit incorrectly, simplified by making an assumption that the only particles of concern are those that can readily penetrate to the pulmonary region of the lung: typically particles less than 5microm in aerodynamic diameter. Inhalability for particles of this size is effectively 100%, so there is little need to develop a mathematical representation of the phenomenon. However, chemical irritants, biological agents, or radioactive material, in the form of large particles or droplets, can cause adverse biological responses by simply being taken into the head and depositing in the extrathoracic area. As a result, it is important to understand the inhalability of both small and large particles. The concept of particle inhalability received little consideration until the 1970s; since then it has been the subject of many experiments with a fairly wide disparity of results, in part due to the variety of dependent variables and the difficulty in adequate measurement methods. This article describes the currently utilized models of inhalability, recommends specific methods for implementing inhalability into mathematical models of respiratory deposition, and identifies outstanding issues and limitations. In this article, we describe inhalability as it applies to particulate matter and liquid droplets; modeling the inhalability of fibers is a work in progress and is not addressed.

Abstract  Because of limitations on conducting exposure experiments using human subjects to evaluate adverse health effects, the deposition and fate of airborne particles in animals are often studied. The results of such studies are extrapolated to humans to estimate equivalent dose and subsequent response. In this article, particle inhalability and respiratory deposition of micron-size particles are determined for female Long-Evans rats. Monodisperse aerosols were generated from a solution of radiolabeled iron chloride (59FeCl3). Long-Evans rats were exposed to the radiolabeled particles in a Cannon nose-only exposure tower to determine head, lung lobar, and total lung deposition fractions. Particle deposition fractions in a hypothetical situation, when all particles are inhalable, were found from an experimentally validated deposition model. Particle inhalability in a Cannon nose-only exposure scenario was obtained by comparing the measured deposition fractions with the predicted values for the case of 100% inhalability. Particle deposition fraction and inhalability were compared with data available in the literature. For large particles, the measured deposition fraction was lower than the literature values. Consequently, our inhalability estimates were found to be lower than previously published values. The findings here will directly affect health risk assessments in humans from exposure to airborne particles. The deposition results will improve the database on particle deposition in the lung airways of rats, and inhalability information will improve the accuracy of rat-to-human data extrapolation.

Abstract  Health risks of inhaled nasal toxicants were reviewed with emphasis on chemically induced nasal lesions in humans, sensory irritation, olfactory and trigeminal nerve toxicity, nasal immunopathology and carcinogenesis, nasal responses to chemical mixtures, in vitro models, and nasal dosimetry- and metabolism-based extrapolation of nasal data in animals to humans. Conspicuous findings in humans are the effects of outdoor air pollution on the nasal mucosa, and tobacco smoking as a risk factor for sinonasal squamous cell carcinoma. Objective methods in humans to discriminate between sensory irritation and olfactory stimulation and between adaptation and habituation have been introduced successfully, providing more relevant information than sensory irritation studies in animals. Against the background of chemoperception as a dominant window of the brain on the outside world, nasal neurotoxicology is rapidly developing, focusing on olfactory and trigeminal nerve toxicity. Better insight in the processes underlying neurogenic inflammation may increase our knowledge of the causes of the various chemical sensitivity syndromes. Nasal immunotoxicology is extremely complex, which is mainly due to the pivotal role of nasal lymphoid tissue in the defense of the middle ear, eye, and oral cavity against antigenic substances, and the important function of the nasal passages in brain drainage in rats. The crucial role of tissue damage and reactive epithelial hyperproliferation in nasal carcinogenesis has become overwhelmingly clear as demonstrated by the recently developed biologically based model for predicting formaldehyde nasal cancer risk in humans. The evidence of carcinogenicity of inhaled complex mixtures in experimental animals is very limited, while there is ample evidence that occupational exposure to mixtures such as wood, leather, or textile dust or chromium- and nickel-containing materials is associated with increased risk of nasal cancer. It is remarkable that these mixtures are aerosols, suggesting that their "particulate nature" may be a major factor in their potential to induce nasal cancer. Studies in rats have been conducted with defined mixtures of nasal irritants such as aldehydes, using a model for competitive agonism to predict the outcome of such mixed exposures. When exposure levels in a mixture of nasal cytotoxicants were equal to or below the "No-Observed-Adverse-Effect-Levels" (NOAELs) of the individual chemicals, neither additivity nor potentiation was found, indicating that the NOAEL of the "most risky chemical" in the mixture would also be the NOAEL of the mixture. In vitro models are increasingly being used to study mechanisms of nasal toxicity. However, considering the complexity of the nasal cavity and the many factors that contribute to nasal toxicity, it is unlikely that in vitro experiments ever will be substitutes for in vivo inhalation studies. It is widely recognized that a strategic approach should be available for the interpretation of nasal effects in experimental animals with regard to potential human health risk. Mapping of nasal lesions combined with airflow-driven dosimetry and knowledge about local metabolism is a solid basis for extrapolation of animal data to humans. However, more research is needed to better understand factors that determine the susceptibility of human and animal tissues to nasal toxicants, in particular nasal carcinogens.

Abstract  The nasal mucosa protects the delicate lower respiratory tract by warming, moistening and cleaning inspired air. The nose also contains the receptors for olfaction and is an important target site for inhaled toxic materials. For use in future dosimetry studies of inhaled gases, morphometric analysis of the primate nasal cavity has been undertaken to determine total nasal cavity surface area and volume of the Rhesus monkey and to quantify the surface areas of squamous, respiratory and olfactory epithelia. Measurements were made on 20, 4μ thick, plastic, step cross-sections (3.89 mm apart) through the nasal cavity and naso-pharynx of an adult male Rhesus monkey. Surface area and airway volume measurements of the nasal passage and maxillary sinus were determined using a Videoplan image analyzer. Data points were collected every .05 mm around the perimeter of each section. The nasal cavity surface area was 81.97 cm2 and the volume was 8.25 cm3. The surface area and volume of the maxillary sinus were 10.67 cm2 and 1.92 cm3 respectively. The information provided by this study, once coupled with data from more animals, will provide useful baseline values for ongoing regional dosimetry studies of inhaled formaldehyde in monkeys.