Abstract  This document describes the U .S . Environmental Protection Agency (EPA) methodology for estimation of inhalation reference concentrations (RfCs) (earlier terminology was inhalation reference dose or RfDi) as benchmark estimates of the quantitative doseresponse assessment of chronic noncancer toxicity for individual inhaled chemicals. Noncancer toxicity refers to adverse health effects other than cancer and gene mutations. This overview chapter discusses general principles of dose-response assessment for noncancer toxicity, the development of the RfC methodology, and its role within the context of the risk assessment process. Subsequent chapters of the document discuss criteria and information to be considered in selecting key studies for RfC derivation, provide an overview of the respiratory system and its intra- and interspecies variables, and discuss areas of uncertainty and data gaps in relation to the proposed methodology.

Abstract  The aspiration of large particles (18–30.5 μm) in the human nose was studied to determine the inhalation efficiency as a function of particle size, and to evaluate the upper size cutoff for inhalable particles in still air. Under these conditions, the ability of a particle to be inhaled is dependent on the inhalation velocity entering the nose and the particle terminal settling velocity. Nasal inhalation of radiolabeled pollen and wood dust aerosols was measured in four subjects at normal resting breathing rates. The efficiency of nasal aspiration was found to decrease as the square of the particle size. The upper size cutoff for inhalability was estimated to be approximately 39 μm in still air.

Abstract  The fractional deposition of inhaled particles during spontaneous breathing is an important parameter in defining lung dose of inhaled particles for occupational and clinical exposures. Yet few investigators have studied particle deposition under spontaneous breathing conditions. Variability in spontaneous breathing deposition fraction (DF) may play a role in the variability of lung response to inhaled particles. This review attempts to address the degree of variability in spontaneous breathing DF measured in normal human subjects at rest, but more specifically attempts to address the causes of this variability. There are primarily two factors which likely contribute to variability in spontaneous DF, breathing pattern and the size of the airspaces. Included is a review of these factors only as they relate to spontaneous DF of particles depositing primarily in the periphery of the lung. This author concludes that present evidence, as set forth in this review, suggests that breathing pattern variability in humans is greater than variability in peripheral airspace size, and as a result plays a greater role in the variability observed in spontaneous breathing DF.

Abstract  Radon and thoron progeny are ultrafine particles in the size range of 1-200 nm, depending on whether or not they are attached to other aerosol particles. The diffusion coefficient of radon progeny is a critical parameter in determining its dynamics while airborne. Depending on their diffusion coefficient and the breathing pattern of the subject, ultrafine particles have been shown to deposit in the nasal or oral airways. Substantial deposition in the head airways reduces the amount of radioactivity that deposits in the tracheobronchial tree. Thus, for accurate dosimetric calculations, it is important to know the deposition fraction of radon progeny in the head airways. Several adult head airway models were used to study the radon progeny deposition in human nasal and oral airways. Radon-220 progeny (Pb-212) were used in the study. The particle size as measured by a graded screen diffusion battery was between 1.2 and 1.7 nm, indicating that the particles were molecular clusters. Deposition was measured by collecting filter samples before and after the model and gamma counting the Pb-212. Experiments were performed under the constant flow rates of 4-20 L/min. Deposition efficiences were between 63% and 85% in the nasal airway and 48% and 78% in the oral airway. Previously reported deposition data in the same airway model for ultrafine particles between 4.6 and 200 nm and the deposition data of radon progeny were used to establish a turbulent deposition equation covering particle sizes from 1 to 200 nm, the entire size range for attached and unattached radon progeny.

Abstract  This report describes a revision of the model used in ICRP Publication 30 to calculate radiation doses to the respiratory tract of workers resulting from the intake of airborne radionuclides. This revision was motivated by the availability of increased knowledge of the anatomy and physiology of the respiratory tract and of the deposition, clearance, and biological effects of inhaled radioactive particles, and by greatly expanded dosimetry requirements. To meet fully the needs of radiation protection, a dosimetric model for the respiratory tract should: - provide calculations of doses for individual members of the populations of all ethnic groups, in addition to workers; - be useful for predictive and assessment purposes as well as for deriving limits on intakes; - account for the influence of smoking, air pollutants, and respiratory tract diseases; - provide for estimates of respiratory tract tissue doses from bioassay data; and - be equally applicable to radioactive gases as well as to particles. Addressing all of these requirements has resulted in a dosimetry model that is more complex than previous models.

Abstract  THE interest of those concerned in any way with the provision of protection against inhalation hazards, especially those associated with work with radioactive materials, has been stimulated by the publication of the report of the Task Group on Lung Dynamics for Committee II of the International Commission on Radiological Protection1. Investigations in the Health Physics and Medical Division at AERE, Harwell, into the behaviour of inhaled radioactive aerosol particles in the human respiratory tract have started—with the cooperation of three volunteer subjects—with a study of deposition in the nasopharyngeal compartment. The experiments followed the somewhat artificial procedure of earlier investigators and aerosols were drawn through the nose and mouth at flow rates of 5, 10, 20, 30 and 40 l./min while the subject held his breath.

Abstract  A model for the evaluation of particle deposition in the human respiratory tract is described which considers the respiratory tract as a series of aerosol filters (Rudoll; 1983}. Each filter is associated with a functional region of the respiratory tract. When depositions in these regions are known, the model allows the evaluation of the efficiencies of these regions to collect inspired particles. It also allows an insight into mechanisms by which particles are deposited, into airway physiology and into local distributions of inspired particles.

Abstract  Total particle deposition in the respiratory tract of 20 subjects was experimentally determined for both controlled and spontaneous steady mouth-breathing of uncharged monodisperse aerosols in the diameter range 0.5 to 7.5 µm. A small intrasubject but a large intersubject variability of deposition was found. For spontaneous breathing the intersubject variability of deposition is determined by morphological factors but the intersubject variability of deposition rate by physiological factors.

Abstract  Techniques utilizing the inhalation and deposition of radioactive particles followed by gamma-camera imaging were applied to the problem of differentiating mucociliary function at various generations of the tracheobronchial tree in man. Quantitative values for linear velocities of mucus movement in the trachea and large bronchi could be compared with whole or peripheral (small bronchi) lung clearance rates. Mucus velocity in main bronchi averaged 2.4 mm/min and correlated (r = 0.81) with tracheal mucus velocity, which averaged 5.5 mm/min. Subjects removed an average of 68% of their total deposition during the initial 24 h after inhalation; particles cleared the ciliated airways at a mean rate of 0.51%/min . ./l-Adrenergic (/3-AD) aerosols enhanced mucociliary function by increasing both central airway mucus transport (bronchial and tracheal velocities were raised 156 and 37%, respectively) and peripheral lung clearance (by at least 40%). Whole lung clearance correlated better with main bronchial velocities (r = 0.71) than did peripheral lung clearance (r = 0.27). These data indicate that J) the ratio of tracheal to bronchial mucus velocities in the normal lung equals 2.7; 2) tracheal mucus velocities are normally close to the maximum that could be stimulated by /3-AD, and main bronchi have velocities of only 40% of maximum; and 3) peripheral ciliated airways increase mucus clearance after fl-AD and contribute to the overall effect of /3-AD on whole lung clearance.

Abstract  Inhaled insoluble particles that deposit along normal healthy tracheobronchial airways of humans and other mammals are transported on the proximally moving mucous lining to the larynx, where they are swallowed. The transit time from the most distal ciliated airways varies from 0.1 to 1 d, with each individual having a relatively constant, characteristic time. The exact time course of clearance depends on the distributions of both particle deposition and mucus velocities along the airways. There are too few data on intrabronchial deposition and mucociliary transport rates for laboratory animals to permit a thorough intercomparison among species. However, enough is known about the relative lung sizes and anatomical differences among the various species to make some preliminary, but important, distinctions. As compared to commonly used experimental animals, humans have larger lungs and a more symmetric upper bronchial airway branching pattern. In addition, humans do considerable oral breathing, thus bypassing the effective air cleaning capability of the nasal airways. These differences contribute to a greater amount of upper bronchial airway particle deposition in humans, as well as to greater concentrations of deposition on localized surfaces near airway bifurcations. Airborne irritants that deposit in small ciliated airways may produce marked changes in mucociliary transport. Such materials include cigarette smoke, submicrometer-sized sulfuric acid mist, nitrogen dioxide, and ozone. For cigarette smoke and sulfuric acid, which have been studied for transient effects following single brief exposures in both humans and animals, the responses are similar. Upon repetitive exposures in animals, both of these irritants produce persistant alterations in clearance rates and airway morphometry. Studies of the effects of ozone on mucociliary clearance have, up to now, been limited to tests of the responses of rats to single exposures. The similarities between the known effects of various irritants suggests a nonspecific response.

Abstract  Atmospheric sulfate aerosols [H2SO4, (NH4)2SO4, and NH4HSO4] are of international concern because of their global prevalence and potential irritant or toxic effects on humans. To assess hazards following inhalation exposure, the total dose delivered to the human respiratory tract and its regional distribution must be determined. The mass median aerodynamic diameter of the inhaled aerosol will influence the sites of deposition in the respiratory tract. Atmospheric sulfate aerosols are hygroscopic and will have changing particle sizes and densities as they absorb water vapor in the humid environment of the human respiratory tract. Experimental and theoretical data that describe particle size as a function of temperature and relative humidity were used in computer subroutines of an aerosol deposition model in order to calculate the dose dispersion of H2SO4, (NH4)2SO4, and NH4HSO4 aerosols in man. Different temperature and relative humidity environments that approximately correspond to nasal and oral breathing were studied. The predicted deposition patterns are very different from those of nonhygroscopic aerosols with identical inhaled mass median aerodynamic diameter values.

Abstract  The deposition of ultrafine particles in the human respiratory system was studied under a variety of steady breathing conditions. The monodisperse aerosols tested were hydrophobic kerosene heater, aluminosilicate, and hygroscopic NaCl in the size range of 0.03 to 0.4 microm in diameter. The results for all aerosols show that particle deposition increases with an increase in tidal volume, but with a decrease in breathing frequency. Also, deposition during breath holding increases nearly exponentially with an increase in time. However, particle deposition as a function of particle size is different between hydrophobic and hygroscopic aerosols in the size range tested. The hydrophobic aerosols increase with a decrease in particle size, while hygroscopic aerosols show minimum value in the size range of 0.06 to 0.09 microm. The hydrophobic kerosene heater and aluminosilicate particle deposition confirms the recent theoretical calculations of Yeh and Schum (1980), Yu and Diu (1982), and Yu and Hu (1983). The NaCl particles show a 3.5 to 4.5 fold growth under conditions approximating the respiratory tract.

Abstract  This paper briefly reviews the available evidence on dust overloading of the lungs. a condition which has come to the forefront in many recently reported chronic inhalation studies. A general hypothesis is developed that dust overloading, which is typified by a progressive reduction of particle clearance from the deep lung, reflects a breakdown in alveolar macrophage (AM)-mediated dust removal due to the loss of AM mobility. The inability of the dust-laden AMs to translocate to the mucociliary escalator is correlated to an average composite particle volume per alveolar macrophage in the lung, When this particulate volume exceeds approximately 60 Ám3/AM, on the basis of a uniform distribution of particles over the AM pool size (-2.5 X 10(7) cells) in the Fischer 344 rat, the overload effect appears to be initiated. When the distributed particulate volume exceeds -600 Ám3 per cell, the evidence suggests that AM-mediated particle clearance virtually ceases and agglomerated particle-laden macrophages remain in the alveolar region. This paper considers possible mechanisms why these particle-laden cells are immobilized, viz., one is based on excessive particle-cell, cell-cell chemotactic interactions, and migratory inhibition factors; the other considers the volumetric increase by phagocytized particles, per se, as leading to an inability of the AM to spread and migrate probably through a competitive requirement for surface membrane and cytoskeleton in both endocytotic and migratory functions.

Abstract  A chronic inhalation study of a test toner was conducted by exposure of groups of F-344 rats for 6 hr/day, 5 days/week for 24 months The test toner was a special Xerox 9000 type xerographic toner, enriched in respirable-sized particles compared to commercial toner, such that it was about 35% respirable according to the ACGlH criteria. The target test aerosol exposure concentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high) mg/m3. Titamum dioxide (5 mg/m3) and crystalline silicon dioxide (1 mg/m3), used as negative and pasitive controls for fibrogenicity, were also evaluated. Inhalation of the test toner or the control materials showed no signs of overt toxicity. Body weight, clinical chemistry values, food consumption, and organ weights were normal in the toner- and TiO2-exposed groups, except for a 40% increase in lung weight in the toner highexposure group. All of the changes in the toner-exposed groups were restricted to the lungs or associated lymph nodes. A chronic inflammatory response was evident from the bronchoalveolar lavage parameters for the toner high-exposure group. The incidence of primary lung tumors was comparable among the three toner-exposed groups and the TiO2-exposed, and air-only controls, as well as consistent with historical background levels A mild to moderate degree of lung fibrosis was observed in 92% of the rats in the toner high-exposure group, and a minimal to mild degree of fibrosis was noted in 22% of the animals in the toner high-exposure group. The pulmonary changes in the toner high-exposure group were smaller in magnitude than those found in the crystalline silica-exposed group. The comparative fibrogenic potency of TiO2, toner, and SiO2 was estimated to be 1:5:418 using a dasimetric model and assuming a common mechanistic basis. There were no pulmonary changes of any type at the toncr low-exposure level, which is most relevant in regard to potential human exposures The lung alterations in the toner high-exposure group are interpreted in terms of "lung overloading," a generic response of the respiratory system to saturation of its detoxification capacity. The maximum tolerated dose (MTD) criterion was met at the toner high (16 mg/m3)-exposure level.

Abstract  Theoretical calculations are made on total and regional deposition of inhaled particles in the human respiratory system based upon various current lung models. It is found that although total deposition does not vary appreciably from model to model, considerably large differences are present in regional deposition. Deposition profiles along the airways from different models also show very different patterns. These differences can be explained in terms of airway dimensions and the number of structures in different models. Extension to explain intersubject variability is also made.

Abstract  Allometric studies have shown that lung volume, alveolar surface area, and diffusing capacity increase proportionally with body weight across a broad range of mammalian species. Changes in the number of cells and in average cell size and surface areas with increasing body weight have not been defined. We speculated that cell size is determined more by cell function than by species and body weight. To test this hypothesis, nine species ranging in size from shrew (2 to 3 g) to horse (510 kg) were studied. Random sites from the distal alveolar region of each species were analyzed using morphometric techniques. Six to 10 nuclei from each of the major classes of parenchymal lung cells were three-dimensionally reconstructed to determine their average diameter, volume, and surface area. To calculate the cell density, nuclear profiles were counted using electron microscopy. The number of cells per lung increased with body mass and lung volume with a slope of 1.01 (r2 = 0.99). The lung is unique among organs in the diversity and function of individual cell types, such as mechanical, sensory, secretory, transporting, and circulating cells. Excluding the circulatory cells, the lung has greater than 60 different cell types, making it an ideal organ for examining the varieties in cell characteristics across different species. Up to 6-fold differences in size were found between different lung cell types within a single species; however, for cells having secretory functions, such as type II cells, there was no detectable change in cell size with increasing lung surface area or body mass. In general, a larger alveolar surface area is constructed with more, not necessarily larger, cells. The average alveolus in the inflation-fixed lungs of the rats we studied had a surface area of 20,800 pm2 and was covered by only four type I and six type II cells. In contrast, the average human alveolus had a surface area of 206,900 m2 and was covered by 40 type I and 67 type II cells. These data support the hypothesis that cell size and surface area are determined by cell function and not by species size.

Abstract  An ongoing objective of ICRP is to evaluate dose coefficients (doses per unit intake) for members of the public. The purpose of ICRP Publication 71 is to provide updated inhalation dose coefficients for selected radioisotopes of hydrogen, carbon, sulphur, calcium, iron, cobalt, nickel, zinc, selenium, strontium, zirconium, niobium, molybdenum, technetium, ruthenium, silver, antimony, tellurium, iodine, caesium, barium, cerium, lead, polonium, radium, thorium, uranium, neptunium, plutonium, americium and curium. Age dependent biokinetic models for calcium, curium and for decay products formed following the intake of lead, radium, tellurium, thorium and uranium are provided in annexes.

Abstract  Experiments have been made to measure the deposition of radioactive monodisperse polystyrene particles of size between 1 and 10 μm dia. aspirated through the nose and mouth at known flow-rates. The arrangements permitted the pressure difference across the nose and mouth to be determined as deposition occurred. When, for particles of the same size, deposition is plotted against flow-rate there is considerable scatter in the results. A much closer relationship is found with the pressure difference.

Abstract  The mission of National Center for Environmental Assessment (NCEA) of EPA's Office of Research and Development is to provide guidance and risk assessments aimed at protecting human health and the environment. To accomplish this mission, NCEA works to develop and improve the models, databases, tools, assumptions, and extrapolations used in risk assessments. This handbook is a tool developed by NCEA aimed at refining the assumptions used in exposure assessments and reducing uncertainty. This handbook was first published in 1989 and later updated in 1997 to provide statistical data on the various human factors used in assessing exposure. This revised edition of the handbook provides the most up-to-date data on these exposure factors. The recommended values are based solely on our interpretations of the available data. In many situations different values may be appropriate to use in consideration of policy, precedent or other factors. The Exposure Factors Handbook provides a summary of the available statistical data on various factors used in assessing human exposure. This Handbook is addressed to exposure assessors inside the Agency as well as outside, who need to obtain data on standard factors to calculate human exposure to environmental agents. These factors include: drinking water consumption, soil ingestion, inhalation rates, dermal factors including skin area and soil adherence factors, consumption of fruits and vegetables, fish, meats, dairy products, homegrown foods, human milk intake, human activity factors, consumer product use, and building characteristics. Recommended values are for the general population and also for various segments of the population who may have characteristics different from the general population. NCEA has strived to include full discussions of the issues that assessors should consider in deciding how to use these data and recommendations.

Abstract  Nickel oxide (NiO) "sinters" are used in stainless steel and alloy steel production. Nickel oxide was nominated by the National Cancer Institute to the NTP for testing because exposure to this form of nickel is prevalent in the nickel industry. Increased incidences of lung and nasal sinus cancers have occurred among workers in certain nickel refining facilities, and nickel oxide was studied as part of a class study of nickel compounds. Male and female F344/N rats and B6C3F1 mice were exposed to nickel oxide (high temperature, green nickel oxide; mass median diameter 2.2 ± 2.6 mm; at least 99% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in peripheral blood of B6C3F1 mice exposed to nickel oxide for 13 weeks. Sixteen-day study in rats Groups of five male and five female F344/N rats were exposed to 0, 1.2, 2.5, 5, 10, or 30 mg nickel oxide/m3 (equivalent to 0, 0.9, 2.0, 3.9, 7.9, or 23.6 mg nickel/m3) by inhalation for 6 hours per day, 5 days per week for a total of 12 exposure days during a 16-day period. Additional groups of five male and five female rats were exposed to 0, 1.2, 5, or 10 mg/m3 for tissue burden studies. All core study rats survived until the end of the study, final mean body weights of exposed male and female rats were similar to those of the controls, and there were no clinical findings related to nickel oxide exposure. Absolute and relative lung weights of male and female rats exposed to 10 or 30 mg/m3 were significantly greater than those of the controls. Pigment particles in alveolar macrophages or within the alveolar spaces were observed in the lungs of exposed groups of males and females. Chronic-active inflammation and accumulation of macrophages in alveolar spaces of the lungs and hyperplasia in the respiratory tract lymph nodes were most severe in 10 and 30 mg/m3 males and females. Hyperplasia of bronchial lymph nodes occurred in 30 mg/m3 rats. Atrophy of the olfactory epithelium was observed in one male and one female exposed to 30 mg/m3. The concentrations of nickel oxide in the lungs of exposed groups of rats were greater than those in the lungs of control groups (males, 42 to 267 mg nickel/g lung; females, 54 to 340 mg/g lung). Sixteen-day study in mice Groups of five male and five female B6C3F1 mice were exposed to 0, 1.2, 2.5, 5, 10, or 30 mg nickel oxide/m3 by inhalation for 6 hours per day, 5 days per week for a total of 12 exposure days during a 16-day period. Additional groups of five male and five female mice were exposed to 0, 1.2, 2.5, or 5 mg/m3 for tissue burden studies. No exposure-related deaths occurred among core study mice, and final mean body weights of exposed male and female mice were similar to those of the controls. There were no chemical-related clinical findings. Pigment particles were present in the lungs of mice exposed to 2.5 mg/m3 or greater. Accumulation of macrophages in alveolar spaces was observed in the lungs of 10 and 30 mg/m3males and females. The concentrations of nickel oxide in the lungs of exposed groups of mice were significantly greater than those in the lungs of control animals (males, 32 to 84 mg nickel/g lung; females, 31 to 71 mg/g lung). Thirteen-week study in rats Groups of 10 male and 10 female F344/N rats were exposed to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, 3.9, or 7.9 mg nickel/m3) by inhalation for 6 hours per day, 5 days per week for 13 weeks. Additional groups of 18 male and 18 female rats were exposed to 0, 0.6, 2.5, or 10 mg/m3 for tissue burden studies. No exposure-related deaths occurred among core study rats, final mean body weights of exposed male and female rats were similar to those of the controls, and no clinical findings in any group were related to nickel oxide exposure. Lymphocyte, neutrophil, monocyte, and erythrocyte counts; hematocrit values; and hemoglobin and mean cell hemoglobin concentrations in exposed rats were minimally to mildly greater than those of the controls; these differences were most pronounced in females. Mean cell volumes in exposed rats were generally less than those in the controls. Absolute and relative lung weights of exposed groups of males and females were generally significantly greater than those of controls. Chemical-related nonneoplastic lesions were observed in the lungs of male and female rats exposed to concentrations of 2.5 mg/m3 or higher, and the severity of these lesions generally increased with exposure concentration. Accumulation of alveolar macrophages, many of which contained black, granular pigment, was generally observed in all exposed groups of males and females, and increased incidences of inflammation occurred in males and females exposed to 2.5 mg/m3 or higher. In addition, lymphoid hyperplasia and pigment occurred in the bronchial and mediastinal lymph nodes of 2.5, 5, and 10 mg/m3 males and females. The concentration of nickel oxide in the lungs of 0.6, 2.5, and 10 mg/m3males was greater than in the lungs of controls at 4, 9, and 13 weeks, and nickel continued to accumulate in the lung at the end of the 13-week exposures (4 weeks, 33 to 263 mg nickel/g lung; 9 weeks, 53 to 400 mg/g lung; 13 weeks, 80 to 524 mg/g lung). Thirteen-week study in mice Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m3 by inhalation for 6 hours per day, 5 days per week for 13 weeks. Additional groups of six male and six female mice were exposed to 0, 0.6, 2.5, or 10 mg/m3 for tissue burden studies. No exposure-related deaths occurred among core study animals, final mean body weights of exposed male and female mice were similar to those of the controls, and no clinical findings in any group were related to nickel oxide exposure. Hematocrit values and erythrocyte counts in 5 and 10 mg/m3 females were minimally greater than those of the controls, as was the hemoglobin concentration in 5 mg/m3 females. Absolute and relative lung weights of 10 mg/m3 males and females were significantly greater than those of controls, and absolute and relative liver weights of 10 mg/m3 males were significantly less than those of controls. Accumulation of alveolar macrophages, many of which contained pigment particles, occurred in all groups of mice exposed to nickel oxide. Inflammation (chronic active perivascular infiltrates or granulomatous) occurred in 2.5, 5, and 10 mg/m3 males and females. In addition, lymphoid hyperplasia and pigment occurred in the bronchial lymph nodes of males and females exposed to 2.5 mg/m3 or higher. The concentration of nickel in the lung was greater than that of controls in 0.6, 2.5, and 10 mg/m3 males at 13 weeks (42 to 736 mg nickel/g lung). Two-year study in rats Survival, body weights, clinical findings, and hematology Groups of 65 male and 65 female F344/N rats were exposed to 0, 0.62, 1.25, or 2.5 mg nickel oxide/m3 (equivalent to 0, 0.5, 1.0, or 2.0 mg nickel/m3) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed male and female rats was similar to that of the controls. Mean body weights of 1.25 mg/m3 females and 2.5 mg/m3 males and females were slightly lower than those of the controls during the second year of the study. No chemical-related clinical findings were observed in male or female rats during the 2-year study. No chemical-related differences in hematology parameters were observed in male or female rats at the 15-month interim evaluation. Pathology findings Absolute and relative lung weights of 1.25 and 2.5 mg/m3 males and females were significantly greater than those of the controls at 7 and 15 months. At 2 years, there were exposure-related increased incidences of alveolar/bronchiolar adenomas alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. Incidences of atypical alveolar epithelial hyperplasia in the lungs generally increased with increasing exposure concentration in male and female rats. Chronic inflammation of the lung was observed in most exposed rats at 7 and 15 months and at 2 years; the incidences in exposed males and females at 2 years were significantly greater than those in the controls, and the severity of the inflammation increased in exposed groups. The incidences of pigmentation in the alveolus of exposed groups of males and females were significantly greater than those of the controls at 7 and 15 months and at 2 years. Pigmentation in the bronchial lymph nodes similar to that in the lungs was observed in all exposure groups with the exception of 0.62 mg/m3males and females at 7 months. Lymphoid hyperplasia was observed in the bronchial lymph nodes of 1.25 and 2.5 mg/m3 males and females at 7 and 15 months, and the incidence at 2 years generally increased with exposure concentration. At 2 years, there was an exposure-related increase in the incidence of benign pheochromocytoma in males and females. The incidences of benign pheochromocytoma and adrenal medulla hyperplasia in 2.5 mg/m3 females and the incidence of benign or malignant pheochromocytoma (combined) in 2.5 mg/m3 males were significantly greater than those in the controls. Tissue burden analyses Nickel concentrations in the lungs of exposed rats were greater than those in the controls at 7 and 15 months (7 months, 173 to 713 mg nickel/g lung; 15 months, 262 to 1,116 mg/g lung), and nickel concentrations increased with increasing exposure concentration and with time. Two-year study in mice Survival, body weights, clinical findings, and hematology Groups of 74 to 79 B6C3F1 mice were exposed to 0, 1.25, 2.5, or 5 mg nickel oxide/m3 by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed male and female mice was similar to that of the controls. Mean body weights of 5 mg/m3 females were slightly lower than those of the controls during the second year of the study. No chemical-related clinical findings were observed in male or female mice during the 2-year study. No chemical-related differences in hematology parameters were observed in male or female mice at the 15-month interim evaluation. Pathology findings At 2 years, the incidence of alveolar/bronchiolar adenoma in 2.5 mg/m3 females was significantly greater than that of the controls, as was the incidence of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/m3 females. Generally, incidences of chronic inflammation increased with exposure concentration in males and females at 7 and 15 months. Bronchialization of minimal severity in exposed animals and proteinosis were first observed at 15 months. At 2 years, the incidences of chronic inflammation, alveolar epithelial hyperplasia, and proteinosis in exposed groups of males and females were significantly greater than those of the controls. The severity of chronic inflammation increased with exposure concentration in females, and proteinosis was most severe in 5 mg/m3 males and females. Pigment occurred in the lungs of nearly all exposed mice at 7 and 15 months and at 2 years, and the severity increased with exposure concentration. Lymphoid hyperplasia occurred in two animals after 7 months; at 15 months, lymphoid hyperplasia occurred in males exposed to 2.5 and 5 mg/m3 and in all exposed groups of females. At 2 years, lymphoid hyperplasia occurred in some control animals, but this lesion was still observed more often in exposed males and females and the incidence increased with exposure concentration. Pigmentation was observed in the bronchial lymph nodes of exposed males and females at 7 and 15 months and in nearly all exposed animals at 2 years. Tissue burden analyses Nickel concentrations in the lungs of exposed mice were significantly greater than those in the controls at 7 and 15 months (7 months, 162 to 1,034 mg nickel/g lung; 15 months, 331 to 2,258 mg/g lung), and nickel concentrations increased with increasing exposure concentration and with time. Genetic toxicology No increase in the frequency of micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male or female mice exposed to nickel oxide. Conclusions Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of nickel oxide in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign or malignant pheochromocytoma (combined) of the adrenal medulla. There was some evidence of carcinogenic activity of nickel oxide in female F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign pheochromocytoma of the adrenal medulla. There was no evidence of carcinogenic activity of nickel oxide in male B6C3F1 mice exposed to 1.25, 2.5, or 5 mg/m3. There was equivocal evidence of carcinogenic activity of nickel oxide in female B6C3F1 mice based on marginally increased incidences of alveolar/bronchiolar adenoma in 2.5 mg/m3 females and of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/m3 females. Exposure of rats to nickel oxide by inhalation for 2 years resulted in inflammation and pigmentation in the lung, lymphoid hyperplasia and pigmentation in the bronchial lymph nodes, and hyperplasia of the adrenal medulla (females). Exposure of mice to nickel oxide by inhalation for 2 years resulted in bronchialization, proteinosis, inflammation, and pigmentation in the lung and lymphoid hyperplasia and pigmentation in the bronchial lymph nodes.

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Abstract  The morphology of postnatal human lung development and growth has been investigated by light and by scanning and transmission electron microscopy in seven children dying from non-respiratory causes and aged between 26 days and 64 months. The findings are compared with those of adult human lungs and are discussed in relation to the postnatal lung development in other species, particularly rodents. Within the first 1 1/2 postnatal years lung parenchyma undergoes a substantial structural remodeling due to bulk alveolar formation and to the restructuring of septal morphology. At one month alveolar formation appears to be well under way: The human lung is comparable then to a rat lung aged one week. In the parenchyma, numerous short and blunt tissue ridges, so-called secondary septa, subdivide the peripheral airspaces into an increasing number of still very shallow alveoli. The parenchymal septa present during and after alveolization are immature: they contain a double capillary network with a central, highly cellular sheet of connective tissue. The septal maturation sets in a few months after birth and consists of a reduction in the interstitial tissue mass and a complex process of capillary remodeling. Both alveolization and parenchymal maturation progress rapidly: by 6 months the lung has taken a big step towards maturity. By 1 1/2 years most septa show the adult structure where a single capillary network interwoven with connective tissue strands stabilizes the interalveolar wall. After the septal restructuring, lung development is considered complete, and the lung enters a period of normal growth that lasts until adulthood. From our observations we conclude that postnatal human lung development is made of two overlapping stages: (a) the alveolar stage, which starts in late fetal life and lasts to about 1-1 1/2 years, and (b) a stage of microvascular maturation, thought to extend from the first months after birth to the age of 2-3 years.