Abstract  Numerous studies have reported that the toxicity differences among metals are widespread; however, little is known about the mechanism of differences in metal toxicity to aquatic organisms due to the lack of quantitative understanding of their adverse outcome pathway. Here, we investigated the effects of Cd and Cu on bioaccumulation, gene expression, physiological responses, and apical effects in zebrafish larvae. RNA sequencing was conducted to provide supplementary mechanistic information for the effects of Cd and Cu exposure. On this basis, we proposed a quantitative adverse outcome pathway (qAOP) suitable for metal risk assessment of aquatic organisms. Our work provides a mechanistic explanation for the differences in metal toxicity where the strong bioaccumulation of Cu enables the newly accumulated Cu to reach the threshold that causes different adverse effects faster than Cd in zebrafish larvae, resulting in a higher toxicity of Cu than that of Cd. Furthermore, we proposed a parameter CIT/BCF (the ratio of internal threshold concentration and bioaccumulation factor) that helps to understand the toxicity differences by combining the information of bioaccumulation and internal threshold of adverse effects. This work demonstrated that qAOP is an effective quantitative tool for understanding the toxicity mechanism and highlight the importance of toxicokinetics and toxicodynamics at different biological levels in determining the metal toxicity.

Abstract  Internal dose determination is an essential component of individual monitoring programmes for workers or members of the public exposed to radionuclides, and methods and computer programs are required for dose assessment. A recent international European Radiation Dosimetry Group (EURADOS) intercomparison has shown unacceptably large ranges in the results assessment. An ICRP working party has been initiated to consider what guidance ICRP can give on the use of models and interpret bioassay data in terms of intake/dose. In this field, six codes for bioassay data interpretation, which implement the current ICRP publication 78 biokinetic models, have been reviewed against several criteria with different levels of importance: minor criteria such as the practical use of the code and the graphical capabilities, and major criteria such as the choice of available parameters, peculiarities of data fitting and interpretation, the choice of biokinetic models and the use of uncertainties. All these criteria were assessed using one artificial set of data and two examples extracted from the previous international EURADOS intercomparison.

Abstract  Ten healthy males inhaled monodisperse Teflon particles (geometric diameter 3.6 microns, aerodynamic diameter 5.3 microns) labeled with 195Au (half-life 183 days). The leakage of 195Au from the particles in vitro in water was less than 0.2% per year. Retention over the thorax was followed for about 900 days using two separate detector systems. One system consisted of four Ge detectors placed close to the front of the chest over the upper and lower regions of the lungs. The other system consisted of three NaI crystals placed in a ring around the thorax at some distance from the chest wall. Activities of 195Au in feces (24- or 48-h samples) could be measured as long as activities in the thorax could be measured. For the period 7-250 days, the half-times were similar for the two detectors, on the average 740 days for the NaI detectors and 680 days for the Ge detectors. The average half-times estimated from measurements from about 250 days to about 900 days were 1750 days with the NaI detectors and 880 days with the Ge detectors. Clearance curves constructed from measurements from feces agreed very well with clearance measured with the NaI detectors. The excretion via feces was well described by a power function with days after exposure as base. This total clearance from the thoracic region was slower than in earlier studies. No activity could be measured in the urine. The measurements with the two detector systems show that a translocation within the thoracic region occurred. This might be explained by transportation of particles from the lung parenchyma to the regional lymph nodes. The accumulation of particles in the regional lymph nodes was tentatively calculated on the basis of that assumption.

Abstract  Introduction: Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. Areas covered: In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Expert opinion: Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.

Abstract  New approach methodologies (NAMs) are emerging chemical safety assessment tools consisting of in vitro and in silico (computational) methodologies intended to reduce, refine, or replace (3R) various in vivo animal testing methods traditionally used for risk assessment. Significant progress has been made toward the adoption of NAMs for human health and environmental toxicity assessment. However, additional efforts are needed to expand their development and their use in regulatory decision making. A virtual symposium was held during the 2021 Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Smoke Science and Product Technology (SSPT) conference (titled "Advancing New Alternative Methods for Tobacco Harm Reduction"), with the goals of introducing the concepts and potential application of NAMs in the evaluation of potentially reduced-risk (PRR) tobacco products. At the symposium, experts from regulatory agencies, research organizations, and NGOs shared insights on the status of available tools, strengths, limitations, and opportunities in the application of NAMs using case examples from safety assessments of chemicals and tobacco products. Following seven presentations providing background and application of NAMs, a discussion was held where the presenters and audience discussed the outlook for extending the NAMs toxicological applications for tobacco products. The symposium, endorsed by the CORESTA In Vitro Tox Subgroup, Biomarker Subgroup, and NextG Tox Task Force, illustrated common ground and interest in science-based engagement across the scientific community and stakeholders in support of tobacco regulatory science. Highlights of the symposium are summarized in this paper.

Abstract  A laboratory system has been developed in which the atmosphere and fluid dynamics of the upper tracheobronchial (TB) tree of the human are simulated. It is used to measure the hygroscopic growth rates of monodisperse NaCl and bronchodilator (Isuprel ® hydrochloride with and without glycerine) aerosols. Dry particles are mixed with water vapour-laden air at the entrance to a growth chamber temperature controlled at 37°C with a relative humidity (RH) between 88 and 95%. Hygroscopic growth rates increased with degree of RH and magnitude of Reynolds number in the chamber. The growth data are incorporated into an aerosol deposition model to calculate the effect of hygroscopic growth upon the dose distribution of medicinal aerosols in the human TB network. The model uses some original deposition formulae to compute particle deposition efficiencies. Calculations show that the rate of water vapour absorption within TB airways is an important factor affecting the fate of particles used in aerosol therapy.

Abstract  The development of predictive aerosol dosimetry models has been a major focus of environmental toxicology and pharmaceutical health research for decades. One-dimensional (1D) models successfully predict overall deposition averages but fail to accurately predict local deposition. Computational fluid-particle dynamics (CFPD) models provide site-specific predictions but at a computational cost that prohibits whole lung predictions. Thus, there is a need for developing multiscale strategies to provide a realistic subject-specific picture of the fate of inhaled aerosol in the lungs. CT-based 3D/CFPD models of the large airways were bidirectionally coupled with individualized 1D Navier-Stokes airflow and particle transport based upon the widely used Multiple Path Particle Dosimetry Model (MPPD). Distribution of airflows among lobes was adjusted by measured lobar volume changes observed in CT images between FRC and FRC +1.5 L. As a test of the effectiveness of the coupling procedures, deposition modeling of previous 1 mu m aerosol exposure studies was performed. The complete coupled model was run for 3 breaths, with the computation-intense portion being the 3D CFPD Lagrangian particle tracking calculation. The average deposition per breath was 11% in the combined multiscale model with site-specific doses available in the CFPD portion of the model and airway- or region-specific deposition available for the MPPD portion. In conclusion, the key methods developed in this study enable predictions of ventilation heterogeneities and aerosol deposition across the lungs that are not captured by 3D or 1D models alone. These methods can be used as the foundation for multi-scale modeling of the full respiratory system.

Abstract  "Standard saccharine test is used to detect nasal mucociliary clearance time in healthy individuals both adults and children. The length of the nose was measured radiologically and with the help of a soft malleable rubber catheter. For healthy individuals, mean nasal mucociliary clearance lime is 8.2 minutes in children and 9.5 minutes in adults. The mean nasal mucociliary clearance rates were 11.1 mm/min for children and 12.7 mm/min for adults.Deviated nasal septum, chronic sinusitis, allergic rhinitis, atrophic rhinitis, chronic smokers and patients with recent nasal packings were taken as diseased conditions in adults, whereas children with adenoid hyperplasia were taken for the study. In all of these, nasal mucociliary clearance was significantly prolonged."

Abstract  Traditionally, empirical correlations for predicting respiratory tract deposition of inhaled aerosols have been developed using limited available in vivo data. More recently, advances in medical image segmentation and additive manufacturing processes have allowed researchers to conduct extensive in vitro deposition experiments in realistic replicas of the upper and central branching airways. This work has led to a collection of empirical equations for predicting regional aerosol deposition, especially in the upper, nasal and oral airways. The present section reviews empirical correlations based on both in vivo and in vitro data, which may be used to predict total and regional deposition. Equations are presented for predicting total respiratory deposition fraction, mouth-throat fraction, nasal, and nose-throat fractions for a large variety of aerosol sizes, subject age groups, and breathing maneuvers. Use of these correlations to estimate total lung deposition is also described.

Abstract  Risk assessment has become a dominant public policy tool for making choices, based on limited resources, to protect public health and the environment. It has been instrumental to the mission of the U.S. Environmental Protection Agency (EPA) as well as other federal agencies in evaluating public health concerns, informing regulatory and technological decisions, prioritizing research needs and funding, and in developing approaches for cost-benefit analysis. However, risk assessment is at a crossroads. Despite advances in the field, risk assessment faces a number of significant challenges including lengthy delays in making complex decisions; lack of data leading to significant uncertainty in risk assessments; and many chemicals in the marketplace that have not been evaluated and emerging agents requiring assessment. Science and Decisions makes practical scientific and technical recommendations to address these challenges. This book is a complement to the widely used 1983 National Academies book, Risk Assessment in he Federal Government (also known as the Red Book). The earlier book established a framework for the concepts and conduct of risk assessment that has been adopted by numerous expert committees, regulatory agencies, and public health institutions. The new book embeds these concepts within a broader framework for risk-based decision-making. Together, these are essential references for those working in the regulatory and public health fields.

Abstract  Occupational exposures to inhalation of certain metal dusts or aerosols can cause loss of olfactory acuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or sinonasal cancer. Anosmia and hyposmia have been observed in workers exposed to Ni- or Cd-containing dusts in alkaline battery factories, nickel refineries, and cadmium industries. Ulcers of the nasal mucosa and perforated nasal septum have been reported in workers exposed to Cr(VI) in chromate production and chrome plating, or to As(III) in arsenic smelters. Atrophy of the olfactory epithelium has been observed in rodents following inhalation of NiSO4 or alphaNi3S2. Cancers of the nose and nasal sinuses have been reported in workers exposed to Ni compounds in nickel refining, cutlery factories, and alkaline battery manufacture, or to Cr(VI) in chromate production and chrome plating. In animals, several metals (eg, Al, Cd, Co, Hg, Mn, Ni, Zn) have been shown to pass via olfactory receptor neurons from the nasal lumen through the cribriform plate to the olfactory bulb. Some metals (eg, Mn, Ni, Zn) can cross synapses in the olfactory bulb and migrate via secondary olfactory neurons to distant nuclei of the brain. After nasal instillation of a metal-containing solution, transport of the metal via olfactory axons can occur rapidly, within hours or a few days (eg, Mn), or slowly over days or weeks (eg, Ni). The olfactory bulb tends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greater avidity than other regions of the brain. The molecular mechanisms responsible for metal translocation in olfactory neurons and deposition in the olfactory bulb are unclear, but complexation by metal-binding molecules such as carnosine (beta-alanyl-L-histidine) may be involved.

Abstract  The rapid growth in the use of in vitro methods for nanoparticle toxicity assessment has proceeded with limited consideration of the unique kinetics of these materials in solution. Particles in general and nanoparticles specifically, diffuse, settle, and agglomerate in cell culture media as a function of systemic and particle properties: media density and viscosity and particle size, shape, charge and density, for example. Cellular dose then is also a function of these factors as they determine the rate of transport of nanoparticles to cells in culture. Here we develop and apply the principles of dosimetry in vitro and outline an approach for simulation of nanoparticle particokinetics in cell culture systems. We illustrate that where equal mass concentrations (mu g/ml) imply equal doses for dissimilar materials, the corresponding particle number or surface area concentration doses differ by orders of magnitude. More importantly, when rates of diffusional and gravitational particle delivery are accounted for, trends and magnitude of the cellular dose as a function of particle size and density differ significantly from those implied by "concentration" doses. For example, 15-nm silver nanoparticles appear similar to 4000 times more potent than micron-sized cadmium oxide particles on a cm(2)/ml media basis, but are only similar to 50 times more potent when differences in delivery to adherent cells are considered. We conclude that simple surrogates of dose can cause significant misinterpretation of response and uptake data for nanoparticles in vitro. Incorporating particokinetics and principles of dosimetry would significantly improve the basis for nanoparticle toxicity

Abstract  This study was carried out to test the hypothesis that nanogold particles can accumulate in the olfactory bulb, and translocate from the lung to other organs after inhalation exposure. Gold nanoparticles were aerosolized and introduced through an exposure chamber. The number concentration of airborne nano-sized particles was 2106 #NSPs/cm3 with >75% of particulates between 30 and 110 nm. Exposure for 5 days resulted in significant increase of Au in the lung and olfactory bulb as detected by ICP-MS, but after 15 days, significant accumulation of gold was detected in the lung, esophagus, tongue, kidney, aorta, spleen, septum, heart and blood. Microarray analysis showed downregulation of many genes related to muscle in the nanogold-exposed lung. Lipidomic analysis of the lung showed a specific decrease in phosphatidylserine 36:1 species. We conclude that nanogold is able to translocate from the lung to other organs with time, and causes significant effects in exposed tissues.

Abstract  Interest in particle size-selective sampling for aerosols in working and ambient living environments began in the early 1900s when it became apparent that the penetration into-and deposition in-the respiratory tract of aerosol-exposed humans of inhaled particles was dependent on particle size. Coarse particles tended to be filtered out during inhalation and in the upper parts of the respiratory tract, so only progressively smaller particles penetrated down to the deep regions of the lung. Over time, following experimental studies with 'breathing' mannequins in wind tunnels and with human volunteer subjects in the laboratory, a clear picture has emerged of the physical, physiological and anatomical factors that control the extent to which particles may or may not reach certain parts of the respiratory tract. Such understanding has increasingly been the subject of discussions about aerosol standards, in particular the criteria by which exposure might be defined in relation to given classes of aerosol-related health effect-and in to turn aerosol monitoring. The ultimate goal has been to develop a set of criteria by which exposure standards are scientifically relevant to the health effects in question. This paper reviews the scientific basis for such criteria. It discusses the criteria that have already been widely discussed and so are either being applied or are on the threshold of practical application in standards. It also discusses how new advanced knowledge may allow us to extend the list of particle size-selective criteria to fractions that have not yet been widely discussed but which may be of importance in the future.

Abstract  The regional deposition of inhaled monodisperse insoluble particles of about 1,3.5 and 10 Ám in activity median aerodynamic diameter was measured in four small rodent species including CF1 mice, golden Syrian hamsters, Fischer 344 rats and Hartley guinea pigs and in New Zealand rabbits, Near monodisperse aerosols of about 0.05 Ám activity median diffusive diameter were also studied. The five species are commonly utilized in inhalation- toxicology research. Monodisperse aerosols of fused aluminosilicate particles (2.46 g/cm3) labelled with radioactive 169Yb were generated utilizing a modified vibrating liquid stream generator, reduced to Boltzmann charge equilibrium with a 85Kr discharge device, concentrated with a centripeter stage, fused in a 1220?C quartz tube furnace. and delivered to a specially designed nose-only exposure system suitable for use with coarse particles as large as 10 Ám. Twenty unanaesthetized animals (eight rabbits) were exposed simultaneously for up to 45 minutes to each aerosol particle size. Half were sacrificed immediately after exposure and the remaining half were sacrificed after 20 hours to measure bronchial clearance. Radioassay of selected tissues included the individual lung lobes. trachea. larynx, head airways, and gastrointestinal tract to determine deposition quantities. The results show enhanced nasal-pharyngeal deposition for particles larger than 3 Ám in aerodynamic diameter, with over 90 percent nasal-pharyngeal deposition for particles larger than 5 Ám. Conversely, pulmonary (alveolar) deposition approaches nil for the larger particles.

Abstract  Morphometric procedures have been used to study the characteristics of cells in the alveolar region of the lungs of rats, dogs, baboons, and humans. Compared with the other species, human lungs were found to contain greater numbers of macrophages and to have larger alveolar type II, endothelial, and interstitial cells. The thickness of the interstitium and the pulmonary capillary endothelium were also significantly greater in the human lungs. These differences in human lung anatomy may be due to increased exposure to airborne pollutants and to tobacco smoke. Despite the above differences and the fact that there are large variations in size and functional characteristics of the lungs of these mammals, an overall striking similarity in characteristics of individual lung cells was found. The distribution of cells in alveolar tissue was remarkably constant between species as was the average volume and surface area of most cell types. Computer-aided three-dimensional reconstruction techniques were used to determine the spatial relationship of organelles in individual alveolar type II cells from rats. A three-dimensional reconstruction of cells permits quantification of number, size, surface area, and volume of subcellular organelles and correlations of their three-dimensional spatial relationships.

Abstract  This study provides a quantitative description of the small airways and alveolar duct-alveolar architecture of the rat lung. To accomplish this, quantitative three-dimensional reconstructions were made of small airways, the alveolar duct system, and alveoli. The branching pattern of the small airways immediately proximal to the alveolar ducts varied significantly. For example, the number of bronchiole-alveolar duct junctions per parent bronchus (terminal bronchiole) ranged from two to six. The number of bronchiole-alveolar duct junctions per lung was 7,280 +/- 250 (mean +/- SE). The general shape of the ventilatory unit arising from each bronchiole-alveolar junction was that of a space-filling sphere with an outer diameter of 1,490 +/- 130 microns. The average distance from the bronchiole-alveolar duct junction to alveoli at the end of the alveolar sac termination was 1,290 +/- 100 microns. Numerous trifurcations were found in the branching pattern of the alveolar ducts. The branching of the alveolar ducts did not fit a regular dichotomous pattern. The volume of the terminal branches (alveolar sacs) accounted for 64 +/- 5% of the volume of the ventilatory unit. Both of these factors, the pattern of branching and the substantial volume distributed in the most peripheral branches, contribute to the uniform distribution of gas within the ventilatory unit and thus minimize potential diffusion limitations to gas exchange.

Abstract  A critical review is presented of the available experimental data on regional aerosol deposition in man. The data agree well for nasal and extrathoracic deposition. For the fast and slow cleared components of thoracic deposition, however, agreement is less satisfactory. The different experimental techniques are critically evaluated, and possible reasons for the observed discrepancies are discussed. Additionally, a semi-empirical model is presented which takes this evaluation into account, and which enables regional deposition to be calculated as function of particle size and respiratory parameters without lengthy computer models. The proposed equations explain and eliminate some of the intra- and inter-individual scatter of the data, and some of the discrepancies between the data from different laboratories. Where these discrepancies could not be eliminated, an additional 'conservative' model for dose estimations is offered which takes account of the uncertainty inherent to the data. A summary of the model equations is given in the appendix.

Abstract  The epithelium of the nasal airways is recognized as being at risk of developing cancer from inhalation exposure to toxic aerosols. Because groups that are revising or developing respiratory tract dosimetry models have pointed out the lack of information on the deposition of aerosols in human nasal airways, particularly as a function of the size and shape of these airways, we utilized magnetic resonance imaging to obtain invivo measurements of the nasal airways of a human subject. A series of 40 contiguous 3–mm–thick coronal sections were obtained using a 1.5 Tesla proton imaging unit. These images were then digitized and perimeters and cross–sectional areas of the left and right airways were obtained. The results indicated that there were marked differences in areas between the left and right sides of this subject at any given time, and that the size of the airways were significantly smaller than areas that have been reported previously based on measurements obtained from cadavers. A separate set of images were also obtained after the subject had been administered a nasal decongestant. These airways dimensions were quantitatively more similar to the cadaver data. These preliminary data indicate that nasal airway dimensions are likely to be smaller than those previously reported. These differences may play a role in determining the patterns of aerosol deposition to be expected in nasal airways. It has become increasingly evident that the epithelium of the nasal airways is at risk of developing cancer from inhalation exposure to a variety of environmentally derived gases and particles (Bross etal., 1978; Roush 1979; Gerhardsson etal., 1985; Brinton etal., 1985; Olson and Asnaes 1986; Benjamin etal., 1979; Boecker etal., 1986). To establish appropriate exposure-dose-response relationships, particularly among different species, it is important to understand the factors that affect the deposition, retention and translocation of inhaled toxicants in the nasal airways. Several deposition studies of different sized aerosols in the human nasal airways have been reported, both in terms of total airway deposition (Heyder and Rudolf 1960; Hounam etal., 1971) and also deposition in gross subdivisions of the nose (Fry and Black, 1973). Those data, although useful, do not provide the degree of experimental detail needed to improve our current understanding of the regional deposition and retention of aerosols of widely differing sizes in accurately defined anatomical regions. The studies noted above have also not addressed the potential influence of size and shape of the nasal airways on aerosol deposition. To supplement the invivo data, several experimenters have used physical casts of human nasal airways (Patra etal., 1986; Proetz 1951; Itoh etal., 1985; Proctor and Swift, 1970; Girardin etal., 1983). These casts were obtained from cadavers using rubber or plastic injection techniques. Although these techniques are regarded as accurate in their rendering of the size, shape and configuration of the nasal airways at the time that the casts were made, it is doubtful that the casts provide realistic models of the state of the nasal airways in a normal living individual. There are several reasons for this. First, the mucosa that lines the entire nasal cavity, except the vestibule, is endowed with a rich blood supply that allows for the dilation and constriction of the venous cavernous tissue in the mucosa of the conchae and septum. Both unilateral and bilateral changes in nasal airway patency occur with time such that in normal individuals, air flow is neither constant nor equally distributed between the two nasal airways. The size and shape of each nasal airway is not only likely to be different but temporally variable, and the size of the airway is probably significantly smaller than those of human cadavers because the latter represents a nonphysiological state. Second, shrinkage of tissue as a result of fixation would also tend to increase the size of the nasal airways beyond the range of the normal physiological state. The purpose of this study was to obtain data on the dimensions of human nasal airways invivo using magnetic resonance imaging (MRI), a technique that images the air–mucosa interface directly, and to compare the quantitative measurements of airway cross–sectional areas and perimeters to those that have previously been published and that were derived from cadavers. This comparison provides an indication of the realism of the physical models that have been used previously, and the need for additional studies.