Airway Replicas Research Articles

Respiratory deposition of ultrafine welding fume particles

The inhalation and the deposition of welding-generated ultrafine particles in welders’ respiratory tracts have been linked to severe pulmonary impairments. In the present study, a mobile aerosol lung deposition apparatus (MALDA) was developed and applied to study the respiratory deposition of ultrafine welding fume particles. The MALDA was constructed with a set of physiologically representative human tracheobronchial airway replicas made with high-resolution 3D printers. Ultrafine welding fume particles were generated in a welding fume chamber and delivered to the MALDA. A series of respiratory deposition experiments were carried out using the MALDA to investigate the deposition of ultrafine welding fume particles in different airway generations of the tracheobronchial airways. The results showed that the fractional deposition of ultrafine welding fume particle in the human tracheobronchial airways down to the 9th airway generation could be readily and systematically measured by the MALDA. The estimated cumulative respiratory deposition ranged from approximately 9–31% for ultrafine welding fume particles between 10 and 100 nm in diameter. The results acquired demonstrated that the MALDA developed has the potential to become a useful apparatus in the future to estimate the respiratory deposition of ultrafine particles in real workplaces.

Experimental investigation of aerosol deposition through a realistic respiratory airway replica: An evaluation for MDI and DPI performance

PurposeIn the present work, a comparison between MDI and DPI for evaluating performance of the devices were carried out by experimentally investigating the deposition parameters through a realistic airway replica. MethodsComputed tomography (CT) images of the respiratory airway of a healthy subject were used to develop the realistic model. The airway replica was included extrathoracic, trachea, and tracheobronchial tree up to fourth generations which was fabricated by rapid prototyping. Afterward, in vitro experiments were performed to validate the airway model by comparing the total deposition (G0 to G3) of present replica with available data in the literature. Drug deposition (Salbutamol) in the model was measured by determining concentration of the segments sample by High Performance Liquid Chromatography (HPLC) assay. ResultsDeposition parameters were used for investigating the deposition patterns of the inhaled particles. Results showed that inertial impaction is the dominant mechanism in the most regions of the replica. It was found that the MDI delivered more drug to the tracheobronchial tree compared to the DPI for three different flow rate. ConclusionThe developed realistic respiratory airways model provided an opportunity to more accurately evaluate the performance of drug delivery devices and studying mechanisms of the drug deposition.

Airflow limitation in a collapsible model of the human pharynx: physical mechanisms studied with fluid-structure interaction simulations and experiments.

The classical Starling Resistor model has been the paradigm of airway collapse in obstructive sleep apnea (OSA) for the last 30 years. Its theoretical framework is grounded on the wave‐speed flow limitation (WSFL) theory. Recent observations of negative effort dependence in OSA patients violate the predictions of the WSFL theory. Fluid‐structure interaction (FSI) simulations are emerging as a technique to quantify how the biomechanical properties of the upper airway determine the shape of the pressure‐flow curve. This study aimed to test two predictions of the WSFL theory, namely (1) the pressure profile upstream from the choke point becomes independent of downstream pressure during flow limitation and (2) the maximum flowrate in a collapsible tube is VImax=A3/2(ρdA/dP)−1/2, where ρ is air density and A and P are the cross‐sectional area and pressure at the choke point respectively. FSI simulations were performed in a model of the human upper airway with a collapsible pharynx whose wall thickness varied from 2 to 8 mm and modulus of elasticity ranged from 2 to 30 kPa. Experimental measurements in an airway replica with a silicone pharynx validated the numerical methods. Good agreement was found between our FSI simulations and the WSFL theory. Other key findings include: (1) the pressure‐flow curve is independent of breathing effort (downstream pressure vs. time profile); (2) the shape of the pressure‐flow curve reflects the airway biomechanical properties, so that VImax is a surrogate measure of pharyngeal compliance.

An in vitro evaluation of importance of airway anatomy in sub-regional nasal and paranasal drug delivery with nebulizers using three different anatomical nasal airway replicas of 2-, 5- and 50-Year old human subjects

Intranasal delivery of nebulized drugs with the consideration of the nasal anatomy is not adequately studied. The objective of this study was to evaluate nasal and paranasal drug delivery with nebulizers, with and without pulsating airflow, in three anatomically-different nasal models in different age groups, considering normal and bidirectional breathing techniques. Anatomically-accurate nasal models of 2-, 5-, and 50-year old subjects were developed and tested to quantify sub-regional deposition of an aqueous solution of a model drug, nebulized with PARI SinuStar™ and Sinus™ nebulizers. Paranasal delivery was significantly enhanced using pulsating nebulization under bidirectional breathing administration technique for all subjects (p < 0.05). Airway morphology resulted in significantly different drug delivery efficiency (p < 0.05). Use of a modified nasal adaptor enhanced the inhaled dose and resulted in significantly higher percent recovery, 68.41±13.56%, compared to the standard design,10.35±1.75%. In the adult subject, paranasal delivery was equal to 19.34±1.21%, and 5.99±0.95% using PARI Sinus™ nebulizer, with and without pulsating airflow, respectively. In the pediatric subjects, pulsating paranasal delivery was 12.80±0.28%, but without pulsating airflow no drug reached the target. This study confirmed that bidirectional breathing and pulsating airflow are beneficial for improved paranasal aerosol delivery in children similar to previous findings for adults.

High flow nasal cannula: Influence of gas type and flow rate on airway pressure and CO2 clearance in adult nasal airway replicas

BackgroundHigh flow nasal cannula therapy is a form of respiratory support which delivers high flow rates of heated, humidified gas to the nares via specialized cannula. Two primary mechanisms of action attributed to the therapy are the provision of positive airway pressure as well as clearance of CO2-rich exhaled gas from the upper airways. MethodsPhysiologically accurate nose-throat airway replicas were connected at the trachea to a lung simulator, where CO2 was supplied to mimic the CO2 content in exhaled gas. Cannula delivered either air, oxygen or heliox (80/20%volume helium/oxygen) to the replicas at flow rates ranging from 0 to 60 l/min. Five replicas and three cannulas were compared. Tracheal pressure and CO2 concentration were continuously measured. The lung simulator provided breaths with tidal volume of 500 ml and frequency of 18 breaths/min. Additional clearance measurements were conducted for tidal volume and breathing frequency of 750 ml and 27 breaths/min, respectively. FindingsCannula flow rate was the dominant factor governing CO2 concentration. Average CO2 concentration decreased with increasing cannula flow rate, but above 30 L/min this effect was less pronounced. Tracheal positive end-expiratory pressure increased with flow rate and was lower for heliox than for air or oxygen. A predictive correlation was developed and used to predict positive end-expiratory pressure for a given cannula size as a function of supplied flow rate and occlusion of the nares. InterpretationCompared with administration of air or oxygen, administration of heliox is expected to result in similar CO2 clearance from the upper airway, but markedly lower airway pressure.

Aerosol drug delivery to the lungs during nasal high flow therapy: an in vitro study

BackgroundAerosol delivery through a nasal high flow (NHF) system is attractive for clinicians as it allows for simultaneous administration of oxygen and inhalable drugs. However, delivering a fine particle fraction (FPF, particle wt. fraction < 5.0 μm) of drugs into the lungs has been very challenging, with highest value of only 8%. Here, we aim to develop an efficient nose-to-lung delivery system capable of delivering improved quantities (FPF > 16%) of dry powder aerosols to the lungs via an NHF system.MethodsWe evaluated the FPF of spray-dried mannitol with leucine with a next generation impactor connected to a nasopharyngeal outlet of an adult nasal airway replica. In addition, we investigated the influence of different dispersion (20–30 L/min) and inspiratory (20–40 L/min) flow rates, on FPF.ResultsWe found an FPF of 32% with dispersion flow rate at 25 L/min and inspiratory flow rate at 40 L/min. The lowest FPF (21%) obtained was at the dispersion flow rate at 30 L/min and inspiratory flow rate at 30 L/min. A higher inspiratory flow rate was generally associated with a higher FPF. The nasal cannula accounted for most loss of aerosols.ConclusionsIn conclusion, delivering a third of inhalable powder to the lungs is possible in vitro through an NHF system using a low dispersion airflow and a highly dispersible powder. Our results may lay the foundation for clinical evaluation of powder aerosol delivery to the lungs during NHF therapy in humans.

A new approach to estimate ultrafine particle respiratory deposition

Ultrafine particles (UFPs) in workplaces have been and continue to be an important occupational health concern. The inhalation and the consequent deposition of UFPs in workers’ lower airways can lead to many adverse health effects. Therefore, it is vital to study the deposition of UFPs in the human respiratory tract from the viewpoint of occupational health. In this study, a set of physiologically representative human tracheobronchial airway replicas were made using high-resolution 3D printers, and a new approach that was distinct from the traditional methods was developed to apply these airway replicas in estimating UFP respiratory deposition. The results showed that UFP respiratory deposition could be readily and systematically measured by the differential-based approach. The results of this study imply the feasibility of developing a mobile aerosol lung deposition apparatus in the future for on-site workplace UFP respiratory deposition to evaluate the UFP inhalation dosimetry for workers in the real workplaces.

Experimental evaluation of pressure drop for flows of air and heliox through upper and central conducting airway replicas of 4- to 8-year-old children

Airway resistance describes the ratio between pressure drop and flow rate through the conducting respiratory airways. Analytical models of airway resistance for tracheobronchial airways have previously been developed and assessed without upper airways positioned upstream of the trachea. This work investigated pressure drop as a function of flow rate and gas properties for upper and central airway replicas of 10 child subjects, ages 4–8. Replica geometries were built based on computed tomography scan data and included airways from the nose through 3–5 distal branching airway generations. Pressure drop through the replicas was measured for constant inspiratory flows of air and heliox. For both the nose-throat and branching airways, the relationship between non-dimensional coefficient of friction, CF, with Reynolds number, Re, was found to resemble the turbulent Blasius equation for pipe flow, where CF∝Re-0.25. Additionally, pressure drop ratios between heliox and air were consistent with analytical predictions for turbulent flow. The presence of turbulence in the branching airways likely resulted from convection of turbulence produced upstream in the nose and throat. An airway resistance model based on the Blasius pipe friction correlation for turbulent flow was proposed for prediction of pressure drop through the branching bronchial airways downstream from the upper airway.

Effect of morphology on nanoparticle transport and deposition in human upper tracheobronchial airways

Aerosol transport and deposition in human lungs has attracted considerable attention in the past few years, as it has significant value to the study of toxicity consequence as well as therapeutic potential in occupational health and medical applications. In reproducing human tracheobronchial airways, two approaches were frequently taken: (1) anatomical realistic reconstruction through image scans (e.g. CT and MRI) or cadaver casts and (2) mathematical description using simplified models. Strengths and limitations are primarily focused on accuracy, resolution, repeatability, and computational\physical expenses. While both approaches were reported in literature, detailed comparison of aerosol transport and deposition in the two representations were scarcely performed, largely due to the challenge to acquire comprehensive data from the irregular structured airway replicas (approach 1). To fill the gap, the current study performed a numerical comparison of nanoparticle transport and deposition in human upper tracheobronchial airways by using an anatomical realistic reconstruction (through CT scans) and a mathematically simplified airway model. As the first step, the current study was focused on the variation in breathing airflow pattern and the effect towards fate of the inhaled nanoparticles in human upper tracheobronchial airways. The study provided important information to understand geometric sensitivity of nanoparticle modeling in the human tracheobronchial tree and is of significant value to predict the whole lung uptake of inhaled nanoparticles in the human respiratory system.

Deposition of micrometer-sized aerosol particles in neonatal nasal airway replicas

ABSTRACTThe nasal aerosol filtration properties of infants 0–3 months old have been quantified through in vitro measurements. Computed tomography (CT) scan data was obtained of seven individuals with ages of 5–79 days. Nasal airway replicas based on these images were manufactured using rapid prototyping. Deposition in the replicas was measured using an electrical low pressure impactor (ELPI) to measure the concentration of aerosol particles in the inertial regime. Comparing the difference in concentration when sampling through the model versus sampling through a blank line gave the deposition fraction. Deposition was measured for particles with aerodynamic diameters between 0.53 and 5.54 μm. Nonlinear least squares curve fitting was performed to collapse intersubject variability and represent the data with a single curve. To achieve satisfactory intersubject variability collapse, a non-dimensional pressure drop, the Euler number (Eu), was required in addition to the Reynolds number (Re) and the particle S...

Scaling an idealized infant nasal airway geometry to mimic inertial filtration of neonatal nasal airways

Idealized extrathoracic airways are a valuable tool for the development and testing of pharmaceutical aerosol delivery devices. These airways are designed to mimic the average filtration properties of the extrathoracic airways of the population on which they are based. We have investigated the ability to scale a previously developed infant nasal airway to generate a model with the correct filtration properties to mimic the neonatal population. Prospective scale factors were identified based on the dimensions of realistic nasal replicas, and based on 50th percentile body mass, body length, and head circumference. Inertial deposition was measured for four geometrically similar idealized nasal airway models. These data were compared to deposition in nasal airway replicas based on computed tomography (CT) images of seven infants between the ages of 5 and 79 days. Isotropically scaling the model that mimics the infant population (average age approximately 9 months) by 0.75 produced a model that mimics the neonatal population (average age approximately 1 month). This scale factor was consistent with the ratio of model characteristic diameters (airway volume divided by surface area, DV/As) and with the ratio of 50th percentile body lengths for the two average ages. A predictive correlation based on Reynolds and Stokes numbers was identified that provides deposition efficiency of this geometry for DV/As between 1.20mm and 0.72mm. This equation can be used to provide expected deposition characteristics of our idealized nasal model before construction at scales not specifically considered here.

Correlation of high flow nasal cannula outlet area with gas clearance and pressure in adult upper airway replicas

BackgroundPrimary benefits of high flow nasal cannula therapy include washout of carbon dioxide rich exhaled gas and increased airway pressures during tidal breathing. This work reports on the influence of high flow nasal cannula outlet area on upper airways gas clearance and tracheal pressures using measurements in five realistic adult nose-throat airway replicas. MethodsTwo commercial high flow nasal cannulas and one generic nasal cannula of varying size were compared. 100% oxygen was supplied via cannulas at flow rates ranging from 30 to 90l/min to replicas originally filled with air, and oxygen concentrations at the larynx and trachea were compared over time. Additionally, and separately, replicas were connected to a mechanical lung simulator to simulate tidal breathing while undergoing high flow nasal cannula therapy, with tracheal pressure–time waveforms recorded. FindingsFaster gas clearance corresponded with higher flow rates (P<0.001), and with smaller cannula outlet area (P<0.001). Observed pressures were in approximate agreement with limited available in-vivo data in the literature. Between 0 and 60L/min cannula flow rates, tracheal positive end expiratory pressures increase was greater with the smallest cannula (∆PPEEP=785SD(185) Pa) compared to the largest cannula (∆PPEEP=380SD(120)Pa). Regression analysis indicates that positive end expiratory pressure is proportional to the square of flow velocities exiting the cannula and nares (R2=0.906). InterpretationSince increased pressure and clearance rate have been associated with improved clinical outcomes in previous studies, our results suggest that smaller cannula outlet area may be preferable.

Experimental methods for flow and aerosol measurements in human airways and their replicas

Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given.

Human nasal olfactory deposition of inhaled nanoparticles at low to moderate breathing rate

Olfactory pathway, susceptible for direct translocation of inhaled nanoparticles into the brain, has been verified in a number of animal studies over past decades. In case of toxic substances, the extremely low dose strongly suggests a subclinical condition that prevents noticeable neurodegeneration until years after prolonged exposure. The exact mechanism, between elevated presence of toxic substances (e.g. heavy metals) and deteriorated neurofunction in human central nervous system, is still not clear; however, nasal olfactory, being portal of the entry for such a transport route, is undoubtedly a critical junction where hint to the time course and dose dependency might be inferred. Using a physiologically realistic nasal and upper airway replica, this study performed human inhalation simulations of nanoparticles (1–100nm) under low to moderate breathing conditions (5–14L/min). Emphasis is on olfactory deposition and the various factors contributing to the process. Details on airflow pattern and particle flux in nasal and olfactory were made visible through a 2D unwrapped surface mapping technique, and it was found out that airflow pattern, especially nasal wall shear had a remarkable correlation to particle movement and deposition at the ultrafine scale (< 1–2nm). Olfactory deposition efficiency was found to be extremely low (< 3.5%), and showed distinctive variation in high diffusivity region when compared to that in the entire nasal cavity. The entrance profile of olfactory deposited particles was seen to be highly selective and unanimously originated from upper section of the nostril near nasal septum. Current study is of significant value to the understanding of human uptake of inhaled nanoparticles through olfactory pathway.

Powder aerosol delivery through nasal high-flow system: In vitro feasibility and influence of process conditions

We aimed to obtain fundamental information for potential pulmonary delivery of powder aerosols using a clinically-approved nasal high-flow system (AIRVO), with spray-dried mannitol (SD-Man) being a model powder. Compressed air exiting the AIRVO at set ‘dispersion’ air flow rates dispersed SD-Man loaded in an Osmohaler® into a human nasal airway replica (NAR) coupled downstream to a Next Generation Impactor (NGI) running at specific ‘inspiratory’ flow rates. Increasing the dispersion flow rate from 30 to 60L/min increased powder deposition in the NAR from 50 to 70% of the emitted dose, while decreased the NGI deposition from 50 to 30% of the emitted dose. The inspiratory flow rate did not affect powder deposition in the NAR and NGI. In contrast, as the inspiratory flow rate was increased from 15 to 40L/min, powder recovery, emitted fraction, and fine particle fraction below 5μm (as aerosol performance indices) were increased from 90, 30 and 5% to 97, 45 and 8% of the loaded dose, respectively. The dispersion flow rate did not change the performance indices. Importantly, heating and humidification of dispersion airflow, loaded doses, and nasal cannula sizes did not greatly affect the aerosol characteristics.

A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop

BackgroundsExposure to nanoparticles in the workplace is a health concern to occupational workers with increased risk of developing respiratory, cardiovascular, and neurological disorders. Based on animal inhalation study and human lung tumor risk extrapolation, current authoritative recommendations on exposure limits are either on total mass or number concentrations. Effects of particle size distribution and the implication to regional airway dosages are not elaborated.MethodsReal time production of particle concentration and size distribution in the range from 5.52 to 98.2 nm were recorded in a wire-cut electrical discharge machine shop (WEDM) during a typical working day. Under the realistic exposure condition, human inhalation simulations were performed in a physiologically realistic nasal and upper airway replica. The combined experimental and numerical study is the first to establish a realistic exposure condition, and under which, detailed dose metric studies can be performed. In addition to mass concentration guided exposure limit, inhalation risks to nano-pollutant were reexamined accounting for the actual particle size distribution and deposition statistics. Detailed dosimetries of the inhaled nano-pollutants in human nasal and upper airways with respect to particle number, mass and surface area were discussed, and empirical equations were developed.ResultsAn astonishing enhancement of human airway dosages were detected by current combined experimental and numerical study in the WEDM machine shop. Up to 33 folds in mass, 27 folds in surface area and 8 folds in number dosages were detected during working hours in comparison to the background dosimetry measured at midnight. The real time particle concentration measurement showed substantial emission of nano-pollutants by WEDM machining activity, and the combined experimental and numerical study provided extraordinary details on human inhalation dosimetry. It was found out that human inhalation dosimetry was extremely sensitive to real time particle concentration and size distribution. Averaged particle concentration over 24-h period will inevitably misrepresent the sensible information critical for realistic inhalation risk assessment.ConclusionsParticle size distribution carries very important information in determining human airway dosimetry. A pure number or mass concentration recommendation on the exposure limit at workplace is insufficient. A particle size distribution, together with the deposition equations, is critical to recognize the actual exposure risks. In addition, human airway dosimetry in number, mass and surface area varies significantly. A complete inhalation risk assessment requires the knowledge of toxicity mechanisms in response to each individual metric. Further improvements in these areas are needed.

Theoretical and experimental evaluation of the effects of an argon gas mixture on the pressure drop through adult tracheobronchial airway replicas

Argon has the potential to be a novel inhaled therapeutic agent, owing to the neuroprotective and organoprotective properties demonstrated in preclinical studies. Before human trials are performed, an understanding of varying gas properties on airway resistance during inhalation is essential. This study predicts the effect of an 80% argon/20% oxygen gas mixture on the pressure drop through conducting airways, and by extension the airway resistance, and then verifies these predictions experimentally using 3-D printed adult tracheobronchial airway replicas.The predicted pressure drop was calculated using established analytical models of airway resistance, incorporating the change in viscosity and density of the 80% argon/20% oxygen mixture versus that of air. Predicted pressure drop for the argon mixture increased by approximately 29% compared to that for air. The experimental results were consistent with this prediction for inspiratory flows ranging from 15 to 90slpm. These results indicate that established analytical models may be used to predict increases in conducting airway resistance for argon/oxygen mixtures, compared with air. Such predictions are valuable in predicting average patient response to breathing argon/oxygen mixtures, and in selecting or designing delivery systems for use in administration of argon/oxygen mixtures to critically ill or injured patients.

Determination of the deposited amount of inhalation drugs in realistic human airways by Raman and infrared spectroscopy

Abstract Vibrational (Raman and infrared) spectroscopy based methods have been developed to determine the distribution of inhalation drugs (and other aerosols) in human airway replicas. The tested medication was introduced by metered dose inhaler into a realistic human lung tract prepared by 3D printing from computer tomographic data of human respiratory system. The deposited material was collected with silicon substrates attached to the hollow airway’s walls in different points. The analysis of the substrates was performed by Raman and infrared spectroscopic mapping of drug’s characteristic peak intensities over the surface. The method was verified by comparison with optical microscopic images recorded on the same surface area.

Prediction of localized aerosol deposition in a realistic replica of human airways using experimental data and numerical simulation

The presence of aerosol deposition hot-spots in human airways presumably contributes to development of various diseases. The overall aerosol deposition in human lungs can be predicted with sufficient accuracy nowadays. However, the prediction of localized aerosol deposition poses arduous challenge, namely in diseased lungs. Numerical simulation is considered to be a promising tool for the successful prediction. Yet, the validation of such simulations is difficult to perform, as not enough experimental data acquired using realistic airway replicas is available. This paper presents a first comparison of localized deposition measurement and simulation performed on the identical realistic geometry. The analysis indicates that both approaches yield similar results for low Reynolds number flows.

Modeling of inertial deposition in scaled models of rat and human nasal airways: Towards in vitro regional dosimetry in small animals

Rodents are routinely used in inhalation toxicology tests as human surrogates. However, in vitro dosimetry tests in rodent casts are still scarce due to small rodent airways and in vitro tests to quantify sub-regional dosimetry are still impractical. We hypothesized that for inertial particles whose deposition is dominated by airflow convection (Reynolds number) and particle inertia (Stokes number), the deposition should be similar among airway replicas of different scales if their Reynolds and Stokes numbers are kept the same. In this study, we aimed to (1) numerically test the hypothesis in three airway geometries: a USP induction port, a human nose model, and a Sprague-Dawley rat nose model, and (2) find the range of applicability of this hypothesis. Five variants of the USP and human nose models and three variants of the rat nose model were tested. Inhalation rates and particle sizes were scaled to match the Reynolds number and Stokes numbers. A low-Reynolds-number k–ω model was used to resolve the airflow and a Lagrangian tracking algorithm was used to simulate the particle transport and deposition. Statistical analysis of predicted doses was conducted using ANOVA. For normal inhalation rates and particle diameters ranging from 0.5 to 24µm, the deposition differences between the life-size and scaled models are insignificant for all airway geometries considered (i.e., human nose, USP, and rat nose). Furthermore, the deposition patterns and exit particle profiles also look similar among scaled models. However, deposition rates and patterns start to deviate if inhalation rates are too low, or particle sizes are too large. For the rat nose, the threshold velocity was found to be 0.71m/s and the threshold Froude number to be 50. Results of this study provide a theoretical foundation for sub-regional in vitro dosimetry tests in small animals and for interpretation of data from inter-species or intra-species with varying body sizes.