Dosimetry modeling of inhaled formaldehyde: binning nasal flux predictions for quantitative risk assessment.

Interspecies extrapolations of tissue dose and tumor response have been a significant source of uncertainty in formaldehyde cancer risk assessment. The ability to account for species-specific variation of dose within the nasal passages would reduce this uncertainty. Three-dimensional, anatomically realistic, computational fluid dynamics (CFD) models of nasal airflow and formaldehyde gas transport in the F344 rat, rhesus monkey, and human were used to predict local patterns of wall mass flux (pmol/[mm(2)-h-ppm]). The nasal surface of each species was partitioned by flux into smaller regions (flux bins), each characterized by surface area and an average flux value. Rat and monkey flux bins were predicted for steady-state inspiratory airflow rates corresponding to the estimated minute volume for each species. Human flux bins were predicted for steady-state inspiratory airflow at 7.4, 15, 18, 25.8, 31.8, and 37 l/min and were extrapolated to 46 and 50 l/min. Flux values higher than half the maximum flux value (flux median) were predicted for nearly 20% of human nasal surfaces at 15 l/min, whereas only 5% of rat and less than 1% of monkey nasal surfaces were associated with fluxes higher than flux medians at 0.576 l/min and 4.8 l/min, respectively. Human nasal flux patterns shifted distally and uptake percentage decreased as inspiratory flow rate increased. Flux binning captures anatomical effects on flux and is thereby a basis for describing the effects of anatomy and airflow on local tissue disposition and distributions of tissue response. Formaldehyde risk models that incorporate flux binning derived from anatomically realistic CFD models will have significantly reduced uncertainty compared with risk estimates based on default methods.

Dosimetry modeling of inhaled formaldehyde: the human respiratory tract.

Formaldehyde (HCHO), which has been shown to be a nasal carcinogen in rats and mice, is used widely and extensively in various manufacturing processes. Studies in rhesus monkeys suggest that the lower respiratory tract may be at risk and some epidemiologic studies have reported an increase in lung cancer associated with HCHO; other studies have not. Thus, an assessment of possible human risk to HCHO exposure based on dosimetry information throughout the respiratory tract (RT) is desirable. To obtain dosimetry estimates for a risk assessment, two types of models were used. The first model (which is the subject of another investigation) used computational fluid dynamics (CFD) to estimate local fluxes in a 3-dimensional model of the nasal region. The subject of the present investigation (the second model) applied a 1-dimensional equation of mass transport to each generation of an adult human symmetric, bifurcating Weibel-type RT anatomical model, augmented by an upper respiratory tract. The two types of modeling approaches were made consistent by requiring that the 1-dimensional version of the nasal passages have the same inspiratory air-flow rate and uptake during inspiration as the CFD simulations for 4 daily human activity levels. Results obtained include the following: (1) More than 95% of the inhaled HCHO is predicted to be retained by the RT. (2) The CFD predictions for inspiration, modified to account for the difference in inspiration and complete breath times, are a good approximation to uptake in the nasal airways during a single breath. (3) In the lower respiratory tract, flux is predicted to increase for several generations and then decrease rapidly. (4) Compared to first pulmonary region generation fluxes, the first few tracheobronchial generations fluxes are over 1000 times larger. Further, there is essentially no flux in the alveolar sacs. (5) Predicted fluxes based on the 1-dimensional model are presented that can be used in a biologically based dose-response model for human carcinogenesis. Use of these fluxes will reduce uncertainty in a risk assessment for formaldehyde carcinogenicity.

Simulated blood levels of CF3I in personnel exposed during its release from an F-15 jet engine nacelle and during intentional inhalation.

Of the agents under consideration for protecting unoccupied areas from fire, CF3I (trifluoroiodomethane) has physicochemical properties that give it potential as a "drop-in" replacement for halon 1301. One of the issues concerning the use of CF3I is the potential hazard to ground crews should an inadvertent discharge occur while workers are in or near an engine nacelle. A discharge test of CF3I was conducted on an F-15A jet to record CF3I concentration time histories at locations near the aircraft. The conditions of the discharges simulated an inadvertent ground discharge with the engine nacelle doors open and also with the doors closed. The use of three types of gas analysis instrumentation allowed gas sampling from several locations during the discharge tests. Concentrations measured at selected sensor locations were used as the input to a physiologically based pharmacokinetic model to simulate blood levels that would be attained by individuals inhaling CF3I at sensor locations. Blood levels reached during these exposures were compared with the blood level associated with the lowest observable adverse effect level (LOAEL) for cardiac sensitization to evaluate the possibility of safe egress. The highest blood concentrations simulated were twice the target blood concentration associated with cardiac sensitization. However, simulated blood concentrations of subjects who actually inhaled CF3I reached levels that were 100 times the target level without reported adverse effect. Thus, actual human data may supersede the use of the cardiac sensitization LOAEL obtained from animal studies.

Simulation of the uptake of a reactive gas in a rat respiratory tract model with an asymmetric tracheobronchial region patterned on complete conducting airway cast data.

Generally, the uptake of reactive gases by the respiratory tract is simulated assuming that all paths from the trachea to the most distal airspaces are equivalent. As this is not the case, especially for nonhumans, the adequacy of this approach to predict doses that can be useful in the fields of toxicology and risk assessment is subject to question. To explore this issue, a dosimetry model is developed which combines the use of one-dimensional convection-dispersion equations in conjunction with multiple path anatomic models so that the dosimetry model simultaneously simulates transport and uptake in all the airways and airspaces of the anatomic model. For this work, the anatomic model of the tracheobronchial (TB) region is patterned on cast data which describe the dimensions and branching network of the 4807 airways of the TB region of a rat. Distal to each of the 2404 terminal bronchioles of the anatomical model, the air space is modeled as a single path. The results presented are preliminary; they focus on the predictions themselves to obtain an understanding of what the model has to say about uptake in a complex set of branching airways. Results include the following predictions: (1) Regardless of path there is a similarity along different paths in the shape of concentration profiles as well as a similarity in the shape of dose profiles. (2) Along a path in the TB or pulmonary region, dose decreases distally. (3) Generally, proximal alveolar region (PAR, a region of major morphological damage due to O3 and NO2) dose decreases the more distal the PAR. (4) There is considerable variation in the doses of the different airways or alveolar surfaces in the same generation. (5) The maximum and minimum PAR doses do not correspond to paths with, respectively, the smallest and largest number of generations from the trachea to the PAR. (6) The ratio of the maximum to minimum PAR dose is very sensitive to tidal volume. These results give a more realistic understanding of respiratory tract gas transport and uptake. The model also predicts aspects that equivalent path models cannot, such as the dose distribution of different but morphologically equivalent sites.

Parental presence at induction of anaesthesia: a survey of N.S.W. hospitals and tertiary paediatric hospitals in Australia.

We undertook a survey of N.S.W. hospitals and tertiary paediatric hospitals in other States to determine their practice in relation to parental presence at induction of anaesthesia of children. There were 135 responses to 174 questionnaires. Twenty-one indicated that no children were anaesthetized at their institution and one was inadequately filled out. One hundred and thirteen questionnaires were assessed. Only 44% of departments had an official policy on parental attendance. A quarter of all hospitals described their facilities as entirely suitable, and a half compromised to allow parents to be present. The remaining quarter described their facilities as unsuitable. Overall, two-thirds of hospitals never or only sometimes had parents present at induction, and this applied equally to day stay patients and inpatients. Tertiary hospitals were more likely to have parents present, however they were more likely to have suitable facilities. The most common reason cited for parental attendance was parental expectation of being present, closely followed by the individual anaesthetist's philosophy. The most common reason for parents not attending was the individual anaesthetist's philosophy, followed by inadequate staffing.

Parental attitudes to presence at induction of paediatric anaesthesia.

Previous studies of parental presence at induction of anaesthesia in children have examined parental reaction to being present and the benefits gained from their presence. This study was undertaken specifically to assess parents' attitudes to being present at induction of their child's anaesthetic. A total of 154 questionnaires were distributed over a two-week period to parents of children presenting to the Day Stay Unit for procedures requiring general anaesthesia. Eighty-eight percent would have liked to be present at induction. Only 41% of parents expected to be present and only 40% of parents were actually present for their child's induction. Of those parents present, 94% felt it helpful to their child, 65% helpful to themselves and 41% helpful to the anaesthetist. No-one felt their presence to have been unhelpful. These results may provide an incentive for anaesthetists to review their current paediatric anaesthetic practices.

Advances in biologically based models for respiratory tract uptake of inhaled volatiles.

Physiologically based pharmacokinetic models for volatile organic chemicals typically describe the respiratory tract as a single compartment in which chemicals in the alveolar air space and the arterial blood are in instantaneous equilibrium. These models also assume that the distribution of chemical in the air-stream is uniform throughout the respiratory tract and that uptake is significant only in the alveolar region. A functional role for the upper respiratory tract in the uptake of volatile chemicals has been largely ignored. While these models have worked well for chemicals with low aqueous solubility in biological fluids, systemic uptake of highly soluble volatiles is overestimated. Thus, there is a significant effort to describe the critical determinants for uptake of soluble chemicals and to formulate models with more biologically relevant descriptions of respiratory tract structure and function. Investigators have addressed this problem from several viewpoints. Airflow patterns in the respiratory tract, regional metabolism, diffusion-dependent uptake, and the cyclic nature of respiration are now being incorporated into current models. Use of dosimetric models that incorporate relevant biology for inhaled chemicals will ultimately result in more meaningful human risk assessments.

A respiratory tract dosimetry model for air toxics.

The development of a physiologically based pharmacokinetic model for the whole body in which inhalation, exhalation, and metabolism in respiratory tract tissues are taken into account is described. As an example of the model's use, the results of several experiments in which rats and humans were exposed to styrene were simulated; these results are discussed. The predicted results agree with the empirical data and with the modeling results of others.

The U.S. Environmental Protection Agency's inhalation RfD methodology: risk assessment for air toxics.

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. This paper presents a brief background on the development of the inhalation reference dose (RfDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated into the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extrarespiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.

Estimating equivalent human concentrations of no observed adverse effect levels: a comparison of several methods.

Four methods for intra- and inter-species dose extrapolation for inhalation reference doses are discussed. Dichloromethane is used as an example to illustrate quantitative differences in the methods. The methods include a procedure recommended by the U.S. EPA in 1980, 2 approaches to using physiologically-based pharmacokinetic (PB-PK) models that depend on the extent of knowledge of the values of physiological parameters, and a proposed method based on the concepts inherent to PB-PK models but requiring significantly less data on physiological parameters.

Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Predictions of ozone absorption in human lungs from newborn to adult.

Although children are an important human population, dosimetry models for gases have been used to predict absorption mainly in laboratory animals and adult humans. To correct this omission, we have used several sources of data on age-dependent lower respiratory tract (LRT) volumes, age-dependent airway dimensions, a model of the adult tracheobronchial region, and a model of the adult acinus to construct theoretical LRT lung models for humans from birth to adulthood. An ozone (O3) dosimetry model was then used to estimate the regional and local uptake of O3 in the (theoretical) LRT of children and adults. For sedentary or quiet breathing, the LRT distribution of absorbed O3, the percent uptake (84 to 88%) and the centriacinar O3 tissue dose are not very sensitive to age. For maximal work during exercise, predicted LRT uptakes range from 87 to 93%, and the regional percent uptakes are more dependent on age than during quiet breathing. In general, the total quantity of O3 absorbed per minute increases with age. Regardless of age and state of breathing, the largest tissue dose of O3 is predicted to occur in the centriacinar region, where many animal studies show the maximal morphological damage from O3.

A model of the regional uptake of gaseous pollutants in the lung. II. The sensitivity of ozone uptake in laboratory animal lungs to anatomical and ventilatory parameters.

An O3 dosimetry model is used to simulate the local absorption of O3 in the lower respiratory tract of rats and guinea pigs. The model takes into account lower respiratory tract anatomy, transport in the lumen and air spaces, and transport and chemical reactions in the mucous and surfactant layers and in the underlying tissue and capillaries. For each species two anatomical models were used to investigate their influence in predicting absorption. Results with all four anatomical models and various ventilatory parameters showed a qualitative similarity in the shape of the dose versus airway number curves but significant differences in predicted percentage total and percentage pulmonary uptake. The percentage uptake was also sensitive to breathing frequency and tidal volume. Rat lobe models were used to study absorption in lobes and show that O3 tissue dose in centriacinar regions decreases with increasing distance from the trachea. The effect on results of values used for functional residual capacity and of values used for the chemical rate constants for O3 reactions in mucous were explored. Results differed quantitatively but not qualitatively.

Anaesthesia for patients with arthrogryposis multiplex congenita: what is the risk of malignant hyperthermia?

Arthrogryposis multiplex congenita has been linked with malignant hyperthermia. A review of the anaesthetic experience at the Royal Alexandra Hospital for Children over a 32-year period revealed no episode of malignant hyperthermia occurring in patients with arthrogryposis multiplex congenita despite many and varied exposures to known triggering agents.

Effect of halothane on spinal somatosensory evoked potentials in sheep.

The effects of increasing concentrations of halothane on the morphology of spinal somatosensory evoked potentials (SEP) were studied in seven anaesthetized sheep. Anaesthesia was induced with thiopentone and maintained with nitrous oxide in oxygen. Ventilation was controlled throughout. Arterial pressure, temperature and end-tidal carbon dioxide tension were monitored. A lumbar laminectomy was performed, the sciatic nerve exposed and a baseline spinal SEP was recorded from the surface of the lumbar spinal cord. Halothane was introduced in incremental steps of 1% up to 3% and further SEP were recorded. These recordings revealed that the spinal SEP peak latencies and general waveform configuration were stable under halothane anaesthesia. Baseline SEP amplitude was similar to that obtained with 1% halothane; however, at concentrations of 2% halothane or greater, there was a significant (P less than 0.005) attenuation of all components of the spinal SEP. These findings have important anaesthetic implications for patients undergoing spinal cord monitoring using SEP, although interspecies differences may occur.

A model of the regional uptake of gaseous pollutants in the lung. I. The sensitivity of the uptake of ozone in the human lung to lower respiratory tract secretions and exercise.

An ozone (O3) dosimetry model is presented that takes into account convection and diffusion of O3 in the lumen and airspaces of the lower respiratory tract and transport and chemical reactions in the mucous and surfactant layers and in the underlying tissue and capillaries. The model was applied to human airway morphometric data. Values for the chemical and physical parameters that define the liquid tissue and blood compartments were based on reported experimental data. Simulation results illustrate the variability of results due to an uncertainty in the knowledge of transport parameters, liquid, tissue, and blood compartment thicknesses, and chemical reaction rates. Results were most sensitive to mucous compartment thickness and reaction rate constant and least sensitive to transport and blood parameters. Exercise was simulated, showing little effect on tracheobronchial uptake but a pronounced effect on pulmonary uptake.

Acute epiglottitis in children.

The records of one hundred and sixty-one children with acute epiglottitis admitted to the Royal Alexandra Hospital for Children between January 1975 and June 1984 were reviewed. Forty-five complications occurred in thirty-four patients, including five deaths. The preferred method of airway management is direct laryngoscopy and nasotracheal intubation under general anaesthesia in the presence of skilled assistance. There should be no attempt to lie the child down prior to this, nor should awake laryngoscopy be attempted, as this may precipitate a respiratory arrest. Chloramphenicol (with or without ampicillin) should be commenced after blood cultures are obtained, as 20% of the sensitivities available demonstrated resistance to ampicillin.