Improved predictive model for n-decane kinetics across species, as a component of hydrocarbon mixtures.

n-Decane is considered a major component of various fuels and industrial solvents. These hydrocarbon products are complex mixtures of hundreds of components, including straight-chain alkanes, branched chain alkanes, cycloalkanes, diaromatics, and naphthalenes. Human exposures to the jet fuel, JP-8, or to industrial solvents in vapor, aerosol, and liquid forms all have the potential to produce health effects, including immune suppression and/or neurological deficits. A physiologically based pharmacokinetic (PBPK) model has previously been developed for n-decane, in which partition coefficients (PC), fitted to 4-h exposure kinetic data, were used in preference to measured values. The greatest discrepancy between fitted and measured values was for fat, where PC values were changed from 250-328 (measured) to 25 (fitted). Such a large change in a critical parameter, without any physiological basis, greatly impedes the model's extrapolative abilities, as well as its applicability for assessing the interactions of n-decane or similar alkanes with other compounds in a mixture model. Due to these limitations, the model was revised. Our approach emphasized the use of experimentally determined PCs because many tissues had not approached steady-state concentrations by the end of the 4-h exposures. Diffusion limitation was used to describe n-decane kinetics for the brain, perirenal fat, skin, and liver. Flow limitation was used to describe the remaining rapidly and slowly perfused tissues. As expected from the high lipophilicity of this semivolatile compound (log K(ow) = 5.25), sensitivity analyses showed that parameters describing fat uptake were next to blood:air partitioning and pulmonary ventilation as critical in determining overall systemic circulation and uptake in other tissues. In our revised model, partitioning into fat took multiple days to reach steady state, which differed considerably from the previous model that assumed steady-state conditions in fat at 4 h post dosing with 1200 ppm. Due to these improvements, and particularly the reconciliation between measured and fitted partition coefficients, especially fat, we have greater confidence in using the proposed model for dose, species, and route of exposure extrapolations and as a harmonized model approach for other hydrocarbon components of mixtures.

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species.

The effects of perchlorate on the incorporation of iodide into thyroid hormones have been studied for more than 40 years in many species and under varying exposure conditions. Nevertheless, the database for this drinking water contaminant is still incomplete, particularly with regard to human developmental risk. A method for integrating the available data and forming meaningful conclusions for risk assessment is needed. To this end, an initial suite of physiologically based pharmacokinetic (PBPK) models has been developed, which incorporates physiological data for the relevant species and life stages and kinetic data for perchlorate and iodide, as well as the interaction between the two anions. The validated models successfully describe perchlorate-induced inhibition of thyroid iodide uptake and perchlorate and iodide kinetics in the male, pregnant, lactating, fetal, and neonatal rats and the adult humans. The relationships of model-predicted internal dose metrics and kinetic parameters allow a direct comparison of internal dose metrics across life stages in rats and humans. By incorporating all the available data, these models provide a framework for species and life stage extrapolation where the lack of specific data sets would otherwise limit predictive capability. This paper demonstrates two approaches for calculating life stage-specific equivalent doses in a risk assessment for perchlorate: the direct combination of validated model predictions, and the development of preliminary PBPK models for the human-sensitive populations based on the relationship of the parameters in the validated rat and human models. Either approach can be used to perform the needed dosimetry. However, the second approach provides the advantage of a preliminary human life stage-specific PBPK model that can be used for identification of key data gaps and estimation of uncertainty.

Diurnal and seasonal variations of radon levels, effects of climatic conditions, and radon exposure assessment in a former uranium metal production facility.

Storage of radon-producing material in two silos and two waste pits is one of the major environmental and occupational issues at a former uranium production facility, now a Superfund site. In addition, up to 100 metric tons of thorium is stored on the northeast side of the site. Concentrations of radium up to 17,600 Bq g(-1) (477,000 pCi g(-1)) or higher for silos and up to 45 Bq g(-1) (1,200 pCi g(-1)) for waste pits have been reported. This study was conducted to identify factors and climatic conditions that contribute to higher radon levels and to assess workers' exposure at the site. Data covering a 12-mo period were compiled from monitoring hourly real-time radon levels at indoor (within 3 buildings) and outdoor (at 14 on-site and 2 off-site monitoring stations) locations and from hourly site-specific meteorological information. The ranges of radon levels were as follows: 1.8-3,655 Bq m(-3) (0.05-98.8 pCi L(-1)) outdoor on-site, 3.7-329 Bq m(-3) (0.1-8.9 pCi L(-1)) outdoor off-site, and 1.8-111 Bq m(-3) (0.05-3.0 pCi L(-1)) indoor on-site. Only radon levels in the vicinity of the storage silos were significantly higher than levels off-site. Radon concentrations showed diurnal variations, with maximum levels occurring in the early morning and minimum levels in the afternoon. Seasonal variation was also observed, with radon levels higher during the summer through early fall and lower during the late winter through spring. Wind speed, relative humidity, and wind direction appeared to be the most significant predictors of radon concentration. The estimated radon dose to workers, calculated by using exposure models and annual average levels of radon in the work area, was below recommended exposure limits. These results suggest that the emission control methods at this site have been effective in maintaining environmental radon contamination and workers' exposure at acceptable levels.

Managing fever in infants and toddlers: toward a standard of care.

Fever in infants and toddlers can portend a serious bacterial illness requiring a prompt medical response. When dealing with a febrile child between 1 and 36 months of age, physicians should consider toxicity, focal infections, age, and the results of a sepsis workup and then use a strategy based on the Rochester criteria to assess whether the patient is at low risk for a serious bacterial illness. On the basis of that determination, a plan for inpatient or outpatient management can be selected. Variations in treatment can reasonably be based on clinical judgment and physician and parent preferences.

The depiction of guns on prime time television.

Two weeks of regular prime-time programming on four major networks (ABC, CBS, Fox, and NBC) was monitored for scenes in which guns were either used or displayed. Guns were seen most often on CBS, Saturdays and Sundays, and later in the evenings. Middle-aged, white males were depicted as gun users in better than 75% of the scenes. Most scenes involved pistols. Most often the person who used the gun suffered no repercussions. When a victim was depicted as being shot, seldom was the pain of the victim, the victim's family, or friends demonstrated.