Dosimetry of nasal uptake of water-soluble and reactive gases: a first study of interhuman variability.

Certain inhaled chemicals, such as reactive, water-soluble gases, are readily absorbed by the nasal mucosa upon inhalation and may cause damage to the nasal epithelium. Comparisons of the spatial distribution of nasal lesions in laboratory animals exposed to formaldehyde with gas uptake rates predicted by computational models reveal that lesions usually occur in regions of the susceptible epithelium where gas absorption is highest. Since the uptake patterns are influenced by air currents in the nose, interindividual variability in nasal anatomy and ventilation rates due to age, body size, and gender will affect the patterns of gas absorption in humans, potentially putting some age groups at higher risk when exposed to toxic gases. In this study, interhuman variability in the nasal dosimetry of reactive, water-soluble gases was investigated by means of computational fluid dynamics (CFD) models in 5 adults and 2 children, aged 7 and 8 years old. Airflow patterns were investigated for allometrically scaled inhalation rates corresponding to resting breathing. The spatial distribution of uptake at the airway walls was predicted to be nonuniform, with most of the gas being absorbed in the anterior portion of the nasal passages. Under the conditions of these simulations, interhuman variability in dose to the whole nose (mass per time per nasal surface area) due to differences in anatomy and ventilation was predicted to be 1.6-fold among the 7 individuals studied. Children and adults displayed very similar patterns of nasal gas uptake; no significant differences were noted between the two age groups.

The role of developmental toxicity studies in acute exposure assessments: analysis of single-day vs. multiple-day exposure regimens.

In accordance with most toxicity guidelines, developmental studies typically utilize repeated exposures, usually throughout gestation or during organogenesis in particular. However, it is known that developmental toxicity may occur in response to single exposures, especially during specific windows of susceptibility. An overview of the available literature gave sufficient evidence that for many agents, the same endpoints observed in repeated dose, multiple-day studies were also observed in single-day exposures, thus indicating the relevance of developmental toxicity to health assessments of acute exposures. Further, results of benchmark dose modeling of developmental endpoints indicated that for embryo lethality, single-day exposures required a two- to fourfold higher dose than the multiple-day exposures to produce the same level of response. For fused sternebrae, exposures on specific days produced equivalent levels of response at doses that were more similar to those utilized in the repeated exposures. Appreciable differences in biological half-life (and corresponding dose metrics) as well as specific windows of susceptibility may partially explain the observed multiple- vs. single-day exposure dose-response relationships. Our results highlight the need of a more thorough evaluation of outcomes from repeated dose developmental toxicity studies in regards to their importance to chronic and acute risk assessments.

Concentration-time-response modeling for acute and short-term exposures.

Risk of health effects from acute and short-term exposure depends on exposure time as well as exposure concentration. A general approach to extending a concentration-response model to include time as a variable is described using mortality of rats exposed to hydrogen sulfide (H(2)S) as an example. This particular example resulted in a logit model with concentration-time (c-t) relationship linear in time and log-concentration. It provided an improved statistical fit, based on the Akaike information criterion in the observed time range, 30 m-360 m, over implementing the c-t relationship of [ten Berge, W.F., Zwart, A., Appelman, L.M., 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13, 301--309] as a default in the logit model. This approach also indicated that there might be a fundamental difference in the relationship between concentration, time, and response at short exposure times, somewhere less than 30 m, a hypothesis for further consideration from a biological perspective. In general, the proposed approach provides flexibility to develop a concentration-time-response model, and the associated concentration-time relationship, from the data. Interpretation and potential implications, however, need to be considered within the context of biological plausibility as well. Implementation of the proposed approach requires adequate data for separate concentration-response modeling at each of several exposure durations.

A real-time method to evaluate the nasal deposition and clearance of acetone in the human volunteer.

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [(13)C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [(13)C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [(13)C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [(13)C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.

Bisphenol A levels in human urine.

The estrogenic effects of bisphenol A (BPA) have been reported in human cells (E-screen assays) and in (italic)in vivo(/italic) studies of rodents, although the latter reports remain controversial, as do the exposure levels and adverse health effects of BPA in humans. In this study we report on an analytical high-performance liquid chromatography/fluorescence method for BPA and its conjugate in human urine and on the application of this method in two student cohorts. Urine, along with information on smoking, alcohol intake, and coffee/tea consumption, was collected in two different years from two different groups of university students, 50 in 1992 and 56 in 1999. Overall, the urinary BPA levels in the students in 1992 were significantly higher than were those in 1999. The BPA levels were also positively correlated with coffee and tea consumption in the 1992 cohort but not in the 1999 cohort. We speculate that recent changes made in Japan regarding the interior coating of cans used to package these beverages may partly explain these findings.

US EPA's acute reference exposure methodology for acute inhalation exposures.

The US Environmental Protection Agency (EPA) National Center for Environmental Assessment is engaged in the development of a methodology for Agency use to perform risk assessments for non-cancer effects due to acute inhalation exposures. The methodology will provide general guidance for deriving chemical-specific acute exposure benchmarks called acute reference exposures (AREs). Chemical-specific AREs are analogous to reference concentra tions (RfCs) for chronic non-cancer effects and will be incorporated in chemical-specific files in the US EPA's Integrated Risk Information System (IRIS) as they are developed and reviewed. AREs will have wide applicability in assessing the potential health risks of accidental and routine acute releases of chemicals to the environment. The proposed methodology for ARE development provides a framework for choosing an optimal derivation approach, depending on the type of data available, from the no-observed-adverse-effect level (NOAEL), benchmark concentration (BMC), or categorical regression approaches. Uncertainty factors are applied to the point of departure, determined by one of the recommended approaches, to derive the ARE. Due to the capability to use more exposure-response information than the NOAEL approach allows, exposure-response analyses such as BMC and categorical regression are favored as methods to develop the point of departure when the available database will support such analyses. The NOAEL approach is suitable when the data are insufficient to support exposure-response modeling. Applications of the proposed ARE methodology are illustrated by the derivation of example AREs for hydrogen sulfide and hexachlorocyclopentadiene, which showcase the categorical regression and NOAEL approaches, respectively. In addition, a recent review of the proposed ARE methodology by the US EPA Risk Assessment Forum is discussed.