Modeling the toxicokinetics of inhaled toluene in rats: influence of physical activity and feeding status.

Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals, whether exposure duration is acute or chronic. The goals of this physiologically based pharmacokinetic (PBPK) model development effort were twofold: (1) to evaluate and explain the influence of feeding status and activity level on toluene pharmacokinetics utilizing our own data from toluene-exposed Long Evans (LE) rats, and (2) to evaluate the ability of the model to simulate data from the published literature and explain differing toluene kinetics. Compartments in the model were lung, slowly and rapidly perfused tissue groups, fat, liver, gut, and brain; tissue transport was blood-flow limited and metabolism occurred in the liver. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Sensitivity analysis revealed that the single most influential parameter for our experimental conditions was alveolar ventilation; other moderately influential parameters (depending upon concentration) included cardiac output, rate of metabolism, and blood flow to fat. Based on both literature review and sensitivity analysis, other parameters (e.g., partition coefficients and metabolic rate parameters) were either well defined (multiple consistent experimental results with low variability) or relatively noninfluential (e.g. organ volumes). Rats that were weight-maintained compared to free-fed rats in our studies could be modeled with a single set of parameters because feeding status did not have a significant impact on toluene pharmacokinetics. Heart rate (HR) measurements in rats performing a lever-pressing task indicated that the HR increased in proportion to task intensity. For rats acclimated to eating in the lab during the day, both sedentary rats and rats performing the lever-pressing task required different alveolar ventilation rates to successfully predict the data. Model evaluation using data from diverse sources together with statistical evaluation of the resulting fits revealed that the model appropriately predicted blood and brain toluene concentrations with some minor exceptions. These results (1) emphasize the importance of experimental conditions and physiological status in explaining differing kinetic data, and (2) demonstrate the need to consider simulation conditions when estimating internal dose metrics for toxicity studies in which kinetic data were not collected.

Consistent pulmonary and systemic responses from inhalation of fine concentrated ambient particles: roles of rat strains used and physicochemical properties.

Several studies have reported health effects of concentrated ambient particles (CAP) in rodents and humans; however, toxicity end points in rodents have provided inconsistent results. In 2000 we conducted six 1-day exposure studies where spontaneously hypertensive (SH) rats were exposed to filtered air or CAPs (< or = 2.5 microm, 1,138-1,765 microg/m3) for 4 hr (analyzed 1-3 hr afterward). In seven 2-day exposure studies in 2001, SH and Wistar Kyoto (WKY) rats were exposed to filtered air or CAP (< or = 2.5 microm, 144-2,758 microg/m3) for 4 hr/day times 2 days (analyzed 1 day afterward). Despite consistent and high CAP concentrations in the 1-day exposure studies, no biologic effects were noted. The exposure concentrations varied among the seven 2-day exposure studies. Except in the first study when CAP concentration was highest, lavageable total cells and macrophages decreased and neutrophils increased in WKY rats. SH rats demonstrated a consistent increase of lavage fluid gamma-glutamyltransferase activity and plasma fibrinogen. Inspiratory and expiratory times increased in SH but not in WKY rats. Significant correlations were found between CAP mass (microgram per cubic meter) and sulfate, organic carbon, or zinc. No biologic effects correlated with CAP mass. Despite low chamber mass in the last six of seven 2-day exposure studies, the levels of zinc, copper, and aluminum were enriched severalfold, and organic carbon was increased to some extent when expressed per milligram of CAP. Biologic effects were evident in those six studies. These studies demonstrate a pattern of rat strain-specific pulmonary and systemic effects that are not linked to high mass but appear to be dependent on CAP chemical composition.

World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory protection, individual differences in sensitivity to WTC PM2.5, and species differences in responses must be considered in assessing the risks of exposure to WTC PM2.5.