Biomedical subjects

Lisa M Sweeney

Publications and source records attributed to Lisa M Sweeney.

3 recordsLinked to original sources

PubMed2004

Estimation of interindividual variation in oxidative metabolism of dichloromethane in human volunteers.

A modified version of the original physiologically based pharmacokinetic (PBPK) model by Andersen et al. (1987) has been developed and used in conjunction with previously published human kinetic data for dichloromethane (DCM) metabolism and to assess interindividual variability in the rate of oxidative metabolism. Time-course data for 13 volunteers (10 males, 3 females) exposed to one or more concentrations of DCM (50 ppm, 100 ppm, 150 ppm, or 200 ppm) for 7.5h were used to optimize the maximal rate of hepatic metabolism (V(maxC)) through the cytochrome P450 pathway for each individual. DCM breath and blood concentrations were used, along with carboxyhemoglobin concentrations in blood and carbon monoxide (CO) concentrations in exhaled breath, to estimate the model parameters. Significant improvements in model fit were achieved when extrahepatic oxidative metabolism of DCM was added to the model structure. The 13 individual V(maxC) values ranged from 7.1 to 23.6 mg/h/kg0.7 and appeared to be bimodally distributed. The distribution was not sex related and may be related to differential CYP2E1 induction. A comparison of the observed variation in V(maxC) values to other estimates of variability in the rate of oxidative metabolism and human CYP2E1 activity suggest a relatively narrow range in human hepatic activity toward DCM.

Adult↗

PubMed2004

Ethyl acrylate risk assessment with a hybrid computational fluid dynamics and physiologically based nasal dosimetry model.

Cytotoxicity in the nasal epithelium is frequently observed in rodents exposed to volatile organic acids and esters by inhalation. An interspecies, hybrid computational fluid dynamics and physiologically based pharmacokinetic (CFD-PBPK) dosimetry model for inhaled ethyl acrylate (EA) is available for estimating internal dose measures for EA, its metabolite acrylic acid (AA), and EA-mediated reductions in tissue glutathione (GSH). Nasal tissue concentrations of AA were previously used as the dose metric for a chronic Reference Concentration (RfC) calculation with this compound. However, EA was more toxic than expected, based on calculated tissue AA concentrations. Unlike AA, EA causes depletion of tissue GSH. We have developed an RfC for EA using tissue GSH depletion in the olfactory epithelium as the primary measure of nasal tissue dose. The hybrid CFD-PBPK model was refined to improve the accuracy of simulations for GSH in rat olfactory tissues. This refined model was used to determine the concentration for continuous human exposures to EA predicted to reduce nasal GSH levels to the same extent as seen in rats exposed to EA at the no-observed-effect level (NOEL). Importantly, AA concentrations in the human nasal olfactory epithelium at the proposed chronic RfC were predicted to be lower than the AA concentrations estimated in the rat at the NOEL. Thus, a chronic RfC based on maintaining GSH in the human nasal olfactory epithelium at levels equivalent to the rat NOEL would also provide an adequate margin of safety with respect to AA concentrations in nasal tissues.

Acrylates↗

PubMed2003

Physiologically based pharmacokinetic model parameter estimation and sensitivity and variability analyses for acrylonitrile disposition in humans.

A physiologically based pharmacokinetic (PBPK) model of acrylonitrile (ACN) and cyanoethylene oxide (CEO) disposition in humans was developed and is based on human in vitro data and scaling from a rat model (G. L. Kedderis et al., 1996, TOXICOL: Appl. Pharmacol.140, 422-435) for application to risk assessment. All of the major biotransformation and reactivity pathways, including metabolism of ACN to glutathione conjugates and CEO, reaction rates of ACN and CEO with glutathione and tissues, and the metabolism of CEO by hydrolysis and glutathione conjugation, were described in the human PBPK model. Model simulations indicated that predicted blood and brain ACN and CEO concentrations were similar in rats and humans exposed to ACN by inhalation. In contrast, rats consuming ACN in drinking water had higher predicted blood concentrations of ACN than humans exposed to the same concentration in water. Sensitivity and variability analyses were conducted on the model. While many parameters contributed to the estimated variability of the model predictions, the reaction rate of CEO with glutathione, hydrolysis rate for CEO, and blood:brain partition coefficient of CEO were the parameters predicted to make the greatest contributions to variability of blood and brain CEO concentrations in humans. The main contributor to predicted variance in human blood ACN concentrations in people exposed through drinking water was the Vmax for conversion of ACN to CEO. In contrast, the main contributors for variance in people exposed by inhalation were expected to be the rate of blood flow to the liver and alveolar ventilation rate, with the brain:blood partition coefficient also contributing to variability in predicted concentrations of ACN in the brain. Expected variability in blood CEO concentrations (peak or average) in humans exposed by inhalation or drinking water was modest, with a 95th-percentile individual expected to have blood concentrations 1.8-times higher than an average individual.

Acrylonitrile↗