Physiologically Based Pharmacokinetic Model Parameter Estimation and Sensitivity and Variability Analyses for Acrylonitrile Disposition in Humans

Abstract

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.

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

“…There are also a large number of good examples of PBPK models which describe the kinetics of important environmental contaminants, including methylene chloride (8,44,45), trichloroethylene (46)(47)(48), chloroform (49, 50), 2-butoxyethanol (51), kepone (52), polybrominated biphenyls (53), polychlorinated biphenyls (54) and dibenzofurans (55), dioxins (56,57), lead (58)(59)(60)(61)(62), arsenic (63,64), methylmercury (65), atrazine (66,67), acrylonitrile (68)(69)(70), perchlorate (71)(72)(73)(74)(75)(76), and BTEX components (77)(78)(79)(80)(81). The U.S. EPA is currently compiling a compendium of PBPK models including source code.…”

Cancer dose–response assessment for acrylonitrile based upon rodent brain tumor incidence: Use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity

“…A large amount of information has been collected over the past 22 years, much of which can be used to speciWcally address data gaps identiWed by USEPA in their 1983 assessment, including the following (numbers in parentheses correspond to numbered data gaps listed in the introduction): (1) several large well-designed, epidemiology studies have been conducted including those with extensive exposure information (Blair et al, 1998;Swaen et al, 1998Swaen et al, , 2004Wood et al, 1998); (2) two follow-up studies have been conducted for the O'Berg (1980) cohort (O'Berg et al, 1985;Wood et al, 1998); (3) a three-generation reproductive toxicity study in rats has been published for AN (Friedman and Beliles et al, 2002); (4) additional cancer bioassays have been conducted for AN using mice following oral exposure (NTP, 2001) and rats following oral and inhalation exposure (Bigner et al, 1986;Ghanayem et al, 2002;Maltoni et al, 1988); (5) an in vitro cell transformation study has been conducted for AN in Syrian hamster embryo cells (Zhang et al, 2000); (6) a number of mechanistic studies have been conducted for AN that demonstrate a role for oxidative stress in the formation of rat brain tumors (Jiang et al, 1998;Kamendulis et al, 1999a;Murata et al, 2001;Whysner et al, 1998a;Zhang et al, 2002); (7) a large amount of pharmacokinetic data has been collected and compiled into physiologically based pharmacokinetic (PBPK) models for AN in rats (Gargas et al, 1995;Kedderis and Fennell, 1996) and humans (Sweeney et al, 2003); (8) a mutagenicity study has been conducted for AN in human lymphoblasts (Recio and Skopek, 1988); and (9) dominant lethal studies have been conducted for AN (Working et al, 1987;Butterworth et al, 1992).…”

“…b Internal dose measures were estimated from the values for intensity using the human PBPK model for AN (Sweeney et al, 2003). Values in the In the Blair et al (1998) study, there was no evidence to indicate that exposure to AN at the levels experienced by these workers was associated with any signiWcant increased relative risk for most cancers.…”

Assessing the dose-dependency of allometric scaling performance using physiologically based pharmacokinetic modeling

“…The impact of uncertainty and variation in PBPK model parameters on the resulting internal dose measures was not evaluated in this assessment. However, experience with similar chemicals (glycol ethers and acrylonitrile) indicates that the impact of uncertainty/variation in model parameters on internal dose is generally within a factor of two (Sweeney et al, 2001(Sweeney et al, , 2003. An additional limitation is that the comparison herein is based principally on PBPK models which describe the pharmacokinetics of volatile, lipophilic compounds.…”