In silico toxicology: simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane.

Abstract

In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.

Assessing Human Variability in Kinetics for Exposures to Multiple Environmental Chemicals: A Physiologically Based Pharmacokinetic Modeling Case Study with Dichloromethane, Benzene, Toluene, Ethylbenzene, andm-Xylene

“…Although the number of chemicals involved may also appear as a factor, the data generated show that when the total concentrations of the added chemicals remains low, no marked impact is observed on internal dose metrics of an initial single substance (Bz or DCM). In fact, the concentration of that "inhibitory mixture" in the vicinity of the metabolizing enzymes, whether in terms of number of substances (TOL + EBz + m-XYL) or concentration of TOL alone, is rather the critical factor and needs overall to reach a minimum level, also termed "threshold effect concentration" by Dobrev et al (2001Dobrev et al ( , 2002, in order to effectively compete for CYP2E1 catalytic sites with resulting impact on metabolism of Bz or DCM. Thus, adding inhibitory substances in the mixture results in a decrease of CYP2E1-mediated metabolism of the parent compound and thus a rise in their AUC or Cmax.…”

“…In some cases, this approach allowed the proposition of threshold concentrations in the media for metabolic interactions (Dobrev et al, 2001(Dobrev et al, , 2002. Accounting for metabolic interactions in a PBPK model requires modification of differential equations representing metabolism in order to reflect every binary interaction occurring between all components of a given mixture (Haddad et al, 2010).…”

Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

“…circulation of di-n-butylphthalate to the monobutylphthalate and the glucuronide; compounds that cause impairment of male reproductive tissues (Clewell et al, 2008); the metabolism and oral absorption and of atrazine on toxicity of the pituitary axis and enzyme inhibition (McMullin et al, 2007); the metabolism-associated toxicities of trichloroethylenes (Dobrev et al, 2002); the bioactivation of vinyl chloride to the DNA-reactive epoxide (Reitz et al, 1996;Clewell et al, 2001); and the inhalation toxicity of acrylate ester (Frederick et al, 1998(Frederick et al, , 2002Sweeney et al, 2004). The in vitro/in vivo drug and metabolite transport/distribution and elimination behavior, especially in target organs, should be studied to add to the robustness of the PBPK model.…”

Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures

“…Occupational exposures to chemical mixtures of the three solvents within their threshold limit value (TLV)/time weighted average (TWA) limits were predicted to result in a significant increase (22%) in TCE blood levels compared with single exposures. Dobrev et al [2002] extended this work to humans by developing an interactive human PBPK model to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels, and total amount of TCE metabolites generated in rats and humans. Increases in the TCE blood levels were predicted to lead to higher availability of the parent compound for GSH conjugation, a metabolic pathway that may be associated with kidney toxicity/carcinogenicity.…”