Application of Biologically Based Lumping To Investigate the Toxicokinetic Interactions of a Complex Gasoline Mixture

Abstract

People are often exposed to complex mixtures of environmental chemicals such as gasoline, tobacco smoke, water contaminants, or food additives. We developed an approach that applies chemical lumping methods to complex mixtures, in this case gasoline, based on biologically relevant parameters used in physiologically based pharmacokinetic (PBPK) modeling. Inhalation exposures were performed with rats to evaluate the performance of our PBPK model and chemical lumping method. There were 109 chemicals identified and quantified in the vapor in the chamber. The time-course toxicokinetic profiles of 10 target chemicals were also determined from blood samples collected during and following the in vivo experiments. A general PBPK model was used to compare the experimental data to the simulated values of blood concentration for 10 target chemicals with various numbers of lumps, iteratively increasing from 0 to 99. Large reductions in simulation error were gained by incorporating enzymatic chemical interactions, in comparison to simulating the individual chemicals separately. The error was further reduced by lumping the 99 nontarget chemicals. The same biologically based lumping approach can be used to simplify any complex mixture with tens, hundreds, or thousands of constituents.

A re‐evaluation of PETROTOX for predicting acute and chronic toxicity of petroleum substances

“…[1,2]. It has been broadly applied to assess aquatic, soil, and sediment toxicity, multimedia exposures, product and site risk, and life cycle, in a variety of other research and regulatory contexts [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures – A review

“…The mixture consisted of the parent chemical, benzene, and its metabolites according to Mumtaz et al [11] and Yang and Andersen [12] . This was followed by numerous examples of binary mixtures [12] , [13] , ternary [14] , [15] , quaternary [16] , [17] , [18] , and complex mixtures [19] , [20] , [21] , [22] .…”

“…5 Flow chart depicting the top-down PBK modelling approach to evaluate interactions in complex gasoline mixtures. The complex gasoline mixture is simplified into ‘N’ number of target chemicals and sets of chemical lumps using biologically based lumping methodology as described by Jasper and colleagues [21] . …”

“…The individual PBK models for each chemical and the lump were linked by competitive inhibition of hepatic metabolism at a binary level [19] , [32] . Similarly, Jasper et al [21] have evaluated the role of lumping within the target organ in PBK modelling to describe the toxicokinetics of a complex gasoline mixture following inhalation exposure in rats. A total of 109 chemicals were identified and quantified after inhalation exposure, and the mixture was then simplified to 10 target chemicals and various numbers of lumps.…”

“…A total of 109 chemicals were identified and quantified after inhalation exposure, and the mixture was then simplified to 10 target chemicals and various numbers of lumps. The PBK model simulated well the blood concentration for 10 target chemicals compared to the experimental data when enzymatic interaction was incorporated to the PBK model and by lumping the 99 non target chemicals [21] .…”