Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling

Abstract

Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions.

Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

“…The linear sensitivity analysis now performed was a simple first tier approach aiming to provide initial information about which parameters influence the predicted C max values most, while a more extended analysis of variability in the thus identified most influential parameters, for example via example Monte Carlo modeling, might provide additional insight in intraspecies differences. [ 52,53,54 ]…”

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

“…For the Monte Carlo analysis, a total of 15 000 simulations were performed, where in each simulation, the V max and K m of lasiocarpine depletion and of 7-GS-DHP formation were randomly taken from a log-normal distribution. The distributions were truncated at ± 3SD by excluding individuals with kinetic constants that were three times higher or lower than the geometric mean (GM) values from the Monte Carlo simulation (Punt et al 2016;Strikwold et al 2017). The kinetic constants for the lasiocarpine depletion and 7-GS-DHP formation in the liver were assumed to vary independently, but the maximum allowed ratio of the V max of 7-GS-DHP formation and the V max of lasiocarpine depletion was set to 1.0 to assure 7-GS-DHP formation cannot exceed the total lasiocarpine depletion.…”

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

“…In addition, more sufficient quantitative estimations of kinetic constants, as slices are heterogeneous in composition and impaired diffusion of chemicals into the cells of the slices hampers adequate measurement of the clearance, even if the slices are very thin (Houston and Carlile, 1997;van Eijkeren, 2002;Yoon et al, 2012). A final source of in vitro material includes recombinant enzymes, such as for example cytochrome P450 and UGT enzymes that are transfected into insect cells (Punt et al, 2016;Rostami-Hodjegan and Tucker, 2007). Measurements with these recombinant enzymes are particularly useful to explore human variation in metabolism of chemicals using information on the human variation in expression of these enzymes (Punt et al, 2016;Rostami-Hodjegan and Tucker, 2007).…”

“…A final source of in vitro material includes recombinant enzymes, such as for example cytochrome P450 and UGT enzymes that are transfected into insect cells (Punt et al, 2016;Rostami-Hodjegan and Tucker, 2007). Measurements with these recombinant enzymes are particularly useful to explore human variation in metabolism of chemicals using information on the human variation in expression of these enzymes (Punt et al, 2016;Rostami-Hodjegan and Tucker, 2007). New sources of human metabolically competent cells that do not rely on human donor materials are being explored.…”