Physiologically based kinetic modeling of the bioactivation of myristicin

Abstract

The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of the proximate carcinogenic metabolite 1′-hydroxymyristicin in liver is at most 1.8 fold higher in rat than in human and limited for the ultimate carcinogenic metabolite 1′-sulfoxymyristicin to (2.8–4.0)-fold higher in human. In addition, a comparison was made between the relative importance of bioactivation for myristicin and safrole. Model predictions indicate that for these related compounds, the formation of the 1′-sulfoxy metabolites in rat and human liver is comparable with a difference of <2.2-fold over a wide dose range. The results from this PBK analysis support that risk assessment of myristicin may be based on the BMDL10 derived for safrole of 1.9–5.1 mg/kg bw per day. Using an estimated daily intake of myristicin of 0.0019 mg/kg bw per day resulting from the use of herbs and spices, this results in MOE values for myristicin that amount to 1000–2700, indicating a priority for risk management. The results obtained illustrate that PBK modeling provides insight into possible species differences in the metabolic activation of myristicin. Moreover, they provide an example of how PBK modeling can facilitate a read-across in risk assessment from a compound for which in vivo toxicity studies are available to a related compound for which tumor data are not reported, thus contributing to alternatives in animal testing.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1752-5) contains supplementary material, which is available to authorized users.

Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in nutmeg-based plant food supplements

“…Assuming equal potency of the alkenylbenzenes, combined EDI values obtained ranged from 1.5 to 631 μg kg −1 bw per day resulting in MOE values ranging from 3 to 1309 for the samples in which more than one alkenylbenzene was detected. Using a TEQ concept with TEF values based on in vitro and in vivo data (Miller et al, ; Randerath et al, ; Punt et al, ; Al‐Subeihi et al, ; Martati et al, ; van den Berg et al, ; Alajlouni et al, ; Al‐Malahmeh et al, ), combined EDI values ranged from 0.4 to 295 μg safrole equivalents kg −1 bw leading to MOE values ranging from 6 to 5020. MOE values resulting from both these combined exposure assessments were up to fivefold lower than the MOE values obtained when considering individual exposure to alkenylbenzenes.…”

“…The second one, was the in vivo level of formation of the hepatocarcinogenic 1′‐sulfoxymetabolite of the different alkenylbenzenes predicted using human physiologically based kinetic (PBK) models at a dose level of 0.01 mg kg −1 bw (Punt et al, ; Al‐Subeihi et al, ; Martati et al, ; van den Berg et al, ; Alajlouni et al, ; Al‐Malahmeh et al, ). A third value was defined based on the BMDL 10 values derived from in vivo tumour data for safrole, estragole and methyleugenol (Miller et al, ), and by read‐across from safrole for myristicin and apiol (Alajlouni et al, ; Al‐Malahmeh et al, ), or by read‐across from methyleugenol and estragole for elemicin (van den Berg et al, ). The TEF values for the different alkenylbenzenes defined by the three approaches relative to safrole were subsequently averaged to define the final TEF values (Alajlouni et al, ).…”

“…A third value was defined based on the BMDL 10 values derived from in vivo tumour data for safrole, estragole and methyleugenol (Miller et al, ), and by read‐across from safrole for myristicin and apiol (Alajlouni et al, ; Al‐Malahmeh et al, ), or by read‐across from methyleugenol and estragole for elemicin (van den Berg et al, ). The TEF values for the different alkenylbenzenes defined by the three approaches relative to safrole were subsequently averaged to define the final TEF values (Alajlouni et al, ). Using these TEF values, the EDI of alkenylbenzenes in the nutmeg‐based PFS were expressed in μg safrole equivalents kg −1 bw per day.…”

Study on inter-ethnic human differences in bioactivation and detoxification of estragole using physiologically based kinetic modeling

“…Chromatographic analysis revealed a peak at 1.4 min, identified as the GSH adduct of 1′-sulfooxyestragole. This identification was based on the fact that the peak was absent in the incubations with PAPS and S9 in the absence of GSH (chromatogram not shown), and the previous identification of this (Punt et al 2007 ) and similar alkenylbenzene 1′-sulfooxy adducts by LC-MS (Al-Malahmeh et al 2017 ; Al-Subeihi et al 2012 ; Alajlouni et al 2016 ; Martati et al 2012 ).…”

Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in basil-containing sauce of pesto

“…The first one was the slope of the dose-response curve for DNA-adduct formation in female CD-1 mice liver upon exposure to different alkenylbenzenes [32] . The second one, was the in vivo level of formation of the hepatocarcinogenic 1′-sulfoxymetabolites of the different alkenylbenzenes predicted using human physiologically based kinetic (PBK) models at a dose level of 0.01 mg/kg bw [2] , [1] , [31] , [3] . And finally, the BMDL 10 values derived from in vivo tumor data for safrole, estragole, and methyleugenol [27] , or by read-across from safrole for myristicin and apiol [2] , [1] ( Table 4 ).…”