Use of physiologically based kinetic modelling facilitated read-across in risk assessment of botanical food-borne alkenylbenzenes

Amer Al-Malahmeh

Research output: Thesisinternal PhD, WU


Botanicals and botanical preparations have become widely available on the market in the form of food supplements and other food preparations. In Europe the safety of botanicals and derived food products placed on the market has to comply with the general requirements set out in regulation (EC) No 178/2002. In spite of this regulation, the risks of botanicals and botanical preparations are generally not assessed before they enter the market.

The present thesis aimed to perform a risk assessment of some selected botanicals and derived preparations focusing on samples containing the so-called alkenylbenzenes, including myristicin, apiol, safrole, methyleugenol, elemicin, and estragole.  Samples containing alkenylbenzenes may be of concern because these compounds may be genotoxic and carcinogenic displaying similar characteristics regarding mode of action (MOA) and tumor formation. The aim of the present study was to develop a MOA based approach for read-across in risk assessment from safrole, for which in vivo toxicity studies are available to myristicin and apiol for which tumor data are not reported, thus contributing to alternatives in animal testing. This was done using physiologically based kinetic (PBK) modelling. Botanical preparations included in the risk assessments performed in the present thesis were basil-containing pesto and nutmeg-based plant food supplements (PFS). Given that several of the preparations analyzed contained several alkenylbenzenes a risk assessment of combined exposure to these alkenylbenzenes was included as well, to give a better understanding of when risk management actions would be needed for botanicals and derived preparations containing these ingredients.

The introduction chapter starts with a short background and definition of the aim of the thesis, followed by a description of the physicochemical properties, natural occurrence and estimated daily intake (EDI) of the alkenylbenzenes, as well as of their ADME (absorption, distribution, metabolism and excretion) characteristics, carcinogenicity and MOA, the relevant risk assessment approach, and finally PBK modelling.

Chapter 2 and 3 of the thesis describe the development of PBK models for myristicin and apiol in male rat and human, enabling the prediction of dose-dependent effects in bioactivation and detoxification of these alkenylbenzenes. This allows comparison of the PBK model-based prediction of bioactivation of myristicin or apiol to the PBK model-based predictions for bioactivation of the structurally related compound safrole, enabling estimation of a BMDL10 for myristicin and apiol from read-across to the BMDL10 available for safrole, thereby facilitating risk assessment of current dietary exposure to myristicin or apiol. The results from PBK analysis support that risk assessment of myristicin may be based on the BMDL10 derived for safrole, and that risk assessment of apiol may be performed using a BMDL10 value of 3 times the BMDL10 for safrole. These results enabled a preliminary risk assessment of current exposure to these alkenylbenzenes showing that the current exposure to myristicin results in MOE values indicating a priority for risk management (Chapter 2), while current exposure to apiol does not raise a concern (Chapter 3). The results obtained illustrate that 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.

Subsequently, in Chapter 4 the BMDL10 values obtained were used to perform a risk assessment  for alkenylbenzenes in basil-based pesto sauce. To this end the levels of methyleugenol and other alkenylbenzenes in basil-containing sauce of pesto were quantified enabling an associated risk assessment based on the MOE approach, taking into consideration the possible combined exposure to different alkenylbenzenes and the BMDL10 values as defined in literature and in chapter 2 and 3 of the thesis. The MOE values obtained generally indicated a priority for risk management when assuming daily consumption of basil-based pesto sauce. It was concluded that consumption of pesto sauces would be of concern if consumed on a daily basis over longer periods of time.

Chapter 5 evaluates the risk of exposure to myristicin and related alkenylbenzenes through human exposure to nutmeg-based PFS based on the MOE approach. Chemical analysis of various PFS samples was performed and the amount of alkenylbenzenes that would be consumed through consumption of these nutmeg-based PFS where quantified. MOE values where calculated for the individual alkenylbenzenes as well as taking into account the presence of more than one alkenylbenzenes within selected PFS samples. It was concluded that the results reveal that daily nutmeg-based PFS consumption following recommendations for daily intake for especially longer periods of time would raise a concern.

Chapter 6 summarizes the results obtained in the thesis, compiles the overall discussion and presents the future perspectives that follow from the results obtained.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • Rietjens, Ivonne, Promotor
  • Vervoort, J.J.M., Co-promotor
  • Wesseling, Sebas, Co-promotor
Award date5 Sept 2017
Place of PublicationWageningen
Print ISBNs9789463434591
Publication statusPublished - 5 Sept 2017


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