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Alkenylbenzenes including estragole, methyleugenol, safrole, elemicin, apiol, and myristicin are naturally occurring in many herbs such as parsley, dill, basil, tarragon, fennel and nutmeg (Kreydiyyeh and Usta, 2002, Smith et al., 2002, Semenov et al., 2007). Estragole, methyleugenol and safrole are genotoxic and carcinogenic in rodent bioassays inducing liver tumors (Boberg et al., 1986, Boberg et al., 1983, Drinkwater et al., 1976, Miller et al., 1983, Swanson et al., 1981, Wiseman et al., 1985, Wiseman et al., 1987, Wislocki et al., 1977). Because of that, the use of methyleugenol, safrole and estragole as pure substances in foodstuff has been prohibited in the EU from September 2008 onwards (European Commission (EC), 2008). For apiol and myristicin data for their risk assessment are limited and more research is needed to support the evaluation of the risk resulting from consumption of products containing these compounds (WHO, 2009). The aim of the current thesis was to perform a mode of action based risk assessment of exposure to low doses of apiol and myristicin by using physiologically based kinetic (PBK) modelling based read-across from other alkenylbenzenes and to use the results obtained for risk assessment of consumption of plant food supplements (PFS) and other botanical products containing parsley and dill. Chapter 1 provides general background information to alkenylbenzenes especially apiol and myristicin, a description of the chemical, metabolic and toxicity characteristics of apiol and myristicin and other structurally related alkenylbenzenes, a brief outline of the method used for their risk assessment and a short introduction to PBK modelling. Besides that, Chapter 1 include the aim of the current thesis. In Chapter 2 and Chapter 3, PBK models for respectively apiol and myristicin in male rat and human were defined, enabling prediction of dose-dependent effects in bioactivation and detoxification of these alkenylbenzenes. The PBK model based predictions were subsequently compared to those for safrole enabling estimation of a BMDL10 for apiol and myristicin from read-across from the BMDL10 available for safrole, thereby enabling risk assessment of current dietary exposure to apiol. In Chapter 4 and 5, the risk assessment of exposure to apiol and related alkenylbenzenes through drinking of parsley and dill based herbal teas and consumption of parsley and dill containing PFS was performed using the BMDL10 values derived in Chapter 2 and 3. The results showed that consumption of parsley and dill based herbal teas and PFS would be a priority for risk management if consumed for longer periods of time. Chapter 6 includes a general discussion of the thesis results obtained and the future perspectives that describe the needs to further research, based on alternatives for animals testing, to improve the risk assessment approaches for different botanical preparations. Altogether, the results obtained through different thesis chapters show that integration of different approaches provides the basis for a mode of action and PBK modelling based read-across from compounds for which tumor data are available to related compounds for which such data are lacking. This can contribute to the development of alternatives for animal testing and will facilitate the risk assessment of compounds for which in vivo toxicity studies on tumor formation data are unavailable.

Mode of action based risk assessment of the botanical food-borne alkenylbenzenesapiol and myristicin