Determination and regulation of hepatotoxic pyrrolizidine alkaloids in food: A critical review of recent research
Introduction
Pyrrolizidine alkaloids (PAs) are naturally occurring heterocyclic phytotoxins that are widely distributed in about 3% of the world's flowering plants (Fu et al., 2004; EFSA, 2007). To date, more than 660 PAs and their N-oxide forms (PANOs) have been identified in over 6000 plants. Most of these plants belong to the Asteraceae, Boraginaceae, Orchidaceae, and Fabaceae families, and half of them have been reported to be hepatotoxic (Yang et al., 2001; Zhu et al., 2017; He et al., 2017a). PAs are esters of three types of necine base: Retronecine type, otonecine type, and platynecine type. The former two with the necine base having a double bond at the C1 and C2 positions exhibit high levels of toxicity, while platynecine type PAs with a saturated necine base (without a double bond) are either weakly toxic or nontoxic (Fig. 1) (Fu et al., 2004; Ruan et al., 2014a). The available information indicates that the adverse effects of 1, 2-dehydropyrrolizidine alkaloids (dehydroPAs) in experimental animals include hepatotoxicity, developmental toxicity, genotoxicity and carcinogenicity (EFSA, 2011a; Li et al., 2011; Lin et al., 2011; Yang et al., 2016; Fu et al., 2017; Fu, 2017; Zhu et al., 2017). Acute poisoning with PAs in humans is associated with liver damage, whereas a sub-acute or chronic onset may lead to liver cirrhosis and pulmonary arterial hypertension (Li et al., 2018; EFSA, 2011a). Compared with herbs, PAs are more widespread, more serious and more difficult to control in food. There is now increasing recognition that some widely consumed foods (e.g. grains, milk, meat, eggs, honey, pollen) are sometimes contaminated by PAs and PANOs at levels that, while insufficient to cause acute poisoning, greatly exceed maximum tolerable daily intakes and/or maximum levels determined by a number of independent risk assessment authorities (Edgar et al., 2011).
In Europe, an analysis was done of a total of 1105 samples collected. These comprised milk and milk products, eggs, meat and meat products, teas, and food supplements collected in supermarkets, retail shops, and via the internet. PAs were detected in a large proportion of plant-derived foods: 60% of the food supplements and 92% of teas contained measurable amounts of PAs. As for animal-derived products, 6% of milk samples and 1% of egg samples contained PAs (Mulder et al., 2018). In Hong Kong, a total of 234 samples (48 food items) were collected randomly from a local market and analyzed. About 50% of samples were found to contain detectable amount of PAs (Chung and Lam, 2017).
This review summarized the current global situation with regard to the presence of PAs in food, the method of detecting PAs content, and the regulation of PAs by various countries and authorities. It is hoped that more effective solutions to minimize the consumption of PAs can be developed on this information.
Section snippets
Bee products – honey and pollen
Apiarists in many countries regularly use a number of PA-containing plants for honey production (Edgar et al., 2002). Kempf et al. have demonstrated that honeys from many of these plants contain significant levels of PAs (Kempf et al., 2008).
It has been suggested that the PAs found in honey may have been introduced via pollen accidently dislodged into nectar, e.g. by nectar-collecting bees (Boppre et al., 2005). Pollen from PA-containing plants contains extremely high levels of PANOs (Kempf et
Method of analysis
Many different foods have been analyzed for PAs in the past, and most of the common analytical techniques were applied in the detection of these compounds (Crews et al., 2010). Hence, this part will focus on the most recent and most common techniques used for the trace analysis of PAs in complex matrices like foods.
Regulation
As PAs has been demonstrated to be a health threat for both humans and livestocks, many countries and authorities have set various limitations for PAs as summarized in Table 3.
We summarized the legal provisions of different countries and national organizations on the limitation of PAs. Our list contains all information that we were able to access but does not claim to be complete. The limited information available from human poisoning cases allowed identifying a lowest known dose of
Perspectives
Though several countries and authorities have tried to establish regulations to restrict the exposure to PA-containing food and medicinal herbs, these regulations are only based on case studies and cannot be applied universally to all PAs. It is difficult to determine a toxic dosage threshold for different types of PAs as even within the same PAs type, different PAs may have varied potencies in inducing toxicity. Therefore, a systematic assessment system is needed for predicting the potency of
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgement
The present study was supported by National Natural Science Foundation of China (Grant no. 81603381).
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