Elsevier

Food and Chemical Toxicology

Volume 119, September 2018, Pages 50-60
Food and Chemical Toxicology

Determination and regulation of hepatotoxic pyrrolizidine alkaloids in food: A critical review of recent research

https://doi.org/10.1016/j.fct.2018.05.037Get rights and content

Abstract

Pyrrolizidine alkaloids (PAs) are secondary metabolites of plants. PAs have been reported to be hepatotoxic, mutagenic, and carcinogenic; they are a significant group of natural toxins affecting livestock, wildlife, and humans. To date, over 10,000 PAs poisoning cases have been reported worldwide. In recent years, many articles have reported the detection of PAs in various foods, including honey, milk, meat, eggs, tea and salad. This review summarized the contamination of PAs in foods, state of the art detection methods and regulations by different countries and authorities, hoping to propose effective solutions to minimize the consumption of PAs in food.

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).

References (109)

  • B.M. Mandic et al.

    Optimisation of isolation procedure for pyrrolizidine alkaloids from Rindera umbellata Bunge

    Nat. Prod. Res.

    (2015)
  • D. Rode

    Comfrey toxicity revisited

    Trends Pharmacol. Sci.

    (2002)
  • M. Schulz et al.

    Detection of pyrrolizidine alkaloids in German licensed herbal medicinal teas

    Phytomedicine

    (2015)
  • M.G.M. van de Schans et al.

    Multiple heart-cutting two dimensional liquid chromatography quadrupole time-of-flight mass spectrometry of pyrrolizidine alkaloids

    J. Chromatogr. A

    (2017)
  • F.C. Willmot et al.

    Senecio disease, or cirrhosis of the liver due to Senecio poisoning

    Lancet

    (1920)
  • M. Yang et al.

    Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity

    Chem. Biol. Interact.

    (2016)
  • I.K. Al taee et al.

    Acute renal failure in a renal center, Iraq

    Saudi J. Kidney Dis. Transpl.

    (2004)
  • M. Azadbakht et al.

    Qualitative and quantitative determination of pyrrolizidine alkaloids of wheat and flour contaminated with senecio in mazandaran province farms

    Iran. J. Pharm. Res.

    (2003)
  • K.A. Beales et al.

    Solid-phase extraction and LC-MS analysis of pyrrolizidine alkaloids in honeys

    J. Agric. Food Chem.

    (2004)
  • K. Betteridge et al.

    Improved method for extraction and LC-MS analysis of pyrrolizidine alkaloids and their N-oxides in honey: application to Echium vulgare honeys

    J. Agric. Food Chem.

    (2005)
  • BfR
    (1992)
  • BfR

    Pyrrolizidine Alkaloids in Herbal Teas and Teas

    (2013)
  • BfR

    Nulltoleranzen in lebens- und futtermitteln

    (2007)
  • D. Bodi et al.

    Determination of pyrrolizidine alkaloids in tea, herbal drugs and honey

    Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess.

    (2014)
  • M. Boppre et al.

    Pyrrolizidine alkaloids of Echium vulgare honey found in pure pollen

    J. Agric. Food Chem.

    (2005)
  • R.J. Bushway et al.

    Determination of methyl 2-benzimidazolecarbamate in bulk fruit juice concentrates by competitive-inhibition enzyme immunoassay

    J. AOAC Int.

    (1994)
  • R. Charlermroj et al.

    Multiplex detection of plant pathogens using a microsphere immunoassay technology

    PLoS One

    (2013)
  • M. Chen et al.

    9-Glutathionyl-6, 7-dihydro-1-hydroxymethyl-5 H-pyrrolizine is the major pyrrolic glutathione conjugate of retronecine-type pyrrolizidine alkaloids in liver microsomes and in rats

    Chem. Res. Toxicol.

    (2016)
  • S.W.C. Chung et al.

    Investigation of pyrrolizidine alkaloids including their respective N-oxides in selected food products available in Hong Kong by liquid chromatography electrospray ionisation mass spectrometry

    Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess.

    (2017)
  • COT

    Statement on Pyrrolizidine Alkaloids in Food

    (2007)
  • C. Crews et al.

    Update on analytical methods for toxic pyrrolizidine alkaloids

    Anal. Bioanal. Chem.

    (2010)
  • H. Damianakos et al.

    The chemical profile of pyrrolizidine alkaloids from selected Greek endemic boraginaceae plants determined by gas chromatography/mass spectrometry

    J. AOAC Int.

    (2014)
  • M. de Nijs et al.

    Fate of pyrrolizidine alkaloids during processing of milk of cows treated with ragwort

    Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess.

    (2017)
  • J.O. Dickinson et al.

    Milk transfer of pyrrolizidine alkaloids in cattle

    J. Am. Vet. Med. Assoc.

    (1976)
  • A.1. Dübecke et al.

    Pyrrolizidine alkaloids in honey and bee pollen

    Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess.

    (2011)
  • J. Edgar

    Pyrrolizidine alkaloids and food safety

    Chem. Aust.

    (2003)
  • J. Edgar et al.

    Transfer of pyrrolizidine alkaloids into eggs: food safety implications

    Acs. Sym. Ser.

    (2000)
  • J.A. Edgar et al.

    Honey from plants containing pyrrolizidine alkaloids: a potential threat to health

    J. Agric. Food Chem.

    (2002)
  • J.A. Edgar et al.

    Pyrrolizidine alkaloids in food: a spectrum of potential health consequences

    Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess.

    (2011)
  • J.A. Edgar et al.

    Pyrrolizidine alkaloids: potential role in the etiology of cancers, pulmonary hypertension, congenital anomalies, and liver disease

    Chem. Res. Toxicol.

    (2015)
  • EFSA

    Opinion of the scientific panel on contaminants in the food chain on a request from the european commission related to pyrrolizidine alkaloids as undesirable substances in animal feeds

    EFSA J.

    (2007)
  • EFSA

    Scientific opinion on pyrrolizidine alkaloids in food and feed

    EFSA J.

    (2011)
  • EFSA

    Use of the EFSA comprehensive European food consumption database in exposure assessment

    EFSA J.

    (2011)
  • EFSA

    Dietary exposure assessment to pyrrolizidine alkaloids in the European population

    EFSA J.

    (2016)
  • H. Eroksuz et al.

    Toxicity of senecio vernalis to laying hens and evaluation of residues in eggs

    Vet. Hum. Toxicol.

    (2003)
  • FDA

    FDA Advises Dietary Supplement Manufacturers to Remove Comfrey Products from the Market

    (2001)
  • FSANZ

    Consumers Advised to Limit Consumption of Paterson's Curse/Salvation Jane Honey

    (2004)
  • P.P. Fu

    Pyrrolizidine Alkaloids: metabolic activation pathways leading to liver tumor initiation

    Chem. Res. Toxicol.

    (2017)
  • P.P. Fu et al.

    Pyrrolizidine alkaloids–genotoxicity, metabolism enzymes, metabolic activation, and mechanisms

    Drug Metab. Rev.

    (2004)
  • P.P. Fu et al.

    Detection of pyrrolizidine alkaloid DNA adducts in livers of cattle poisoned with Heliotropium europaeum

    Chem. Res. Toxicol.

    (2017)
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