Chair of Forest Zoology and Entomology, Albert-Ludwigs-Universität Freiburg i.Br. Chair of Forest Zoology and Entomology
Albert-Ludwigs-Universität Freiburg i.Br.

Chair of Forest Zoology and Entomology
Freiburg i.Br.

Health Risks from Pyrrolizidine Alkaloids

Due to their hepatotoxic action, pyrrolizidine alkaloids represent a significant health risk for livestock and also for humans (e.g. WHO 1988 ). Of course, this is not in the focus of research at the FZI. However, our investigations on the chemoecology of PAs have revealed the presence of PAs in pollen of certain plants used by honey bees and thus uncovered a novel health risk: Marketed pollen granules, used as food supplement, can, contain large amounts of pollen from PA-containing plants, and consumption of such 'health food' may exceed the intake of PAs permitted by German pharmaceutical law on pyrrolizidine alkaloids in herbal products. Current research is aimed at finding out if PAs in honeys (cf. Edgar et al. 2002 ) might originate from pollen contamination.

In late 2001 we reported our findings on PAs in pollen and its implications to the Federal Ministry of Consumer Protection, Food and Agriculture and eventually to the DFG-Senate Commission on Food Safety (SKLM) which has followed our advice and release on November 8th 2002 the "Opinion of the SKLM on Pyrrolizidine alkaloids in honeys, bee-keeper products and pollen products", published in the internet.

see also: Opinion of the SKLM on pyrrolizidine alkaloids in honeys, bee-keeper products, and pollen products. In: Eisenbrand G, editor. Lebensmittel und Gesundheit II / Food and Health II. Weinheim (Germany): Wiley-VCH, p. 294.

Details of our collaborative analytical research with JA Edgar and SM Colegate of CSIRO on PAs in pollen and pollen products as well as our chemoecological experiments with PA-pharmacophagous insects as bioindicators are presently being prepared for publication.

German Regulations on Pyrrolizidine Alkaloids in Herbal Products

The German Federal Ministry of Health established regulations in 1992 governing the sale of herbal products containing pyrrolizidine alkaloids (Bundesanzeiger S. 805, 17. Juni 1992). In herbal products with proven health benefits the dose is restricted to 1µg of pyrrolizidine alkaloids per day for oral administration or 100 µg of pyrrolizidine alkaloids per day for external use. Use of such products is, however, restricted to a maximum of six weeks per year. The allowed level for pyrrolizidine alkaloids is reduced to 0.1 µg per daily oral dose or 10 µg for external use if the product is to be used for longer than six weeks per year. Herbal products containing pyrrolizidine alkaloids that have no demonstrated health benefits are prohibited by the German regulations.
The use of pyrrolizidine alkaloid-containing herbal products by pregnant and lactating women is specifically prohibited by the regulations because fetuses and infants are particularly susceptible to poisoning by pyrrolizidine alkaloids. The German regulations require all herbal products containing pyrrolizidine alkaloids within the prescribed level to be labeled with the following: “Not to be used in pregnancy and during the lactation period”.

Boppré M (2011) The ecological context of pyrrolizidine alkaloids in food, feed and forage. Food Addit Contam 28:260-281 link

Plant-produced 1,2-dehydropyrrolizidine ester alkaloids and their N-oxides (PAs) not only cause acute poisoning of humans and livestock, the harmful cryptic effects of chronic exposure pose particular food safety risks that need to be addressed for consumer protection. In natural contexts, however, PAs cause few or no problems. Rather, these secondary plant metabolites are important elements of ecosystems and plant-animal relationships; the existence and persistence of PA-adapted organisms, in various ways, depends on the presence of PA-containing plants or even on PAs as such. PA-plants are widely distributed among unrelated families of the plant kingdom, there is great structural diversity of PAs, and the amounts of PAs produced are subject to great variation due to multiple causes. These realities, coupled with many deficiencies in our scientific understanding, make PAs in nature a subject with limited potential for valid generalizations and predictions, and complex and difficult to summarize. PAs, their producer plants and their users are integral parts of ecosystems worldwide, and we have to learn to live with these allelochemicals by accepting the presence of some harmful natural chemicals in our environment and by taking regulatory action to reduce health risks to humans. Regulations for consumer protection are long overdue. However, any such controls must be flexible enough to accommodate the findings of future research. Multidisciplinary efforts are required to fill gaps in knowledge and to come up with additional means to monitor the presence of PAs in food and feed.

Edgar J, Colegate S, Boppré M, Molyneux R (2011) Pyrrolizidine alkaloids in food: a spectrum of potential health consequences. Food Addit Contam 28:308-324 link

Contamination of grain with 1,2-dehydropyrrolizidine ester alkaloids (dehydroPAs) and their N-oxides is responsible for acute and sub-acute food poisoning in Africa and in central and south Asia, with high morbidity and mortality. Herbal medicines and teas containing dehydroPAs have also caused fatal liver disease in both developed and developing countries. There is now increasing recognition that some staple and widely consumed foods are sometimes contaminated by dehydroPAs and their N-oxides 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. This suggests that there may have been cases of disease resulting from dietary exposure to dehydroPAs in the past but dehydroPAs were not recognised as the cause. A review of the literature shows that there are a number of reports of liver disease where either exposure to dehydroPAs was suspected but no source was identified or a dehydroPA-aetiology was not considered but the symptoms and pathology suggests their involvement. At low levels of exposure dehydroPAs cause progressive, chronic diseases such as cancer and pulmonary arterial hypertension, as well as cirrhosis, but proof of their involvement in human cases of these chronic diseases, including sources of exposure to dehydroPAs, has generally been lacking. Given current and growing recognition of hazardous level of dehydroPA contamination in a range of common foods, physicians and clinicians need to be alerted to this development and a reassessment of the aetiology of some cases of these diseases is warranted.

Boppré M, Fischer OW, Edgar JA, Colegate SM, Burzlaff T. Cryptic health risks from bee products naturally containing hazardous pyrrolizidine alkaloids – facts and perspectives. Submitted abstract, 1st European Foodcongress, SLO-Ljubljana, 04.-09.11.2008

Consumers of honeybee products world-wide are at risk if bees forage from plants that produce 1,2-dehydropyrrolizidine ester alkaloids and their N-oxides (PAs). These secondary plant metabolites transfer into bee products and are recognized natural toxins that cause, for example, liver disease. Unfortunately, clinical effects of PAs are not only dose-related but, insidiously, can also be time-delayed and therefore are difficult to attribute to dietary exposure to PAs. Species of Senecio, Echium and numerous other PA-producing plant species are, in some regions, dominant food sources for honeybees. Although it has been known for some time that honey can contain hazardous levels of PAs, the resulting health risks for consumers are poorly addressed and the significance of PAs in food, and the use of PA-containing honey and pollen as food additives, is not yet fully appreciated or resolved. Recent chemoecological research has shown that pollen from PA-producing plants contains very high levels of PAs, suggesting that, if this pollen is consumed as a "health food supplement", it carries significant health risks for consumers; the possibility that PAs in honey originate from contaminating pollen is also suggested by this finding. Regrettably, lack of chemical screening of commercial honey and bee pollen samples and, in particular, scarcity of information on pollen markets and consumer behaviour, currently makes risk assessments uncertain. While several countries have regulations on PAs in pharmaceutical products, these do not, in most cases, apply to foods or food supplements. This paper, after discussing integrated ecological, medical, technical, economic and legal aspects which urgently need to be considered, studied, and/or regulated, points out deficits in knowledge and proposes options for producing PA-reduced apicultural products. Multidisciplinary action on an international level is needed – but it is important to avoid public concern over honeybee products generally, not least because of the indispensable pollination service honeybees provide.

Boppré M, Colegate SM, Edgar JA, Fischer OW (2008) Hepatotoxic pyrrolizidine alkaloids in pollen and drying-related implications for commercial processing of bee pollen. J Agric Food Chem 56: 5662-5672 more

Using HPLC-ESI-MS, several saturated and 1,2-dehydropyrrolizidine alkaloids were detected, mainly as their N-oxides, in fresh pollen collected from flowers of the pyrrolizidine alkaloid-producing plants Echium vulgare, E. plantagineum, Senecio jacobaea, S. ovatus, and Eupatorium cannabinum, and/or pollen loads from bees (bee pollen) that foraged on those plants. A major alkaloidal metabolite in S. ovatus was tentatively identified, using its mass spectrometric data and biogenic considerations, as the previously unreported, saturated alkaloid, 2-hydroxysarracine. Heating had very little effect on the 1,2-dehydropyrrolizidine alkaloids and their N-oxides from a variety of sources. Considered in conjunction with international concerns about the adverse effects of these alkaloids, the results strongly indicate a need for monitoring pollen supplies intended for human consumption, at least until conditions for processing and/or selection are clearly defined such as to significantly reduce the hepatotoxic (and potentially carcinogenic and genotoxic) pyrrolizidine alkaloid content of bee pollen.

Beales K, Betteridge K, Boppré M, Cao Y, Colegate SM, Edgar JA (2007) Hepatotoxic pyrrolizidine alkaloids and their N-oxides in honey and pollen. Pp 94–100 in Panter K, Wierenga T, Pfister J (eds) Poisonous Plants: Global Research and Solutions. CABI, Wallingford, UK more

Boppré M, Colegate SM, Edgar JA (2005) Pyrrolizidine alkaloids of Echium vulgare honey found in pure pollen. J Agric Food Chem 53: 594-600. read 

The pyrrolizidine alkaloids previously identified in floral honey attributed to Echium vulgare (Boraginaceae) have been detected (8000-14000 ppm) in pure pollen collected from the anthers of E. vulgare. Pyrrolizidine alkaloids and/or their N-oxides were isolated from the aqueous acid extracts of pollen using strong cation exchange, solid phase extraction and identified using LCMS analysis. The pyrrolizidine alkaloids in the pollen are present mainly as the N-oxides. In addition to seven previously described pyrrolizidine alkaloids and/or their N-oxides (echimidine, acetylechimidine, uplandicine, 9-O-angelylretronecine, echiuplatine, leptanthine and echimiplatine), one unidentified (echivulgarine), but previously found in honey, and two previously undescribed (vulgarine and 7-O-acetylvulgarine) pyrrolizidine alkaloids and/or their N-oxides were identified in the pollen. Tentative structures for these unidentified pyrrolizidine alkaloids are proposed based on the mass spectrometric data and biogenetic considerations. The implications of these results for identifying the source and subsequent concentrations of pyrrolizidine alkaloids in honeys and commercial beepollen are briefly discussed.