FAO Consumer Protection Fact Sheets No.

2: Pyrrolizidine Alkaloids

PYRROLIZIDINE ALKALOIDS IN FOODS AND ANIMAL FEEDS
WHAT ARE PYRROLIZIDINE ALKALOIDS?
Pyrrolizidine alkaloids (PAs) are toxins found naturally in a wide variety of plant species. PAs are probably the most widely distributed natural toxins and affect wildlife, livestock and humans. Over 6 000 plant species are known to contain PAs, although direct poisonings in man and animals seems to be associated with only a few species. Poisoning caused by these toxins is associated with acute and chronic liver damage and is commonly fatal. Direct human cases of poisoning are occasional but are well-documented; consumption of grain or grain products (flour or bread) contaminated with seeds from weed species that contain these alkaloids is commonly involved. These occurrences frequently occur as “outbreaks” following dry season or drought conditions that favour the development of weeds in the primary crop. It has been suggested that intoxication may occur as a result of drinking milk from affected animals, but amount of PAs expressed in the milk of animals exposed to PAs is low (0.4-0.8% of the ingested dose). The same holds true for eggs. The ingestion of honey from bees that have fed on toxic plant species has also been suggested as a possible exposure pathway, but again, the levels involved are low and there are no reported cases. The direct and deliberate use of toxic plant species as herbal teas or traditional medicines1 forms another pathway of exposure which is well-documented and has resulted in deaths. Farm animals, particularly cattle, sheep, goats, horses, poultry and pigs are known to be susceptible to poisoning with high levels of mortality, while small animals such as rabbits appear less affected. There are reports of toxicity to fish. Outbreaks in farm animals cause severe economic losses to farmers and rural communities and, as noted above, there is the possibility of transfer of the toxins to humans.

OCCURRENCE
Over 350 PAs are known and the list continues to grow. They are known to be present in more than 6 000 plant species. The main sources are the families Boraginaceae (all genera), Compositae (tribes Senecionae and Eupatoriae), and Leguminosae (genus Crotalaria). Some plant species express several PAs or alkaloid N-oxides and there are some PAs that are expressed by several plant species. The toxins are commonly concentrated in the seeds and the flowering parts of the plant, with decreasing amounts in the leaves, stems and roots. Most plants produce mixtures of PAs in varying concentrations ranging from less than 0.001 % to 5 % in certain plant seeds. Some PA-bearing plants are used as ground cover, soil improvers (Leguminosae), ornamental plants, and for animal feed. Some, especially in the Boraginaceae family, are appreciated for the quality of their honey.

1

Herbal preparations and medicines are considered as therapeutic goods (i.e., not as foods) for the purpose of this Fact Sheet. Nevertheless, some of the human data on exposure to PAs is based on this use and will be referred to as required.

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Trichodesma. 3. The esters can be divided in monoesters. In general. and Crotalaria species. a. a. Afghanistan and India with recent outbreaks occurring in Afghanistan (International Programme on Chemical Safety. otonecine (European Food Safety Authority. The toxins survive the milling. 4. baking and subsequent processes. an unsaturated 3-pyrroline ring. If weedy crops are used for the production of hay or silage the animals can no longer exercise discrimination when feeding because the toxins survive storage processes and are completely intermingled with the fodder. The situation is frequently aggravated by drought and other conditions advantageous to weed growth at the expense of the crop. Mortality is reported to be high. 1988). Outbreaks of veno-occlusive disease and other liver disorders have been reported from parts of Central Asia. 2007). whereas unesterified PAs hardly occur in plants. the acid moiety has a branched chain (Australia New Zealand Food Authority. Retronecine.FAO Consumer Protection Fact Sheets No. c. each attached to the pyrroline ring via one carbon atom. Most of the naturally occurring PAs in plants are esterified necines or alkaloid N-oxides (except for the otonecine-type alkaloids). 2001). 2. 2001). b. c. Poisoning in animals has been reported from all of the sources listed above with known outbreaks attributed to Heliotropium. the plants most commonly reported as being associated with food poisoning in humans are Heliotropium (in the family Boraginaceae ) and Crotolaria. Figure 1 shows the basic structure of the four necine bases forming toxic PAs. Figure 1: Basic structure of the four necine bases forming toxic PAs. These occur as weeds in cereal or legume crops and the seeds are mingled accidentally with the main crop at harvest. at least one of the hydroxyls is esterified. retronecine. (Anonymous. heliotridine and otonecine. b. TOXICITY Page | 2 . heliotridine.2: Pyrrolizidine Alkaloids Excluding the use of herbal teas and medicines. d. one or preferably two hydroxyl groups. The minimum structural requirements for toxicity are: 1. grazing animals will avoid PA-bearing plants but may have little choice in conditions of drought or when searching for food on over-grazed or otherwise depleted pastures. (WHO. platynecine. CHEMISTRY PAs are heterocyclic compounds and most of them are derived from four necine bases: platynecine. Senecio. Retronecine and heliotridine are enantiomers at the C7 position. d. non-macrocyclic diesters and macrocyclic diesters of a necine base. 2001).

photosensitization. Stuart . 2001). In affected animals and humans. The Australia New Zealand Food Authority has estimated a provisional tolerable daily intake (PTDI) for PAs in humans of 1 µg/kg body weight/day. Symptoms are those of liver failure and cirrhosis. it is reported that following a poisoning outbreak in which sub-acute toxicity is observed.FAO Consumer Protection Fact Sheets No. scouring. Bras. 1988). bile. the provisional tolerable daily intake (PTDI) for PAs in humans is 1 μg/kg bw/day” (Australia New Zealand Food Authority. mainly in Drosophila and many have been shown to be carcinogenic. mainly in the rat. 2001). cirrhosis and veno-occlusive disease. A useful review of screening methods and confirmation assay development for plant-assocoated toxins in animal feed is provided by Than et al. It also notes ongoing research into the use of ELISA techniques. PAs demonstrate marked toxicity to the liver. In extreme cases neighbouring organs such as the heart and lungs may be affected. staggering gait. symptoms have been described as “depression. has been validated for the analysis of (mixed) feed samples. depraved appetite. Than. METHODS OF ANALYSIS Methods of analysis for PAs in animal feeds have recently been reviewed by the European Food Safety Authority (European Food Safety Authority. particularly chromatographic methods in conjunction with mass spectrometry can be used to detect PAs in plants or plant derived products. Poisoning by PAs is due to in acute and chronic liver damage. (K. some 50% of patients will recover completely and 20% will die rapidly. In humans. There are no official methods for the detection or determination of PAs in foods and there is apparently no systematic analysis for PAs in grains entering the food supply (Australia New Zealand Food Authority. This was calculated on the basis of venoocclusive disease of the liver as the major toxicological effect of chronic exposure. 2007). straining. According to the Authority. 2007). None of these methods. If an uncertainty factor of 10 to account for human variability is applied to this NOEL. G. 2007). Methods for the detection of PAs in biological fluids (milk. “the available data on cases of veno-occlusive disease in humans indicate that a tentative no-observed-effect level (NOEL) of 10 μg/kg bw/day can be established. Although metabolites of PAs have been shown to have mutagenic activity. Updated reviews are available from the Australia New Zealand Food Safety Authority (Australia New Zealand Food Authority.2: Pyrrolizidine Alkaloids The toxicology of PAs was reviewed comprehensively by the International Programme on Chemical Safety in 1988 (International Programme on Chemical Safety. blood plasma.A. however.L. 2005) Page | 3 . there is no evidence of pyrrolizidine alkaloid-induced cancer in humans. 2001) and the European Food Safety Authority (European Food Safety Authority. resulting in hepatocellular injury. circling and death” (North West Weeds. 1957). In animals. (K. urine) and also in honey were also reviewed by the Authority. Of the survivors about 20% will appear to recover clinically but may go on to develop cirrhosis and liver damage in later years. The Authority notes that various analytical techniques.

It should be noted that these data refer to seeds that can be detected by microscopic examination. belonging to the Graminae family. The EFSA report states that the reason for the inclusion of limits for Lolium remains unclear. with the exception of the three mentioned species.05% and provides a test method (ISO. The current EU maximum levels for PAs in animal feed materials relate to weed seeds and unground and uncrushed fruits containing alkaloids. It appears that controls at the level of the grain are considered to the main control point and are sufficiently effective that maximum limits for the presence of PAs in flour and derived wheat products are considered unnecessary.2 (European Food Safety Authority. contains 2 PAs (loline and norloline). excluded from the present discussion. but neither differentiate between individual plants. however these PAs are not known to be hepatotoxic (International Programme on Chemical Safety. nor provide limits for the amount of individual or groups of PAs. including 1 000 mg/kg of either or both Lolium temulentum L. The maximum limits are: 3 000 mg/kg total. 2 Page | 4 .FAO Consumer Protection Fact Sheets No. Lolium. Measures for the control of PA contamination of food and animal feed focus on agricultural measures during primary production. and 100 mg/kg of Crotolaria spp (0.1% and 0. 0. animals presented for slaughter that show signs of PA-related disease.. This tolerance appears to be close to the limit of determination of the method. and Lolium remotum Schrank. STANDARDS Standards for the control of PAs concentrate on the control of the toxic plants and plant parts. This is especially true of plants and parts of plants used for herbal preparations and medicines. These standards are: • • • • • Maize (corn) CODEX STAN 153-1985 Certain pulses CODEX STAN 171-1989 Sorghum grains CODEX STAN 172-1989 Wheat and durum wheat CODEX STAN 199-1995 Oats CODEX STAN 201-1995 The ISO Specification for Wheat allows a tolerance of 0.01% respectively based on a moisture content of 12% in the feeding stuff).3%. 1988). the Codex Alimentarius states that toxic seeds in wheat should not be present in amounts that represent a hazard to health and mentions specifically the presence of Crotolaria. 2007). are condemned and not allowed to enter the food supply (USDA. glucosides and other toxic substances.2: Pyrrolizidine Alkaloids A method for the determination of toxic seeds in samples of Wheat for human consumption is given in the ISO Specification for Wheat (ISO. For grains and pulses. 2007). CONTROL MEASURES Measures for the control of PA-containing herbal preparations and medicines are outside the scope of this note. 2000). In the United States. 2000).

sieving can be used to separate the PA-bearing weed seeds on the basis of size.4 D) or by mechanical or manual weeding of the fields. water management. soil improvers (Crotolaria spp. Biological methods (classical methods through the introduction of exotic natural enemies and increasing the population of already existing natural enemies). Chemical methods (use of herbicides). Page | 5 . mechanical or manual weeding may be the only option. Cultural methods (crop rotation. and others at the farm level). The safe use of these plants as animal feed depends on the fact that the leaves and stalks of the plant contain less PAs than the flowering parts and the seeds.2: Pyrrolizidine Alkaloids The principal control measure is weed control in accordance with Good Agricultural Practices. should be undertaken using the measures outlined by FAO. Wheat fields. attention should be paid to areas bordering the crop or pasture. for example) should be taken into account. the relative susceptibility of animals to PA intoxication (cattle being less sensitive that sheep. It can also be applied to the Codex Standard.FAO Consumer Protection Fact Sheets No. for the protection of grazing animals. should be weeded prior to planting and periodically during the first six weeks of the growth cycle.. 2007). land preparation. polycropping. In cereal crops.. mulching. etc. Crotolaria and other PA-bearing plants are sometimes used as ground cover. Other non-conventional methods (soil solarization. Control of weeds in pastures. The test method contained in the ISO standard is easily applied and does not require elaborate laboratory equipment or extensive training of operators. In legume crops. This should be taken into account when allowing animals to graze on these plants. and others in development). Long-term measures may include biological pest control but this requires extensive research and evaluation of the environmental impact of the introduced species (North West Weeds. In some cases. hand or mechanical weeding during the crop’s life cycle). In the case of depletion of pastures during drought. use of cover crops. In weeding.g. According to FAO (FAO. 2007). extension services and farmers’ associations should be considered as means of minimising the presence of PAs in foods and feeds. Also. methods most used for weed control include: • • • • • Preventative methods (legal and quarantine procedures. Finally. A final weeding about two weeks before harvest significantly reduces to possibility of contamination of the harvest with toxic seeds. The provisions in the Codex Standards for cereals and pulses for the presence of toxic seeds should be applied BEFORE the crop is milled or distributed for human consumption. millet fields. one of the most significant control measures is awareness and the spread of knowledge about PAs and the implications of PA-bearing weeds and seeds in products destined for human consumption or as animal feeds. use of hot water. alternative animal feeding measures should be implemented by national and local authorities to the extent of their capabilities. bearing in mind the nature of the reporting. are legumes) and as animal feed. weed control may be by the use of herbicides (e. 2. as these may constitute a reservoir for the weeds and create year-after-year problems. Rural radio programmes.

europa. November 2001. Parma : http://www. ISO. Health Talks Afghanistan.fsis. Vol.northwestweeds. 2007. 2001). [Online] November 25. 2007.pdf. 2000.gov. The Lancet. Multi-species Disposition Basics with a Public Health Focus. 1988. WHO. Cited in "Pyrrolizidine Alkaloids in Foods" (ANZFA. Environmental Health Criteria NO. 1070. The EFSA Journal (2007) 447. Knill.2.gov/PDF/PHVt-Multi_Species_Disposition. Geneva : International Organization for Standardization. Animal Feed Science and Technology. 2007.efsa.pdf.80 (EHC 80). Stuart . Canberra and Wellington : http://www. J. Technical Report Series No. 2007. 2001. K.pdf.A. International Programme on Chemical Safety. 1988. G. 2007. 2005. Opininion of the Scientific Panel on Contamiants in the Food Chain on a request from the European Commission related to Pyrrolizidine Alkaloids as undesirable substances in Animal Feeds. K.org/documents/ehc/ehc/ehc080. S. Than. ftp://ftp.au/blue_heliotrope. 2001.A Toxicological Review and Risk Assessment.M. USDA. 2001. 2007. Vol.org/docrep/fao/010/a0884e/a0884e00. Page | 6 . 2005.L. Plant-associated toxins in animal feed: Screening and confirmation assay development.F. Gaul. Reccomendations for Improved Weed Management.L.A.nsw.) ISO 7970:2000. p. 2007.htm. FAO. Veno-occlusive disease of the liver. P.au/_srcfiles/TR2. Canberra and Wellington : Australia New Zealand Food Authority. Gallagher. V. Geneva : World Health Organization. Blue Heliotrope. Pyrollizidine Alkaloids. September 2001.gov. 1957. A. Rome : Food and Agriculture Organization of the United Nations. 1957.FAO Consumer Protection Fact Sheets No. Edgar. Pyrrolizidine Alkaloids in Food . Wheat (Triticum aestivum L. [Cited: April 15. North West Weeds. Bras. 2001.fao.htm. Colegate. Stevens.l. 2000.inchem. 1-51.foodstandards. s. K.2: Pyrrolizidine Alkaloids BIBLIOGRAPHY Anonymous. Food Safety Inspection Service http://www.usda. pp. Australia New Zealand Food Authority. Drought causes re-emergence of liver disease. European Food Safety Authority. 2008. North West Weeds. 121.htm. 358. 2007.] Government of New South Wales http://www. : United States Department of Agriculture. Geneva : WHO. 5-21. January 25. http://www.eu/EFSA/efsa_locale-1178620753812_1178621166892.

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