Opinion of the Scientific Panel CONTAM related to pyrrolizidine alkaloids as undesirable substances in animal feed

The term pyrrolizidine alkaloids (PAs) describes a group of more than 350 individual compounds that share as a basic structure one of the four necine bases platynecine, retronecine,
heliotridine, or otonecine. PAs are produced as secondary metabolites of more than 6000 plant species, belonging to the families of Boraginaceae, Compositae (Asteraceae) and Leguminosae
(Fabaceae) and occur world-wide. The pattern of PAs in plants varies largely, depending on the plant variety, climatic conditions, period of sampling and part of the plant analysed. Basic
alkaloids seem to accumulate in the seeds, whereas the respective N-oxides dominate in the green parts of a plant. It is assumed that PAs are among the most widely distributed natural toxins
affecting wildlife and livestock. In farm animals, however, acute intoxications caused by PAs are rare, as animals avoid PA containing plants if other feed is available. However, this
recognition fails in preserved forages such as silage and hay.

Acute intoxications caused by PAs are characterized by hepatotoxicity and hemorrhagic liver necrosis. Long-term exposure causes hepatic megalocytosis, veno-occlusion in liver and to a lesser
extent in the lungs, proliferation of the biliary tract epithelium, fatty liver degeneration and liver cirrhosis.

The onset of clinical symptoms often occurs with delay, and exposure is recognized only in cases in which significant alteration in the liver occur. The progressive hepatotoxicity is related to
the metabolic activation of the parent alkaloid into toxic dehydropyrrole alkaloids that are highly reactive alkylating agents. In contrast, the transformation into N-oxides represents a common
detoxification pathway. Structural characteristics such as the degree of esterification and the nature of the ester groups determine the degree of bioactivation towards the toxic pyrroles, and
differences in the expression of enzymes involved in the biotransformation seem to explain the typical species differences in the sensitivity toward PAs. At present, the data available for farm
animal species do not allow tolerance levels to be set for individual PAs in feed materials.

In humans, PAs cause primarily hepatic veno-occlusive disease (VOD). Although VOD was endemic in the past century in certain geographic regions of South America, epidemiological evidence for
PA-induced cancers in humans is lacking. Toxicological concerns about the potential human exposure to PAs were based on the results of extensive rodent studies indicating a carcinogenic
potential of this class of compounds, and on the in vitro investigations that convincingly demonstrated that the dehydropyrrolic metabolites of PAs can form DNA-adducts, DNA-cross links and
DNA-protein cross links, and result in genotoxicitiy and mutagenicity in a variety of bioassays conducted in rodent models.

Studies devoted to the carry over of PAs from feed into edible tissues of farm animals did show that PAs are excreted with milk of dairy cows (and lactating sheep) albeit at a low rate, varying
between 0.04 and 0.08 % of the ingested dose. Experimental evidence for the rate of disposition of PAs in eggs is lacking, but market analyses in Australia indicated the presence of certain PAs
in eggs. No residues have been found in other animal tissues. The contribution of the residues in animal derived tissues to human exposure is low; however, honey, in which PA residues are
regularly found, deserves special attention.




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