Large outbreaks of acute food-related poisoning, characterized by hepatic sinusoidal obstruction syndrome, hemorrhagic necrosis, and rapid liver failure, occur on a regular basis in some countries. They are caused by 1,2-dehydropyrrolizidine alkaloids contaminating locally grown grain. Similar acute poisoning can also result from deliberate or accidental consumption of 1,2-dehydropyrrolizidine alkaloid-containing herbal medicines, teas, and spices. In recent years, it has been confirmed that there is also significant, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids in many countries due to consumption of common foods such as honey, milk, eggs, salads, and meat. The level of 1,2-dehydropyrrolizidine alkaloids in these foods is generally too low and too intermittent to cause acute toxicity. However, these alkaloids are genotoxic and can cause slowly developing chronic diseases such as pulmonary arterial hypertension, cancers, cirrhosis, and congenital anomalies, conditions unlikely to be easily linked with dietary exposure to 1,2-dehydropyrrolizidine alkaloids, especially if clinicians are unaware that such dietary exposure is occurring. This Perspective provides a comprehensive review of the acute and chronic toxicity of 1,2-dehydropyrrolizidine alkaloids and their potential to initiate certain chronic diseases, and suggests some associative considerations or indicators to assist in recognizing specific cases of diseases that may have resulted from dietary exposure to these hazardous natural substances. If it can be established that low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids is a significant cause of some of these costly and debilitating diseases, then this should lead to initiatives to reduce the level of these alkaloids in the food chain.

Pyrrolizidine alkaloids and their N-oxides can be extracted from the dried methanolic extracts of plant material using dilute aqueous acid. The subsequent integration of solid-phase extraction (with a strong cation exchanger) of the alkaloids and N-oxides from the aqueous acid solution, together with analysis using HPLC-ESI/MS, provides a method for the simultaneous profiling of the pyrrolizidine alkaloids and their N-oxides in plant samples and the collection of useful structural data as an aid in their identification. The N-oxide character of the analytes may be confirmed by treating analytical samples with a redox resin and observing the formation of the corresponding parent pyrrolizidine alkaloids. The present case study of Echium plantagineum highlighted a higher ratio of N-oxides to the parent tertiary bases than has been previously reported. Furthermore, a higher proportion of acetylated pyrrolizidine-N-oxides was observed in the flower heads relative to the leaves. Six pyrrolizidine alkaloids or pyrrolizidine-N-oxides, not previously reported from E. plantagineum, were tentatively identified on the basis of MS and biogenetic considerations. Three of these, 3'-O-acetylintermedine/lycopsamine, leptanthine-N-oxide and 9-O-angelylretronecine-N-oxide, have been reported elsewhere, whilst three others, 3'-O-acetylechiumine-N-oxide, echimiplatine-N-oxide and echiuplatine-N-oxide, appear unreported from any other source.

The pyrrolizidine alkaloids previously identified in floral honey attributed to Echium vulgare (Boraginaceae) have been detected (8000-14 000 ppm) in pure pollen collected from the anthers of Echium vulgare. Pyrrolizidine alkaloids and/or their N-oxides were isolated from the aqueous acid extracts of pollen by use of strong cation-exchange, solid-phase extraction and identified by liquid chromatographic/mass spectrometric (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 on the basis of 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 bee pollen are briefly discussed.

Contamination of grain with 1,2-dehydropyrrolizidine ester alkaloids (dehydroPAs) and their N-oxides is responsible for large incidents of acute and subacute food poisoning, with high morbidity and mortality, in Africa and in central and south Asia. Herbal medicines and teas containing dehydroPAs have also caused fatalities 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 in the past not recognised as resulting from dietary exposure to dehydroPAs. 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. DehydroPAs also cause progressive, chronic diseases such as cancer and pulmonary arterial hypertension but proof of their involvement in human cases of these chronic diseases, including sources of exposure to dehydroPAs, has generally been lacking. Growing recognition of hazardous levels of dehydroPAs in a range of common foods suggests that physicians and clinicians need to be alert to the possibility that these contaminants may, in some cases, be a possible cause of chronic diseases such as cirrhosis, pulmonary hypertension and cancer in humans.

Following scientific risk assessments, several countries have imposed strict regulations on herbal medicines containing 1,2-dehydro-pyrrolizidine alkaloids. Using published data on the plants used in honey production, pyrrolizidine alkaloid-containing plants are shown in this review to represent a significant source of honey worldwide. This observation, honey consumption data, reported levels of pyrrolizidine alkaloids in honeys, and consideration of tolerable exposure levels determined for pyrrolizidine alkaloids in herbal medicines, leads to the conclusion that some honey is a potential threat to health, especially for infants and fetuses, and further investigation is warranted.