Food contaminants capable of causing cancer, pulmonary hypertension and cirrhosis

Pyrrolizidine alkaloids (PAs) are natural substances with known toxicity that occur in a number of weeds found in agricultural production systems worldwide.1,2 Bread made from PA-contaminated grain is a recurring cause of large regional outbreaks of a food poisoning-like syndrome characterised by rapid liver failure and death or development of hepatic sinusoidal obstruction syndrome (HSOS) and cirrhosis.1,2 Similar liver damage can also result from the consumption of herbal medicines, teas, salads and spices containing PAs.1-4 PAs have been detected worldwide as contaminants in milk, eggs, meat and honey at levels that are too low to cause rapid liver failure or HSOS but perhaps sufficient to initiate chronic diseases, including a range of cancers and pulmonary arterial hypertension (PAH) leading to right-sided heart failure.2,5

PAs are converted by liver enzymes to extremely reactive alkylating agents, which rapidly form adducts with sulfhydryl, hydroxyl and amine groups on DNA and proteins and other vital molecules in hepatocytes and adjacent sinusoids.1,2 The metabolites alkylate and rapidly deplete sinusoidal glutathione, leading to increased activity of matrix metalloproteinases, degradation of the extracellular matrix and release of sinusoidal endothelial cells, which aggregate with blood cells and adherent monocytes to obstruct sinusoidal blood flow and cause HSOS.6 They also react spontaneously with water to produce (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP).1,2 DHP is a less reactive alkylating agent than the initial metabolites, and it enters the circulation and forms complexes with DNA and proteins in a wide range of tissues.1,2 Circulating DHP and protein–DHP adducts formed in the liver are considered to be responsible for the long-lasting and slowly developing effects of PA exposure.1,2

Alkylation of DNA by PA metabolites leads to accumulation of somatic mutations, and cancers of the liver, lung, kidney, skin, intestines, bladder, brain and spinal cord, pancreas, adrenal gland, muscle (rhabdomyosarcoma) and blood (leukaemia) have been produced in experimental animals.1,7

Exposure to levels of PAs lower than those causing acute toxicity (liver failure and HSOS) leads to PAH and right-sided heart failure in a high proportion of treated animals, and PAs (in particular, monocrotaline and its metabolites) have been used experimentally to produce an animal model of these conditions.8 This model is widely used to study somatic mutations leading to vascular remodelling in the pathogenesis of PAH, and also to assess the efficacy of drugs. Intermittent low-level dietary exposure to PAs could therefore be a cause of PAH, especially in susceptible people, such as individuals already carrying bone morphogenetic protein receptor type 2 mutations or other predisposing factors that are associated with primary PAH.9

Genotoxic carcinogens have no safe level of exposure. A tolerable or acceptable level is therefore set for the purpose of food regulation, but a range of opinions currently exist on the acceptable level of PAs in consumed products. For example, a German Federal Pharmaceutical Ordinance has, since 1992, banned the sale of all but a few traditional herbal medicines containing PAs that must be shown to contain no more than 1 μg of PAs per daily dose or 0.1 μg if the herbal product is taken daily for more than 6 weeks per year.2,10 Pregnant and lactating women are advised not to consume these medications, and warning labels must appear on the product. The German Federal Institute for Risk Assessment has more recently expressed the view that a target of zero PA exposure is justified;11 however, this would be impractical to enforce. Therefore, it has suggested that a daily intake of 0.007 μg of PAs/kg bodyweight “should possibly not be exceeded”.12 The United Kingdom Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment has suggested that a PA exposure of 0.1 μg/kg bodyweight/day is unlikely to cause HSOS, and that cancer is unlikely if consumers are exposed to less than 0.007 μg/kg bodyweight/day.13 Dutch authorities have determined a virtual safe level of 0.00043 μg/kg bodyweight/day, leading to at most one person in a million developing cancer, and have proposed a limit of 1 μg/kg of product.10 Food Standards Australia New Zealand (FSANZ) suggests that dietary exposure to 1 μg/kg bodyweight/day is unlikely to cause HSOS and that, despite their undoubted genotoxicity, cancer is probably an unlikely outcome because no cancers in humans have been attributed to PAs.14 FSANZ is currently reconsidering this position in light of new data and recent international risk assessments, and is planning to determine the relative toxicity of PAs in Australian and New Zealand plants before changing its current assessment.15

PA plants of concern in Australia are widespread and include Paterson’s curse (Salvation Jane, Echium plantagineum), fireweed (Senecio madagascariensis), common heliotrope (Heliotropium europaeum) and rattlepods (Crotalaria spp). They can contaminate Australian grain14 and especially fodder and grain fed to livestock.14 Australian livestock are regularly exposed to and poisoned by PAs. Animal products, including milk, eggs and meat, are likely to be occasional sources of low-level dietary exposure.2

Honey from Echium species such as Paterson’s curse may contain over 2500 μg of PAs/kg.16 Some Australian eucalypt honeys have been found to contain as much as 800 μg/kg, and blended honeys labelled “pure Australian honey” have been found to contain 250 μg/kg.16

Pure Paterson’s curse honey clearly contains hazardous levels of PAs. FSANZ therefore recommends that Australian honey producers not sell pure Paterson’s curse honey and that it should be blended with honeys from other sources to reduce the level of PAs to levels that are unlikely to cause HSOS. The Australian honey industry is endeavouring to comply with this suggestion, but it is still possible to buy honey labelled Paterson’s curse or Salvation Jane in Australia.

Overall, 10%–15% of Australian honey derives from Paterson’s curse, with higher proportions in some states such as South Australia, Western Australia and New South Wales. If 10%–15% of Australian honey contains 2500 μg of PAs/kg and if all of this honey is efficiently blended with other Australian honeys (assumed to contain zero PAs), a product containing 250–375 μg/kg will be produced. A daily serving of 25 g of this honey is equivalent to eating 6.2–9.4 μg of PAs/day, which is well above the maximum 0.1 μg/day specified by the German herbal medicine regulations.2,10 For a person weighing 60 kg, this level of consumption would be equivalent to eating 0.1–0.16 μg/kg bodyweight/day, which is well above the 0.007 μg/kg bodyweight/day that would ensure that cancer is unlikely.12,13 At the other extreme, if a pregnant (or lactating) woman bought 1 kg of pure Paterson’s curse honey and consumed a serving of 25 g/day, she could be exposed to 62.5 μg of PAs/day for 40 days. If she weighed more than 62.5 kg, she would be within the tolerable limit set by FSANZ14 and, accordingly, unlikely to suffer HSOS; however, the fetus (or breastfeeding infant) may be exposed to a risk of disease. There is a case report of a pregnant woman in Germany whose daily use of a cooking spice containing 25 μg of PAs led to HSOS, liver failure and death of her fetus.4

More local monitoring and reporting of PAs in all potential food sources is required, to enable clinicians to assess the level of dietary exposure to PAs and to consider possible health consequences. Such data would also provide important information that consumers (especially pregnant or lactating women) could use to guide food-buying decisions. Clinical and epidemiological studies are also needed, to ascertain whether some cases of liver disease, cancer and PAH are being caused by dietary PAs. Methods for measuring DNA–DHP and protein–DHP adducts in vivo are now available — these indicate current dietary exposure to PAs in specific populations and allow comparison with the incidence of chronic diseases. An appropriate history from patients with cancer, PAH or chronic liver disease of unknown aetiology about the foods that they consume will also assist in establishing or refuting PAs as a significant cause.