THE POISONOUS SUBSTANCES (PYRROLIZIDINE ALKALOIDS, PAs) FOUND IN FIREWEED

1. THEPOISONOUS SUBSTANCES (PYRROLIZIDINE ALKALOIDS, PAs) FOUND IN FIREWEED

2. Senecio madagascariensis (Fireweed)

3. Echium plantagineum Paterson’s curse Salvation jane

4. Echium vulgare Viper’s bugloss Blue borage (NZ)

5. Heliotropium europaeum (common heliotrope, potato weed

6. Amsinckia

7. Heliotrine Monocrotaline Lasiocarpine Senecionine

8. Activation of PAs in the Liver DNA PA* DNA Protein PA* DNA PA liver PA* enzymes Protein PA* Protein Activated PA* attaches to DNA and proteins

9. Pyrrolizidine alkaloids cause: • Liver damage (hepatotoxins) • Cancer (carcinogenic) • Mutations (mutagenic, genotoxic) • Fetal abnormalities (teratogenic, fetotoxic) • Lung changes, leading to • Right congestiveheart failure (cor pulmonale)

10. PAs are “genotoxic carcinogens” Unlike many other poisonous substances, e.g. strychnine, they have no threshold of toxicity

11. Genotoxic carcinogens are given a “Provisional Tolerable Daily Intake” “Safe” daily intakes can be determined in the case of strychnine and, for example, all agricultural chemicals.

12. “ Prevention of exposure is the only effective method of limiting toxicity due to PAs. Even low doses over a period of time may present a health risk and exposure should be avoided or minimized as far as possible.” World Health Organization (1989).

13. Dose-related, progressive PA poisoning Acute Subacute Chronic A small amount of PA intermittently A medium amount of PA A lot of PA

14. Acute PA poisoning • Liver enlargement (hepatomegaly) • Fluid buildup in peritoneal cavity (Ascites) • Liver tissue around veins disintegrates with bleeding (haemorrhagic necrosis) • Death or • Progression to sub-acute poisoning

15. Sub-acute PA poisoning • Veins of liver become constricted (veno-occlusive disease) • Poor blood flow • Pooling of blood behind vein constrictions • Breakdown (necrosis) of surrounding liver tissue

16. Chronic PA poisoning • Due to long term, low level intake of PAs or • Final consequence of earlier acute/subacute poisoning or • Intermittent periods of sub-acute damage and regeneration leading to - • Nodular regeneration and fibrosis and eventually to - • Cirrhosis and liver failure, indistinguishable for other causes (alcohol, hepatitis), and to congestive heart failure, also difficult to attribute to PAs.

17. Pulmonary Arterial Hypertension Some PAs cause thickening/narrowing of the arteries in the lungs, leading to effects on the heart and resulting in right heart congestive failure.

18. Progressive effects Leukaemia Liver Lung Rhabdomysarcoma etc cancer Protein PA* Protein PA* Indistinguishable from other causes cirrhosis

19. Clinical Disease in Humans • Humans (esp. foetuses and infants) are considered to be particularly sensitive to PAs. • Veno-occlusive disease and an established source of PA exposure viewed as definitive. • Cirrhosis and liver failure after long symptom-less period difficult to associate with low level of PAs in the diet. • Cancer and congestive heart failure?

21. Traditional herbal medicines, e.g. • Symphytum spp. (Comfrey) • Arnica • Borago officinalis (Borage) • Senecio scandens (Qian liguang) • Tussilago farfara (Kuan donghua)

22. Typical case PA poisoning The mother of a new born child had consumed a herbal tea, bought at a Swiss pharmacy as an expectorant, during her pregnancy. The child was admitted to intensive care 5 days after birth and died of liver failure 33 days later. The death was attributed to PAs (senecionine) in the tea. The mother was not affected Roulet et al., 1988

23. Another recent case A baby was delivered prematurely by cesarean section due to fetal ascites and liver enlargement and died shortly after delivery. Liver histology showed veno-occlusive disease. A cooking spice used daily during the pregnancy contained PAs. The amount of spice used per day was about 2 g. The level of PAs found in 2 grams of spice was about 25 μg. Rasenack et al., 2002

24. In November 2007, WHO reported an outbreak of PA poisoning caused by Heliotrope seeds in flour used to make bread in Herat Province of Afghanistan. By May 2008, 190 people were affected and 17 had died from liver failure. http://www.Irinnews.org/report.aspx?ReportId=78218

25. Examples of large-scale acute poisoning by PA contaminated grain

26. Seeds allowed in Australian wheat for Human use • 20 heliotrope seeds*/kg *9 micrograms of PAs in one seed • 100 Paterson’s curse seeds/kg • Grain “cleaned” before milling. • “Cleaned” grain can still contain PAs • Amount of wheat contaminated at this level or higher prior to “cleaning”?

27. Pigs and poultry poisoned by contaminated feed • In 1992/3 100,000 to 200,000 chickens and 1000 to 4000 pigs were poisoned by commercial feed. • The feed contained high levels of PAs believed to have come from the wheat/wheat screenings component.

28. Wheatextract Relative abundance

29. Egg extract (early) Relative abundance

30. Foods that may become contaminated by PAs • Grains (wheat, sorghum, barley etc) • Milk (including human milk) • Eggs • Honey and pollen (fireweed, Paterson’s curse etc.)

31. Possible dietary intake of PAs Commodity possible (μg/kg) consumption μg/day Wheat¶* 90 408g/day, 36 (ten heliotrope seeds/kg)(12-15year old males) Milk¶** 300 say 500g/day 150 (300-800 μg/kg reported) Eggs¶ 168 say 1x 50g egg/day 8 (19-168 μg/kg reported) Honey 2274 18.1g/day 41 (unifloral Paterson’s curse†)(20-45year old women) Dutch food regs. 1 μg PA/kg food; German herbal regs. 0.1 μg/day, zero for pregnant or nursing women; Austrian and Swiss herbal regs. zero PAs; Australian recommendation 1 μg/kg bw/day. ¶Only some product likely to be contaminated †All product is contaminated *“Cleaned” before milling **Normally expect blending with uncontaminated milk

32. Honeybee with loads of Paterson’s curse pollen

33. If we are exposed to low levels of PAs in our foods why are there not more cases of PA poisoning being diagnosed?

34. “A major reason is that has not been looked for.” Huxtable 1989 Specialists, and some GPs, may be aware of PAs in herbal products like comfrey but they are generally unaware that foods such as Paterson’s curse honey contain PAs at potentially harmful levels.

35. “Despite extensive diagnostic examinations, we could not completely elucidate the aetiology of the liver disease in our case. No history of ingestion of toxic substances or herbal teas was reported by interviewing the mother. Nevertheless we cannot rule out that the mother had consumed food or drinks contaminated with pyrrolizidine alkaloids during pregnancy.” Sergi et al., 1999

36. “Despite extensive examinations and diagnostics, the etiology of VOD in our patient has not been elucidated. Nevertheless, we cannot exclude the possibility that food or drinks consumed by the mother during pregnancy were contaminated with pyrrolizidine alkaloids.” Seibold-Weiger et al., 1997

37. “Surprisingly, no consideration has been devoted to one potential cause that would account for many, if not all, of the aspects of these clusters. …. A coordinated investigation by epidemiologists, toxicologists, and environmental chemists of a PA- leukemia linkage could prove to be a prudent investment.”Daughton 2005

38. Until very recently there was no monitoring of PAs in food in any country in the world. Australia does not monitor foods such as grain, dairy products and honey for PAs. ………….. There are very few laboratories in the world with experience in analyzing foods for PAs

39. Enhanced destruction of PAs in the rumen • Peptostreptococcus heliotrinreducans • 85% destruction of PAs in sheep rumen • Requires free hydrogen • Competes for hydrogen with methane producing bacteria • Inhibition of methane producing bacteria may lead to enhanced PA destruction http://www.pharmcast.com/Patents/Yr2001/June2001/062601/6251879_Antimethanogenic062601.htm

40. Nyctermera (Senecio or magpie moth)

41. Utetheisa pulcheloides (speckled footman)

43. Coremata of male Utetheisa release a PA-derived pheromone during courstship

44. Nephila, cuts web to release PA-containing moths

45. Conclusions PAs are clearly undesirable substances in food and every effort should be made to keep PA plants, such as fireweed out of agricultural production systems.

46. “ Prevention of exposure is the only effective method of limiting toxicity due to PAs. Even low doses over a period of time may present a health risk and exposure should be avoided or minimized as far as possible.” World Health Organization (1989).