Pyrrolizidine TITLE OF THE PRESENTATION alkaloids in teas

Pyrrolizidine TITLE OF THE PRESENTATION alkaloids in teas, GOES HERE herbals and honeys 12 January 2016 Food Safety Group

Food Standards Agency - Food we can trust ‘The main objective of the FSA in carrying out its functions is to protect public health from risks which may arise in connection with the consumption of food (including risks caused by the way in which it is produced or supplied) and otherwise to protect the interests of consumers in relation to food’ We will put consumers first in everything we do.

Food Safety Group - Food we can trust Science Team - Risk assessment - Chemical Risk Assessment Unit Policy Teams - Risk Management - Chemical Contaminants and Residues Team Key Aim • To protect consumers from unacceptable risks that may arise from chemical contaminants and residues in food now and in the future Key Values • We will put consumers first in everything we do • Stakeholder consultation is key • Science and evidence underpins the development of policy • Ensure maximum influence across the EU • Proportionate and pragmatic policy development that: – Reduces regulatory burden – Is enforceable – Empowers consumers to make informed choices.

Key responsibilities • Developing policy - national and EU level • Identifying new risks to the food chain • Commissioning research to underpin policy • Responding to incidents impacting food safety (risk management) • Providing advice (to national and local government, OGDs, agencies, food businesses and consumers)

Key Responsibilities Fungal toxins - Mycotoxins (e. g. aflatoxins, ochratoxin, fusarium toxins DON/ZON etc. ) Plant toxins – pyrrolizidine alkaloids, tropane alkaloids, opium alkaloids, nitrate, cyanide Process contaminants - acrylamide, 3 -MCPD & esters, ethyl carbamate, N-nitrosamines etc. Environmental Contaminants – Organic Contaminants (e. g. dioxins & furans, PAHs, BFRs) and inorganic contaminants (e. g. lead, cadmium, mercury, arsenic and iodine) Residues – Vet Medicine, pesticide residues and biocides

Pyrrolizidine alkaloids • Pyrrolizidine alkaloids (PAs) are toxins found naturally in a wide variety of plants. Approximately 6, 000 plant species are known to contain PAs. Over 600 PAs known. • Produced by plants as a defence against herbivores. • Plants most commonly associated with food poisoning in humans are Heliotropium (in the family Boraginaceae) and Crotalaria. • Occur as weeds in cereal or legume crops and the seeds are mixed accidentally with the main crop at harvest. • Carry-over of PAs from feed into animal derived products?

Pyrrolizidine alkaloids 95% of PAs are found in 5 plant families: Asteraceae (Compositae), Boraginaceae, Fabaceae (Leguminosae), Orchidaceae and Apocynaceae. 7

Pyrrolizidine alkaloids - potential sources • Honey Ø If bees harvest pollen of PA-plants • Pollen dietary supplements § Salad crops Ø contaminated with PA-plants such as Senecio vulgaris § Herbal products, supplements and teas Ø Prepared from, or contaminated by, PA-containing plants § Products of animal origin (meat/milk/eggs) Ø If food producing-animals graze on PA-plants or feed contaminated with them § Cereals Ø If grain crops are contaminated with PA-plants

Pyrrolizidine alkaloids - risk assessments • European Food Safety Authority (EFSA) in 2007 - opinion on PAs as undesirable substances in animal feed. • European Commission requested EFSA for a scientific opinion on the risks to human and animal health from PAs in food and feed. EFSA published scientific opinion in 2011. • Joint FAO/WHO Expert Committee on Food Additives (JECFA) - evaluation in 2015

BACKGROUND TO THE SURVEY AND RESULTS

Pyrrolizidine alkaloids - survey • From EFSA’s scientific opinion: ØNo occurrence data in food other than honey. ØPossible health concern for those toddlers and children who are high consumers of honey. ØRecommendation that efforts should be made to collect occurrence data in food and feed. • Bf. R (Germany) published opinion on PAs in herbal teas and teas in 2013. Short-term intake (up to 14 days) may not pose a health risk. But greater risk for Ølong-term consumption of products with high PA content ØFrequent consumption of large quantities of herbal tea and tea Øchildren, pregnant women and breast feeding mothers.

Pyrrolizidine alkaloids in food • European Commission discussed risk management measures - but no data; recommended monitoring of PA levels in food. • EFSA commissioned a survey in 2014.

Pyrrolizidine alkaloids - survey • FSA commissioned survey to measure levels of PAs in ØHoney (54 samples) ØTeas (59 samples; black and green) and herbal teas (66 samples; teas for babies, fennel, chamomile, rooibos, dandelion, peppermint, nettle, hibiscus, borage, comfrey (intended for human consumption), fruit teas etc. ) ØPlant-based food supplements (46 samples ) • Samples taken from Øretail outlets, health food shops, shops selling specialty teas, convenience stores and via the internet. Øspecific brands selected in proportion to their market share volume using data (Mintel, 2013). Specific products within a manufacture/brand sampled carried out by simple random sampling.

Pyrrolizidine alkaloids - survey Samples analysed using liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). Sample preparation involved extraction into aqueous acid and clean up/concentration on solid phase extraction columns (SPE). 19 PAs were analysed: Echimidine Monocrotaline Intermedine Monocrotaline N-oxide Lycopsamine Retrorsine Lasiocarpine Retrorsine N-oxide Lasiocarpine N-oxide Senecionine Erucifoline Senecionine N-oxide Erucifoline N-oxide Seneciphylline Heliotrine Seneciphylline N-oxide Heliotrine N-oxide Senkirkine Jacobine

Pyrrolizidine alkaloids - Survey - Summary of results No. of Total No. samples of in which samples PAs were detected 0 - 100 - 500 - 1000 - 3000 >3000 (µg/kg) (µg/kg) Range (µg/kg) Teas (black, green and Earl Grey) 59 11 6 4 - 1 - 0 - 1170 Herbal teas 66 34 9 13 6 4 2 052, 508* Plant based supplements 46 5 2 2 - - 1 0 - 7187 Honeys 54 33 27 6 - - - 0 - 251 * The high levels were from borage and comfrey teas which are known to have high levels of PAs

Pyrrolizidine alkaloids - survey Teas and herbal teas - brewing experiments 25 teas were brewed according to the packet instructions. Typically one tea bag or 2 - 4 g of loose tea were brewed by adding 200 ml of boiled water. • PA levels ranged from ~ 0. 001 to 0. 286 µg per cup of 200 ml (0. 3 - 144. 3 µg/kg) • Contamination levels can vary between tea bags within a packet. • Method of extraction different (acid vs hot water) • Needs more investigation.

EXPOSURE TO PYRROLIZIDINE ALKALOIDS Rufina Acheampong Chemical Risk Assessment Unit

Pyrrolizidine alkaloids - Exposure Assessment Risk Assessment 1. Hazard identification 3. Exposure assessment Risk management 2. Hazard characterisation Risk communication 4. Risk characterisation

Pyrrolizidine alkaloids - Exposure Assessment What do we mean by exposure? Exposure is the measurement, estimation or prediction of total intake of a chemical via one or more of the following routes: 1. Oral ingestion 2. Inhalation 3. Dermal contact Dietary Exposure Assessment = Concentration of food chemical x Amount of food consumed

Pyrrolizidine alkaloids - Exposure Assessment Estimation of the quantities of the foods National diet and nutrition survey – • Provides information regarding the types & quantities of foods that we eat • • Dietary information is coded “as consumed” Able to divide NDNS data into different populations – • • E. g. Age, region, gender, weight, height etc. Chronic or acute consumption The surveys are primarily designed for use by nutrition division (Public Health England)

Pyrrolizidine alkaloids - Exposure Assessment Estimation of the quantities of the foods • • • Tea: black, green and herbal teas − 1 percent of tea as served Honey − As eaten from jars (not recipes) Plant-based food supplements − portion size approach (since there were no consumers in the NDNS) Example: Chronic Consumption of honey by UK population groups Age Group Mean consumption (g/kg bw/day) (g/person/day) 97. 5 percentile consumption (g/kg bw/day) Toddlers aged 1½ to 3 years 3. 6 0. 2 9. 7 0. 7 Adults aged 19+ years 7. 5 0. 1 30. 9 0. 4

Pyrrolizidine alkaloids - Exposure Assessment PA Concentrations used to estimate exposure Type of Tea Mixed herbal teas (Peppermint, Camomile, Lemon Balm, Rooibos, Hibiscus, Fennel, Nettle, Liquorice and Mixture with borage) - 59 samples Babies teas - 9 samples Borage and comfrey - 2 samples Black teas - 46 samples Green tea - 9 samples Lower bound mean Upper bound mean concentration of PAs (µg/kg) 311 321 82 86 51377 46 79 51377 63 95 Note: where the analytical results included non detects (zero values), the lower bound mean concentration was derived by calculating the mean of the results as presented (including zeros); whilst the upper bound was estimated by replacing the zero values with the LOQ value of 20 µg/kg.

Pyrrolizidine alkaloids - Exposure Assessment PA Concentrations used to estimate exposure Pyrrolizidine Alkaloids in 54 honey samples Mean value of PAs recorded for all types of honey = 25 ug/kg Mean value of PAs recorded for all types of honey excluding borage = 16 ug/kg Mean value of PAs recorded for borage honey = 132. 5 ug/kg Pyrrolizidine Alkaloids in herbal supplements Rapid release capsules recorded at a level of 343 µg/kg Barley grass powder recorded at a level of 117 µg/kg Mixture of organic herbs capsules recorded at a level of 66 µg/kg Maca powder recorded at a level of 22 µg/kg

Pyrrolizidine alkaloids - Exposure Assessment Exposure to pyrrolizidine alkaloids in honey (µg/kg bw/d) All types of honey Age Group All types of honey excluding borage Borage honey Mean 97. 5 percentile Mean 97. 5 percentile Toddlers aged 1½ to 3 years 0. 006 0. 017 0. 004 0. 011 0. 032 0. 088 Adults aged 19+ years 0. 003 0. 011 0. 002 0. 007 0. 014 0. 059 Note: The reference point for comparison with the estimated dietary exposure is 70 µg/kg b. w. per day

Pyrrolizidine alkaloids - Exposure Assessment Herbal Supplements Example: • • • Marshmallow rapid release capsules with PAs recorded at a level of 343 µg/kg 100 capsules - label indicates that two capsules contain 2, 500 mg Label indicates a adult dosage of two capsules three times daily Assuming the highest recommended dose, results in a consumption estimate of 7500 mg person per day From the NDNS, the average bodyweight for UK adults aged 19+ years is 78. 1 kg Consumption (mg/kg bw/day) Exposure (µg/kg bw/day) 96. 03 0. 033 Note: The reference point for comparison with the estimated dietary exposure is 70 µg/kg b. w. per day

Pyrrolizidine alkaloids - Exposure Assessment Tea samples - examples Table 1: Consumption and Exposure to pyrrolizidine alkaloids in black teas by UK Population groups (µg/kg bw/d) Age Group Mean consumption (g/kg bw/day) 97. 5 percentile consumption (g/kg bw/day) Toddlers aged 1½ to 3 years 0. 06 0. 24 0. 003 - 0. 004 0. 011 - 0. 015 Adults aged 19+ years 0. 07 0. 21 0. 003 - 0. 005 0. 010 - 0. 013 Mean exposure range 97. 5 percentile exposure (µg/kg bw/d) range (µg/kg bw/d) Table 2: Consumption and Exposure to pyrrolizidine alkaloids in Borage and comfrey tea by UK Population groups (µg/kg bw/d) Age Group Mean consumption (g/kg bw/day) 97. 5 percentile consumption (g/kg bw/day) Mean exposure range (ug/kg bw/d) 97. 5 percentile exposure range (ug/kg bw/d) Toddlers aged 1½ to 3 years 0. 16 0. 48 8. 35 24. 6 Adults aged 19+ years 0. 03 0. 14 1. 76 7. 11 Note: The reference point for comparison with the estimated dietary exposure is 70 µg/kg b. w. per day

TOXICITY OF PYRROLIZIDINE ALKALOIDS AND RISK ASSESSMENT Dr Diane Benford Head of Risk Assessment Unit

Toxicity of PAs in humans § § § Cases of poisonings have been reported with PA-containing herbal medicines and teas, and large outbreaks due to grain crops contaminated with PA-containing weeds. Mainly acute hepatic veno-occlusive disease (HVOD). The acute disease is associated with high mortality, and a subchronic or chronic onset may lead to liver cirrhosis. Doses associated with acute and short-term toxicity in humans are in the region of 1 mg PA/kg b. w. per day or more. The lowest known dose associated with long-term toxicity is reported to be 15 μg PA/kg b. w. per day. Substantial, long-term follow-up data or epidemiological studies to assess whether exposure to 1, 2 -unsaturated PAs results in cancer in humans are not available. 28

Toxicity of PAs in laboratory animals § All tested 1, 2 -unsaturated PAs are genotoxic § 1 -2 unsaturated PAs that have been tested caused tumours in rodents, especially in the liver § Based on the available genotoxicity and carcinogenicity data, it is concluded that all 1, 2 -unsaturated PAs have the potential to be carcinogenic in rodents, and could also be in humans § Assume no level is without risk, i. e. no safe level, therefore a “tolerable intake level” cannot be established § Exposure should be reduced to as low as reasonably practicable (ALARP) 29

Risk assessment for genotoxic carcinogens – EFSA/JECFA • Identify a reference point on the dose range in animal studies, • e. g. : • Benchmark dose for 10% increased tumour incidence (BMD 10) and its lower confidence limit (BMDL 10) • BMDL 10 = 70 µg/kg b. w. per day for lasiocarpine. Margin of Exposure (MOE) = BMDL 10 divided by estimated dietary exposure • Mo. E > 10, 000 based on BMDL 10 from animal data “of low concern from a public health point of view ……. low priority for risk management action” (EFSA, 2005) 30

Risk assessment – babies’ teas 12000 10000 8000 6000 Toddlers aged 1½ to 3 years 4000 2000 0 Mean LB Mean UB 97. 5 LB 97. 5 UB

Risk assessment – other herbal teas Peppermint, Camomile, Lemon Balm, Rooibos, Hibiscus, Fennel, Nettle, Liquorice and Mixture with borage

Risk assessment – borage and comfrey teas Exposure at levels where human toxicity has occurred

Risk assessment – black teas, including Earl Grey

Risk assessment – honey, excluding borage

Risk assessment – borage honey

Risk assessment - supplements

CONCLUSIONS

Pyrrolizidine alkaloids - Conclusions • Levels comparable to other published studies (EFSA survey, Bf. R data, literature. ) • 1, 2 -unsaturated PAs are genotoxic and carcinogenic; therefore exposure should be As Low As Reasonably Practicable (ALARP). • Borage and comfrey have high levels of PAs (both teas and honey). • There is concern for carcinogenicity at estimated high exposures from all tested products • There is concern for liver damage in toddlers if they drink borage and comfrey tea

Pyrrolizidine alkaloids - follow up actions • Efforts should be taken to minimise PA content. More rigorous quality control. ØTeas and herbal teas - weed control, good agricultural practices. ØHoneys - blending? ØPlant-based supplements - more work on PA containing plants used in supplements ØBorage and comfrey - known to be PA containing plants.

Pyrrolizidine alkaloids - Follow up action • European Commission looking to set Maximum Levels for PAs in teas, herbal teas, food supplements, honey, herbs and spices. • Asked EFSA to update the exposure assessment.