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Scientific Opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds

EFSA Journal 2011;9(11):2405 [150 pp.]. doi:10.2903/j.efsa.2011.2405
  EFSA Panel on Contaminants in the Food Chain (CONTAM) Panel Members Jan Alexander, Diane Benford, Alan Boobis, Sandra Ceccatelli, Bruce Cottrill, Jean-Pierre Cravedi, Alessandro Di Domenico, Daniel Doerge, Eugenia Dogliotti, Lutz Edler, Peter Farmer, Metka Filipič, Johanna Fink-Gremmels, Peter Fürst, Thierry Guérin, Helle Katrine Knutsen, Miroslav Machala, Antonio Mutti, Martin Rose, Josef Schlatter and Rolaf van Leeuwen Acknowledgment The Panel wishes to thank the members of the Working Group on Poppy seeds: Diane Benford, Andrew Cockburn, Daniel Doerge, Birgit Dusemund, Peter Fürst and Jan-Willem van der Laan for the preparatory work on this scientific opinion and the hearing expert Éva Németh-Zámboriné, and EFSA staff: Katleen Baert, Gina Cioacata, José Cortinas Abrahantes, Jean-Lou Dorne and Liisa Valsta for the support provided to this scientific opinion. The CONTAM Panel acknowledges all European competent authorities and other stakeholders that provided opium alkaloids occurrence data for food and supported the consumption data collection for the Comprehensive European Food Consumption Database. Contact contam@efsa.europa.eu
Type: Opinion of the Scientific Committee/Scientific Panel On request from: European Commission Question number: EFSA-Q-2010-00961 Adopted: 05 October 2011 Published: 08 November 2011 Affiliation: European Food Safety Authority (EFSA), Parma, Italy
Abstract

Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). They are used in bakery products, on top of dishes, in fillings of cakes and in desserts and to produce edible oil. The opium poppy plant contains narcotic alkaloids such as morphine and codeine. Poppy seeds do not contain the opium alkaloids, but can become contaminated with alkaloids as a result of insect damage, or through poor harvesting practices. The European Commission asked the European Food Safety Authority (EFSA) to provide a scientific opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds intended for human consumption. Following a call for data, EFSA received the results from analyses of opium alkaloids, primarily morphine, codeine, thebaine, papaverine and noscapine, in samples of poppy seeds, bakery products and baking ingredients. Based on the relative prevalence of the alkaloids present in poppy seed and food samples analysed, and on their pharmacological potency, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) concluded that the risk assessment could be based on dietary exposure to morphine alone. The CONTAM Panel applied an uncertainty factor of 3 to establish from the lowest known single oral therapeutic dose of 30 µg morphine/kg body weight (b.w.) an acute reference dose (ARfD) of 10 μg morphine/kg b.w. Estimates of dietary exposure to morphine from foods containing poppy seed demonstrate that the ARfD can be exceeded during a single serving by some consumers, particularly children, across the EU. This risk assessment relates to poppy seed samples with an alkaloid profile comparable to that of the submitted data and should not be extrapolated to poppy seed samples with a qualitatively different alkaloid profile.

© European Food Safety Authority, 2011

Summary

Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). The latex (milky sap) of the opium poppy contains alkaloids, referred to here as opium alkaloids, including the narcotic agents morphine and codeine that have been used by man for the treatment of severe pain for generations. Opium alkaloids are also subject to misuse. The alkaloids are synthesised, stored and metabolised in the latex of the poppy plant. The latex permeates all parts of the plant, except the seeds and is to be found in particular in the pericarp of the capsule. The latex of the immature capsules, which is released by incisions and has dried, is called opium. Opium contains approximately 20 – 25 % alkaloids, of which around 50 different alkaloids have been isolated in pure form. The total alkaloid content of the poppy plant depends on various factors such as variety, location, soil conditions, fertilisation, climate, weather and harvesting time. Opium alkaloids can be divided into 2 distinct chemical classes, phenanthrenes and benzylisoquinolines. The principal phenanthrenes are morphine, codeine and thebaine, whereas the principal benzylisoquinolines are papaverine and noscapine. Morphine is generally the predominant alkaloid. Papaver somniferum varieties especially bred with high alkaloid content intended for pharmaceutical purposes are also used for production of poppy seeds for food use. Low morphine varieties of Papaver somniferum are available.

Poppy seeds are used as food in bakery products, on top of dishes, in fillings of cakes and in desserts and to produce edible oil. Whilst the seeds of the poppy plant do not contain the latex, they can become contaminated with alkaloids as a result of insect damage to the capsule, or through poor harvesting practices. Consumption of foods containing poppy seeds that are contaminated with opium alkaloids can lead to adverse health effects and to detectable contents of free morphine in blood as well as measurable concentrations in urine, sufficient to interfere with drug abuse testing. There are currently no European Union regulations relating to alkaloids in poppy seeds used in food, although Hungary has national maximum levels of 30 mg/kg for morphine, 20 mg/kg for noscapine, 40 mg/kg for morphine and noscapine, 20 mg/kg for thebaine and 20 mg/kg for codeine.

The European Commission asked the European Food Safety Authority (EFSA) to provide a scientific opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds intended for human consumption, taking into account the situation for specific (vulnerable) groups of the population (e.g. high consumers, children, people following specific diets, etc.).

Today’s state of the art methodology for the determination of alkaloids in poppy seed samples is liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Detection limits are usually considerably below 1 mg/kg for morphine and related opium alkaloids.

Following a call for data, EFSA received the results from the analysis of 1033 samples including altogether 2678 analytical results for opium alkaloids in poppy seeds (n=785), and poppy seed-containing bakery products (n=186) and baking ingredients (n=62). Four European countries (Germany, Hungary, Austria and The Netherlands) provided data on morphine, codeine, thebaine, papaverine and noscapine. Australia provided data on morphine, codeine, thebaine and, in addition, on oripavine. Oripavine, a phenanthrene, is a biosynthesis precursor of morphine. In the submitted data, and in line with the literature, morphine was the major alkaloid in poppy seed samples. Moreover, morphine and codeine had a high level of co-occurrence, as did codeine and thebaine, and morphine and thebaine. There was a low level of co-occurrence of morphine, codeine and thebaine with noscapine. Based on the relative prevalence of the alkaloids present in poppy seed and food samples analysed and on their pharmacological potency, the Panel on Contaminants in the Food Chain (CONTAM Panel) concluded that the exposure assessment should focus primarily on morphine alone.

Poppy seed consumption varies broadly within the European Union. In some cultures, such as in Central-Eastern European countries, it is traditional to use poppy seeds widely in foods, and in specific instances sometimes in high amounts in bread, fine bakery ware, desserts and other dishes. For other consumers poppy seeds are commonly used as a condiment or decoration. Due to the limited available data on consumption of foods containing poppy seeds, the CONTAM Panel adopted a number of different approaches to estimate dietary exposure to morphine. Since opium alkaloids act acutely, only acute dietary exposure was assessed. In each case lower and upper bound concentrations and mean and 95th percentile occurrence data were used. Firstly, mean exposure to morphine was estimated for three European countries where foods with high poppy seed content are popular and for which poppy seed consumption data were available in the Comprehensive European Food Consumption Database, together with the occurrence data for morphine in poppy seed samples. The estimated mean dietary exposures for the three countries ranged from 3.11 to 90.9 µg/kg body weight (b.w.) per day. The number of consumers in the Database was not sufficient to estimate high level exposure. Secondly, hypothetical single portion scenarios were developed based on recipes for foods with high content of poppy seeds, and the occurrence data for morphine in poppy seed samples. The estimated morphine exposure ranged from 37.8 to 200 µg/kg b.w. per portion for adults and was the highest for children within the age range of 3 to 10 years, at 47.8 to 252 µg/kg b.w. per portion. Thirdly, exposure was estimated based on occurrence data of morphine in poppy seed samples and consumption of bread or fine bakery ware with estimated high or low level poppy seed contents, assuming that certain groups of white bread or fine bakery ware consumed on one day contain poppy seeds. Estimated exposure from bread was lower than from fine bakery ware. For consumers of low poppy seed content foods, the estimated dietary exposure to morphine via fine bakery ware for adults ranged from 0.05 to 16.9 μg morphine/kg b.w. per day. The estimated dietary exposure was the highest for toddlers and ranged from 0.39 to 36.3 μg morphine/kg b.w. per day. The estimated exposures of other children and adolescents were between those of adults and toddlers. For consumers of foods with high poppy seed content, the estimated dietary exposure to morphine via fine bakery ware for adults ranged from 2.48 to 375 μg morphine/kg b.w. per day. The estimated dietary exposure was the highest for children within the age range of 3 to 10 years at 10.2 to 753 μg morphine/kg b.w. per day. The estimated exposures of toddlers and adolescents were between those of adults and other children. Since these exposure estimates are based on the reported data on concentrations of alkaloids in poppy seed samples, they do not necessarily reflect the exposure to morphine in the food as consumed. The alkaloid content of poppy seed samples and poppy seed containing foods can be reduced by several methods of pre-treatment and processing. Food processing may decrease the alkaloid content by up to about 90 %. The most effective methods include washing, soaking and heat treatments, as well as grinding and combinations of these treatments. If the concentrations are reduced by processing, the exposure would be up to 90 % lower.

Finally, exposure was estimated based on the occurrence data for morphine in bakery products, which were all for foods sampled in Germany, together with consumption data for countries where foods with high poppy seed content are popular. The estimated high exposure ranged from 0.50 to 14.6 µg/kg b.w. per day for adults. The exposure was the highest for children within the age range of 3 to 10 years at 1.88 to 30.7 µg/kg b.w. per day.

Morphine and codeine are readily absorbed from the gastrointestinal (GI) tract. The oral bioavailability of morphine is reduced by both Phase I and II pre-systemic metabolism in the GI tract and liver. Codeine is less susceptible to this pre-systemic effect. Extrapolation of codeine toxicity data from rats to humans is complicated by large differences in oral bioavailability and metabolism affecting the conversion to morphine. Oral bioavailability of papaverine, noscapine, thebaine and oripavine, appears to be low due to pre-systemic metabolism in the GI tract and liver primarily involving demethylation reactions but also glucuronidation.

The data on the pharmacology of morphine, codeine and the other opium alkaloids in poppy seeds indicate that morphine is the most pharmacologically active opiate compound, with codeine as the second. Morphine acts mainly via the opiate µ-receptor. And because of its widespread distribution in the body it exerts a number of different effects, both in the central nervous system and in the peripheral nervous system. Chronic and developmental toxicity of morphine have not been systematically evaluated. Morphine is genotoxic only in vivo but most likely by a non-DNA reactive mode of action. Although carcinogenicity data for morphine itself are lacking, based on the lack of carcinogenicity of codeine which is extensively metabolised to morphine in rats, the CONTAM Panel concluded that morphine is unlikely to be carcinogenic. Codeine is not genotoxic in vitro or in vivo. The most prominent side effects of morphine and codeine are sedation and respiratory depression. Only very limited data are available for oripavine and thebaine. They show only partial agonistic activity at the µ-receptor, and thebaine has been shown to act as an antagonist at higher dosages. The benzylisoquinolines papaverine and noscapine do not show opiate-like behaviour, papaverine acting as a smooth muscle relaxant, and noscapine as an antitussive agent.

As morphine and codeine are in long-established use as human therapeutic agents and relevant human data are available, the CONTAM Panel decided to use these data as the primary basis for its risk assessment. Activation of the μ-opiate receptor by morphine leads to analgesia, euphoria, dependence, miosis, respiratory depression, cough calming and obstipation. Patients with pain tolerate larger doses of morphine than pain-free patients, without severe side effects. Therapeutic doses of morphine may also impair the ability to drive or to operate machinery due to changes in attentiveness and reactive skills. The pharmacology of codeine is strongly related to that of morphine, as it acts mainly as a precursor of morphine itself. Up to 20 % of codeine can be converted to morphine. The most frequent side effect of codeine is constipation. Other side effects include slight headaches, minor sleepiness, nausea sometimes linked with vomiting (particularly at the beginning of treatment) and a dry mouth. At higher doses impaired vision, respiratory depression and euphoria may also occur. The side effects of papaverine that occur after oral administration are dizziness, headache, drowsiness, tiredness, gastro-intestinal disturbance, flush, skin rash, tachycardia, sweating and hypotonia.

Since morphine-like central nervous effects have been observed in humans following consumption of a single portion of a meal containing opium alkaloid-contaminated poppy seeds, the CONTAM Panel considered it appropriate to base the risk assessment for poppy seeds on exposure to morphine. Because it is unlikely that morphine has genotoxic or carcinogenic potential at exposures relevant to dietary exposure from poppy seeds, establishing a health based guidance value is appropriate taking into account the short term nature of the effects of morphine, therefore the CONTAM Panel concluded that establishment of an acute reference dose (ARfD) was required. Ensuring exposure is below the ARfD would also protect against possible effects of repeated exposure and therefore establishing a Tolerable Daily Intake (TDI) was not necessary. The available data on central nervous effects following consumption of poppy seed-containing foods did not provide sufficient information on the dose response relationships for the alkaloids. The CONTAM Panel therefore decided to derive the ARfD from the lowest known single oral therapeutic dose used for treatment of pain or dyspnoea, which is 1.9 mg morphine, corresponding to 31.7 μg/kg b.w. for an adult weighing 60 kg. This lowest known single oral therapeutic dose, rounded to a single significant figure of 30 µg/kg b.w., is regarded by the CONTAM Panel as the lowest-observed-effect level (LOEL). It applies to children as well as adults since it is lower than the lowest known single oral therapeutic dose for children of 83 μg morphine/kg b.w. Furthermore, the LOEL is conservative, because it is uncertain whether side effects are actually observed following a single administration at this dose. The CONTAM Panel concluded that an uncertainty factor of 3 was sufficient to allow for extrapolation from the LOEL to a no-observed- effect level (NOEL), considering that the LOEL was derived from patients and not from the general population. The CONTAM Panel applied the uncertainty factor of 3 to establish from the LOEL of 30 μg morphine/kg b.w. an ARfD of 10 μg morphine/kg b.w. This is the dose of morphine from poppy seed-containing foods for which a person would not be expected to experience effects following consumption of one meal or total consumption within one day.

If poppy seeds are consumed as condiments or decoration in bread and fine bakery ware, it is possible that some consumers, particularly toddlers, will exceed the ARfD for morphine on rare occasions. A considerable proportion of consumers of foods that contain large amounts of poppy seeds, such as are common in Central-Eastern European countries, are likely to exceed the ARfD for morphine on at least some eating occasions. The highest estimates of morphine exposure are about 75-fold greater than the ARfD. Due to the lack of data on morphine in food as consumed, the exposure estimates based on morphine content of poppy seed samples do not take into account the effects of food processing, which could, in some circumstances, result in reduction of the morphine content by up to about 90 %. Taking this reduction into account the ARfD is most likely to be exceeded when single large portions are consumed or if foods containing raw, unground poppy seeds are consumed.

There are few reports of side effects arising from traditional consumption of poppy seeds in foods, excluding instances of misuse. However, in the absence of formal reporting systems it cannot be assumed that such reactions do not occur from time to time.

Contrary to expectation, estimations of exposure to morphine based on data available for fine bakery products sampled in Germany, where foods with high poppy seed content are common, were very similar to those for foods using poppy seeds as condiments or decoration. This observation could be due to the influence of processing (e.g. baking) on the alkaloid levels in food and/or the measures that have been taken in Germany to reduce alkaloid contamination of poppy seeds.

This risk assessment relates to poppy seed samples with an alkaloid profile comparable to that of the submitted data and should not be extrapolated to poppy seed samples with a qualitatively different alkaloid profile.

The CONTAM Panel recommended that analysis of poppy seeds and poppy seed containing products should focus not only on morphine, but also on those alkaloids reported to be present, and their ratios to morphine. More data are required on levels of opium alkaloids in food products, on the varieties of poppy seeds that are available on the European market for food use, as well as on their alkaloid content (including alkaloid profile), and on consumption of poppy seed products.

Keywords

poppy seeds, morphine, codeine, dietary exposure, toxicity, pharmacology, acute reference dose (ARfD)