Scientific Opinion on Tropane alkaloids in food and Tropane alkaloids in food and feed EFSA Journal

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Text of Scientific Opinion on Tropane alkaloids in food and Tropane alkaloids in food and feed EFSA Journal

  • EFSA Journal 2013;11(10):3386

    Suggested citation: EFSA CONTAM Panel (EFSA Panel on Contaminants in the Food Chain), 2013. Scientific Opinion on

    Tropane alkaloids in food and feed. EFSA Journal 2013;11(10):3386, 113 pp. doi:10.2903/j.efsa.2013.3386

    Available online: www.efsa.europa.eu/efsajournal

    © European Food Safety Authority, 2013

    SCIENTIFIC OPINION

    Scientific Opinion on Tropane alkaloids in food and feed 1

    EFSA Panel on Contaminants in the Food Chain (CONTAM) 2, 3

    European Food Safety Authority (EFSA), Parma, Italy

    ABSTRACT

    The European Food Safety Authority (EFSA) was asked to deliver a scientific opinion on the risks to human and

    animal health related to the presence of tropane alkaloids (TAs) in food and feed. TAs are secondary metabolites

    which occur in several plant families. Although more than 200 different TAs have been identified in various

    plants, respective data on toxicity and occurrence in food and feed are limited. Therefore, the EFSA Panel on

    Contaminants in the Food Chain (CONTAM Panel) could only perform a risk assessment on (-)-hyoscyamine and

    (-)-scopolamine, the two TAs for which occurrence and toxicity data were available. Since the pharmacological

    effects of (-)-hyoscyamine and (-)-scopolamine occur within a short time after administration, the CONTAM

    Panel concluded that it was appropriate to establish an Acute Reference Dose (ARfD) for these substances. Based

    on the results for decreased heart rate in a human volunteer study, the CONTAM Panel established a group ARfD

    of 0.016 µg/kg body weight (b.w.) expressed as the sum of (-)-hyoscyamine and (-)-scopolamine, assuming

    equivalent potency. Results on TAs in 124 food and 611 feed samples were collected in two Member States. Most

    of the food and feed samples were left-censored (below limit of detection/limit of quantification). A reliable

    exposure estimate was only possible for one food and one age class (toddlers). Based on the limited information,

    the CONTAM Panel concluded that the dietary exposure of toddlers could be up to seven times the group ARfD

    and could exceed the group ARfD on approximately 11 to 18 % of consumption days. TA toxicosis in livestock

    and companion animals is relatively rare.

    © European Food Safety Authority, 2013

    KEY WORDS tropane alkaloids (TAs), origin, chemistry, analysis, dietary exposure, risk assessment, health based guidance

    value

    1 On request from the European Commission, Question No EFSA-Q-2010-01038, adopted on 27 September 2013. 2 Panel members: Diane Benford, Sandra Ceccatelli, Bruce Cottrill, Michael DiNovi, Eugenia Dogliotti, Lutz Edler, Peter

    Farmer, Peter Fürst, Anne Katrine Lundebye, Laurentius (Ron) Hoogenboom, Helle Katrine Knutsen, Manfred Metzler,

    Carlo Stefano Nebbia, Michael O‘Keeffe, Ivonne Rietjens, Dieter Schrenk, Vittorio Silano, Hendrik Van Loveren, Christiane

    Vleminckx and Pieter Wester. Correspondence: contam@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on alkaloids: Diane Benford, Till Beuerle,

    Leon Brimer, Bruce Cottrill, Daniel Doerge, Birgit Dusemund, Peter Farmer, Peter Fürst, Hans-Ulrich Humpf and Patrick

    Mulder for the preparatory work on this scientific opinion and the hearing expert Lutz Edler, and EFSA staff Davide Arcella,

    Katleen Baert, Bistra Benkova, Marco Binaglia, Gina Cioacata, José Angel Gomez Ruiz and Enikö Varga for the support

    provided to this scientific opinion. The CONTAM Panel acknowledges all European competent authorities and other

    stakeholders that provided tropane alkaloids occurrence data for food and feed, and supported the consumption data

    collection for the Comprehensive European Food Consumption Database. The Panel wishes to thank Lucija Perharič for

    providing the heart rate data of all subjects as reported by Perharic et al. (2013a) and further information on the study design.

  • Tropane alkaloids in food and feed

    EFSA Journal 2013;11(10):3386 2

    SUMMARY

    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food

    Chain (CONTAM Panel) was asked to deliver a scientific opinion on the risks to human and animal

    health related to the presence of tropane alkaloids (TA) in food and feed.

    TAs are secondary metabolites which naturally occur in plants of several families including

    Brassicaceae, Solanaceae (e.g. mandrake, henbane, deadly nightshade, Jimson weed) and

    Erythroxylaceae (including coca). The TAs are found in all parts of the plants and are responsible for

    the toxic effects of some of these plants. TAs contain an azabicyclo[3.2.1]octane ring structure. The

    common structural element is the tropane skeleton, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane. The

    group of TAs comprises more than 200 compounds and the wide range of compounds occurring

    especially in the Solanaceae family arises from the esterification of tropine with a variety of acids, such

    as acetic acid, propanoic acid, isobutyric acid, isovaleric acid, 2-methylbutyric acid, tiglic acid,

    (+)-α-hydroxy-β-phenylpropionic acid, tropic acid, and atropic acid.

    Although more than 200 different TAs were so far identified in various plants, respective data on their

    occurrence in food and feed and on toxicity are limited. The most studied TAs are (-)-hyoscyamine and

    (-)-scopolamine, which in contrast to the (+)-enantiomers are formed naturally. The racemic mixture of

    (-)-hyoscyamine and (+)-hyoscyamine is called atropine. Cocaine is also a prominent member of the

    group of TAs. However, since almost no data are available concerning the occurrence of cocaine in food

    and feed, it was not further considered in this opinion. Besides data on toxicity, some information on

    occurrence in feed and food were only available for (-)-hyoscyamine and (-)-scopolamine. Therefore,

    the CONTAM Panel could only perform a risk assessment on these compounds.

    Plant extracts containing TAs have been used for centuries in human medicine and are still used, as are

    atropine, (-)-hyoscyamine and (-)-scopolamine. These uses include for example the treatment of

    wounds, gout and sleeplessness, and pre-anaesthesia. Furthermore, extracts from deadly nightshade

    (Atropa belladonna) were used to dilate pupils for cosmetic reasons and to facilitate ophthalmological

    examination. The genus Datura is long known for its content of TAs. In India, the root and leaves of

    Datura stramonium, commonly called thorn apple or Jimson weed, were burned and the smoke inhaled

    to treat asthma. This plant is widely distributed in temperate and tropical regions of the world. For this

    reason, seeds of this plant have been found as impurities in important agricultural crops such as linseed,

    soybean, millet, sunflower and buckwheat and products thereof. The consumption of a few berries from

    henbane (Hyoscyamus niger) or from Atropa belladonna has caused severe intoxication, including

    deaths in young children.

    Atropine/(-)-hyoscyamine and (-)-scopolamine are readily absorbed from the gastrointestinal tract,

    quickly and extensively distributed into tissues, and excreted predominantly in the urine.

    N-demethylation and Phase II conjugation of atropine, (-)-hyoscyamine and (-)-scopolamine are known

    metabolic pathways in humans. The toxicological effects of (-)-hyoscyamine and (-)-scopolamine relate

    to their pharmacological effects, which are mediated by inhibition of muscarinic acetylcholine receptors

    in the central nervous system (CNS) and the autonomic nervous system (ANS). Inhibition of these

    receptors in the ANS results in decreased secretions from the salivary, bronchial and sweat glands,

    dilation of the pupils, paralysis of accommodation, change in heart rate, inhibition of micturition,

    reduction in gastrointestinal tone and inhibition of gastric acid secretion. (-)-Hyoscyamine and

    (-)-scopolamine differ in their ability to affect the CNS, with (-)-scopolamine having more prominent

    depressing central effects at therapeutic doses. The pharmacological effects of (-)-hyoscyamine and

    (-)-scopolamine occur within a short time after administration, and therefore the CONTAM Panel

    concluded that it was appropriate to establish an Acute Reference Dose (ARfD) for these substances.

    Since they are not bioaccumulative, or genotoxic and do not exhibit chronic toxicity, the ARfD would

    also protect against effects of long-term exposure. Due to the common mode of action through receptor

    interaction, the CONTAM Panel considered it appropriate to establish a group ARfD for

    (-)-hyoscyamine and (-)-scopolamine assuming equivalent potency.

  • Tropane alkaloids in food and feed

    EFSA Journal 2013;11(10):3386 3

    From the results of a study in which human volunteers were given a relevant mixture of

    (-)-hyoscyamine and (-)-scopolamine in food, the CONTAM Panel identified a no–observed-adverse-

    effect level (NOAEL) of 0.16 µg/kg body weight (b.w.), expressed as the sum of (-)-hyoscyamine and

    (-)-scopolamine as the basis for establishing a group ARfD. The Panel noted that the next higher dose in

    the human volunteer study

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