Health and Safety Guide No. 26






    This is a companion volume to Environmental Health Criteria 80: 
    Pyrrolizidine Alkaloids.

    Published by the World Health Organization for the International
    Programme on Chemical Safety (a collaborative programme of the United
    Nations Environment Programme, the International Labour Organisation,
    and the World Health Organization)

    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization

    ISBN 92 4 154347 8
    ISSN 0259-7268

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    (c) World Health Organization 1989

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         1.1. Identity
         1.2. Physical and chemical properties
         1.3. Uses


         2.1. Human exposure to pyrrolizidine alkaloids
         2.2. Metabolism and excretion
         2.3. Effects on experimental animals
         2.4. Effects on human health
         2.5. Effects on the environment



         4.1. Main hazards for man and the environment
         4.2. Prevention of PA poisoning
         4.3. Advice to physicians
         4.4. Precautionary measures to protect the environment and to
               prevent disease
         4.5. First aid
         4.6. Medical management



    The Environmental Health Criteria (EHC) documents produced by the
    International Programme on Chemical Safety include an assessment of
    the effects on the environment and on human health of exposure to a
    chemical or combination of chemicals, or physical or biological
    agents. They also provide guidelines for setting exposure limits.

    The purpose of a Health and Safety Guide is to facilitate the
    application of these guidelines in national chemical safety
    programmes. The first three sections of a Health and Safety Guide
    highlight the relevant technical information in the corresponding EHC.
    Section 4 includes advice on preventive and protective measures.

    The target readership includes occupational health services, those in
    ministries, governmental agencies, industry, and trade unions who are
    involved in the safe use of chemicals and the avoidance of
    environmental health hazards, and those wanting more information on
    this topic. An attempt has been made to use only terms that will be
    familiar to the intended user. However, sections 1 and 2 inevitably
    contain some technical terms. Further background information on the
    subject of this Guide may be found in Environmental Health Criteria
    80:  Pyrrolizidine Alkaloids.

    Revision of the information in this Guide will take place in due
    course, and the eventual aim is to use standardized terminology.
    Comments on any difficulties encountered in using the Guide would be
    very helpful and should be addressed to:

    The Manager
    International Programme on Chemical Safety
    Division of Environmental Health
    World Health Organization
    1211 Geneva 27



    1.1  Identity

    The toxic pyrrolizidine alkaloids (PAs) are a large group of related
    compounds (about 160 are known) that occur in plants, mainly in
    species of  Crotalaria (Leguminosae),  Senecio and related genera
    (Compositae),  Heliotropium, Trichodesma, Symphytum, Echium, and
    other genera of the Boraginaceae. The chemical structures of some
    alkaloids that are important in relation to human disease are shown


    1.2  Physical and Chemical Properties

    The pure alkaloids are mostly crystalline solids; some are gums or
    amorphous solids. Some are only slightly soluble in water, but all
    dissolve when neutralized with acid. They occur in the plants partly
    as  N-oxides, which are water soluble. The alkaloids are fairly
    stable, but are subject to hydrolysis in alkaline solution and to
    enzymatic decomposition. The latter occurs in some plant species
    during wilting and drying. The stability of the alkaloids when the
    plants are cooked is not known.

    1.3  Uses

    One alkaloid, monocrotaline, is marketed commercially as a fine
    chemical for research purposes. Another, indicine  N-oxide, is being
    tested as an antitumour drug in human beings.


    2.1  Human Exposure to Pyrrolizidine Alkaloids

    The contamination of cereal grains with seeds of PA-containing plants
    has caused epidemics of human poisoning in four countries. The plants
    involved were species of  Heliotropium, Trichodesma, Crotalaria, and
     Senecio. Some of these plants thrive under arid conditions and their
    growth may be favoured by drought. Another important form of exposure
    is the use of PA-containing herbs as medicines, food, or beverages;
    this has resulted in occasional cases of human poisoning. The most
    important of such PA-containing plants are  species of Heliotropium,
     Crotalaria, Senecio, and  Symphytum. Symphytum species (comfrey)
    are also available in the form of ointments or as digestive aids in
    the form of capsules.

    Low-level exposure may occur in some countries through the presence of
    PAs in foods, such as honey and milk, but no reports of human
    poisoning caused through these media are available.

    2.2  Metabolism and Excretion

    PAs are readily absorbed from the digestive tract and cause harmful
    effects only after undergoing activation in the liver to toxic
    metabolites. Effects include a variety of changes leading to permanent
    damage to genes and chromosomes, the ability of the cells to divide,
    or to the development of cancer, and even cell death. The alkaloids
    are quickly converted to harmless compounds and are largely cleared
    from the body within a few hours of absorption, so that no traces of
    the ingested PAs or their breakdown products are detectable in the
    body tissues and fluids. There are no indications that the alkaloids
    themselves accumulate in animal tissues, but their effects are
    cumulative, even at low rates of intake. The proportion excreted in
    urine varies according to the water solubility of the alkaloid.
    Estimates of the total intake over a long period can only be

    2.3  Effects on Experimental Animals

    The acute toxicity of PAs varies widely. The rat LD50s of most
    alkaloids known to be significant for human health are in the range of
    34-300 mg/kg, though some approach 1000 mg/kg. When ingested, the
    toxicity of the  N-oxide of an alkaloid is similar to that of the
    parent alkaloid.

    PAs are toxic for a wide variety of domestic, laboratory, and farm
    animals, pigs and poultry being the most sensitive of farm animals
    followed by horses and cattle, and sheep and goats, which are the most
    resistant; sheep and goats are affected only after extended periods of

    The toxic effects of most PAs occur primarily and mainly in the liver.
    Some PAs are particularly prone to cause damage in the lungs,
    principally to the blood vessels, resulting in a rise in blood
    pressure in the lungs, which leads to secondary effects on the
    functioning of the right side of the heart. The kidneys and some other
    organs are less commonly affected. The brain is the principal target
    organ of one or two PAs.

    The effects of PAs in animals may be acute or chronic, depending on
    the dose level and the period of survival after exposure. In acute
    poisoning, death occurs within about 7 days, due to severe liver
    damage. Chronic liver damage may follow administration of a single
    sublethal dose or of repeated low doses.

    PAs produce aberrations in the chromosomes in plant and mammalian
    cells and induce changes in genes that are perpetuated in subsequent
    cell divisions in mutagenesis test systems. Several PAs have been
    shown to be capable of producing cancer, chiefly in the liver in rats.

    2.4  Effects on Human Health

    Although all age groups are affected, children are particularly
    vulnerable to the effects of PAs. The symptoms, which are generally
    acute in onset, are characterized by upper abdominal discomfort that
    develops rapidly and progresses to swelling of the abdomen resulting
    in increased girth, sometimes accompanied by a reduction in the
    quantity of urine excreted and swelling of the feet. The disease is
    called veno-occlusive disease (VOD) because of the characteristic
    obstruction of the small venous blood channels that carry blood from
    the liver back to the heart. The disease often progresses rapidly and
    mortality is high. There may be vomiting of blood in advanced stages
    of the disease. While many patients recover, the disease may continue
    for a long time in others resulting in a severely scarred liver - a
    condition called cirrhosis. Some patients may have only vague symptoms
    and the only sign of the disease may be persistent enlargement of the

    The liver is usually the target organ but, in an epidemic caused by
    contamination of the staple cereal with the seeds of  Trichodesma,
    the brain and the nervous system were mainly affected.

    Chromosome aberrations have been reported in the blood cells of
    children affected by VOD but, as yet, there is no evidence pointing to
    an increased incidence of cancer of the liver or other organs or
    congenital anomalies in the newborn offspring of patients exposed to

    2.5  Effects on the Environment

    Plants containing PAs are likely to grow as weeds among staple food
    crops and pastures, especially following drought, and consumption of
    such crops can cause large scale outbreaks of toxic disease in both
    man and farm animals. Little is known about the effects on wildlife
    but, in one report, the death of deer was ascribed to their grazing on
    toxic plants.

    PAs are believed to be biodegradable so that water supplies are not


    No-observed-adverse-effect levels have not been established in
    experimental animal studies with PAs. Estimates of intakes causing
    toxic effects in human beings indicate that they are more sensitive
    than rats and domestic animals. Rats dosed with lasiocarpine at a rate
    equivalent to 0.2 mg/kg body weight per day (equivalent to about
    2 mg/kg in the diet) developed tumours. Pigs fed monocrotaline at
    1.8 mg/kg of feed (equivalent to about 0.08 mg/kg body weight per day)
    developed chronic liver damage in several months. The lowest intake
    rate causing VOD in a human being was estimated to be 0.015 mg/kg body
    weight per day, and was the result of self-medication with a comfrey
    preparation. In view of the established ability of some PAs to produce
    cancer in rats, plant products containing them should not be eaten or


    4.1  Main Hazards for Man and the Environment

    Consumption of contaminated grain or the use of PA-containing plants
    as herbal medicines, beverages, or food by man, or grazing on
    contaminated pastures by animals, may cause acute or chronic disease.
    The principal target organ in man and most animals is the liver,
    resulting in collection of fluid in the abdomen and swelling of feet,
    etc. In experimental animals, administration of PAs has been known to
    produce cancer. Though there is no proof yet of cancer developing in
    man, such a possibility cannot be entirely ruled out.

    4.2  Prevention of PA Poisoning

    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. Measures are required at several action points.

    4.3  Advice to Physicians

    Occurrence of symptoms of rapidly increasing swelling of the abdomen
    accompanied by dragging discomfort in the right upper abdomen,
    particularly if affecting more than one member of the family or
    several members of a community over a limited period and geographical
    area, should arouse suspicion. The diet of such persons should be
    examined for possible contamination with the seeds of toxic plants and
    the affected persons should be questioned regarding the possible
    intake of herbal preparations. If any such history is positive, the
    suspected toxic seeds/herbs should be analysed for the presence of PAs
    using a simple field test, which can be carried out in a not too
    highly specialized chemical laboratory.

    Examination of the liver by needle biopsy in patients or at post-
    mortem examination is most likely to provide the crucial clue.
    Haemorrhagic centrilobular necrosis and occlusion of the hepatic vein
    radicles in the liver are the hallmarks of the disease, if found in
    patients with the symptoms described above. Needle biopsy of the liver
    should be performed only in a properly equipped hospital with
    facilities for blood transfusion.

    4.4  Precautionary Measures to Protect the Environment and to Prevent

    (a) Toxic PA-containing flora growing in the region, particularly
    those that may contaminate cereal grain crops, and those that are used
    locally as herbal foods, beverages, or medicines, whether grown
    locally or imported, should be identified.

    (b) Appropriate agrotechnical practices should be followed for the
    prevention/control of the growth of PA-containing plants among cereal
    food crops and pastures.

    (c) Appropriate systems should be developed for the routine monitoring
    of seed grain and harvested grain crops to detect the presence of
    PA-containing plants and seeds.

    (d) If the crop is found to be contaminated, immediate steps should be
    taken to remove the toxic plants from the fields and to rid the
    domestic and commercial cereal grain stores of the toxic seeds by
    sieving or winnowing and destroying the toxic seeds/plants.

    (e) The suspected contaminant and its toxic PAs should be identified
    in specialized laboratories.

    (f) Public awareness of the risks arising from the consumption of
    grain contaminated by seeds, and the use of herbal preparations
    containing PAs as food or medicines, should be created through the

    (g) The import and sale of seeds, herbs, and herbal preparations
    containing PAs should be restricted.

    (h) In the event of an outbreak, epidemiological investigations of the
    affected population should be carried out, and plans made for long-
    term follow-up.

    (i) Cases of PA poisoning should be recorded and surveillance
    organized by Poison Control Centres or other appropriate agencies of
    the government.

    4.5  First Aid

    Immediate first aid measures are rarely possible for an acute exposure
    but may be required in the management of emergencies, such as vomiting
    of blood from bleeding blood vessels in the oesophagus.

    No specific antidote is known for PA-induced toxic effects. The only
    immediate valuable measure is to:

    - identify the source of the PA and

    - STOP any continued exposure.

    4.6  Medical Management

    No specific antidote or therapy for PA toxicity is known. Treatment is




    Australia      Symphytum (comfrey)              Scheduled as a poison,
                   (Any part of the dried           effectively preventing sale
                   plant and its extracts or        for medicinal purposes
                   preparations for human
                   internal use)

    Austria        Senecio numorensis               Medicinal preparation must
                   Symphytum officinale             be registered with the
                   Petasites officinalis            Federal Ministry of Health
                   Tussilago farfara                and Environmental Protection
                   Pulmonaria officinalis           and sold only in pharmacies
                   (used as medicinal

    Canada         Senecio jacobaea (ragwort)       Proposed for inclusion in
                   Symphytum asperum Lepech         the list of adulterants, thus
                   (prickly comfrey)                prohibiting sale of such
                   Symphytum officinale L.          compounds in or as food
                   root (common comfrey)            (Section B.01.046 of the
                   Symphytum x uplandicum           Canadian Food and Drug
                   Nym. (Russian comfrey)           Regulations)

                   Echimidine or any of its         Proposed for inclusion in
                   salts or any of the following    the list of adulterants, thus
                   plant species or extracts        prohibiting sale of these
                   or tinctures thereof:            substances in or as drugs
                                                    (Section C.01.038 of the
                   (i) Symphytum asperum            Canadian Food and Drug
                   (ii) Symphytum x uplandicum      Regulations)
                   (iii) Any other plant species
                   containing echimidine

    Indonesia      Symphytum officinale L.          Dispensaries and drug stores
                   or its parts either fresh        not allowed to prepare, sell,
                   or dried                         or advertise it

    USA            Crotalaria spectabilis           Compliance policy guidelines
                   Crotalaria sagittalis            require that the presence of an
                   Crotalaria striata               average of at least one whole
                                                    seed per pound of product
                                                    represents the criterion for
                                                    direct reference seizure to
                                                    the office of regulatory
                                                    affairs (ORA)HFC-25 and
                                                    for direct citation by the
                                                    district offices (OB/01/82)



                   Lasiocarpine                     Any solid waste (except
                                                    domestic) containing
                                                    lasiocarpine must be listed
                                                    as hazardous waste (subject
                                                    to regulation and
                                                    notification requirements);
                                                    where lasiocarpine is a
                                                    principal organic hazardous
                                                    constituent in the EPA
                                                    permit, incineration must
                                                    achieve a destruction and
                                                    removal efficiency of 99.99%

    USSR           Stored grain:                    Contamination limit
                   Heliotropium lasiocarpum
                   -Seed                            0.1%
                   Trichodesma incanum
                   -Seed                            0%
                   -Seed grain                      Contamination with both
                                                    species is prohibited

                                                    (Note: It has been calculated that
                                                    0.1% tolerance for  H. lasiocarpum
                                                    seeds in stored grain could result in
                                                    1.82 mg of PA per kg of stored wheat)

    Note: Besides the above, a number of countries have regulatory proposals under
    development and several others enforce administrative or compliance guidelines
    based on general prohibitory provisions for the basic food and drug products;
    studies are being carried out to further evaluate the risk.

    See Also:
       Toxicological Abbreviations
       Pyrrolizidine alkaloids (EHC 80, 1988)