30/11/2016 SafetyIssuesAffectingHerbs:PyrrolizidineAlkaloids

SAFETYISSUESAFFECTINGHERBS:
PYRROLIZIDINEALKALOIDS
bySubhutiDharmananda,Ph.D.,Director,InstituteforTraditionalMedicine,Portland,Oregon

Pyrrolizidine alkaloids (see Figure 1) are complex molecules named for their inclusion of a
pyrrolizidinenucleus:apairoflinkedpyrrolerings.Eachpyrrolecanbediagramedasfivesidedstructure
withfourcarbonsandonenitrogenformingthering.Pyrrolesareincorporatedintothechlorophyllmolecule
thebiologicalroleofPAsinplantsremainsunknown.

Pyrrolizidinealkaloids(PAs)areofspecialinterestcurrentlybecauseseveralofthemhavebeenshown
to cause toxic reactions in humans, primarily venoocclusive liver disease, when ingested with foods or
herbalmedicines.Comfrey,awellknownmedicinalherbcharacterizedbyU.S.FDAresearchersashaving
been"oneofthemostpopularherbteasintheworld,"containsPAsthatarecapableofcausingliverdamage
(10). Earlier alerts about the potential dangers had reduced demand for comfrey markedly, but herb
proponentsarguedthatthelaboratorystudiesshowingPAtoxicityprobablydidnotapplytohumanuseof
thewholeherbandthatnoreportsofhumantoxicreactionstocomfreyhadappeared(28).Soonafter,when
clinical reports of such human reactions were published, some herbalists argued that other confounding
factors were likely the culprit and that, at any rate, modern drugs were far more likely to cause toxic
reactions(29).ComfreyhasremainedcommerciallyavailableintheU.S.,thoughin1993theAmericanHerb
ProductsAssociation(AHPA)alerteditsmemberstorestrictitsusetoexternalapplications.OnJuly6,2001,
theU.S.FDAtookofficialactiontoremovecomfreyfromalldietarysupplements.

ThePAsareprimarilyfoundinmembersofthreeplantfamilies(7):
1.Asteraceafamily(Compositae):inplantsoftheSenecioneaesubtribe(24genera,thegenus
Senecioisprevelant)andtheEupatorieaesubtribe(mainlyinthegeneraEupatoriumand
Ageratum)
2.Boraginaceaefamily:invirtuallyallplantsofthisfamilyand
3.Fabaceaefamily(Leguminosae):inthesubtribeCrotalariaceae,mainlyinthegenusCrotalaria,
butalsointhegeneraChromolaenaandLotononis.

AlistofplantsforwhichconcernshavebeenraisedabouttheircontentofPAsispresentedinTable1.
Some are foraged by animals, causing toxic reactions if grazed to excess others are weeds that grow
amongstgrainsharvestedforhumanusewheretheycancontaminatethefoodsupply.Severalofthelisted
herbshavebeenusedasmedicinals,afewofthemhavebeenextensivelyrelieduponformanycenturies.
The principal medicinal genera in current use are Senecio, Borago, Lithospermum, Heliotropium, and
Eupatorium. Toxic reactions to some of those medicinal herbs have been reported following longterm
ingestion,usuallyaftermanymonths.Over200PAshavebeenidentifiedtodate,abouthalfofthemdeemed
toxic.

ThecurrentleadingexpertonpyrrolizidinealkaloidsisDr.E.Rder,atthePharmaceuticalInstituteof
Bonn University. Much of the information available about which species contain pyrrolizidine alkaloids,
which alkaloids are present, and in what amounts come from his research and review efforts. He has
publishedextensiveliteraturereportssince1995onEuropean(7)andChineseherbs(9)andonthechemical
analysis methodology for detecting these compounds (8). Dr. C.C.J. Culvenor, of the Commonwealth
ScientificandIndustrialResearchOrganizationinAustralia,hadearlierpioneeredworkintheareasofPA
structures,toxicity,andbothanimalandhumanresponsestoPAingestion.Included in his efforts were an
evaluationofthestructureandtoxicityof62PAs(25)andananalysisoftheamountofPAsconsumedby
personswhohadbeenreportedtosufferadverseeffects(22).HepublishedarticlesonPAsfrom19681992.
Dr.R.J.HuxtableattheDepartmentofPharmacologyoftheUniversityofArizonareportedfrequentlyonthe
pharmacologicaleffectsofPAsandtheirtoxicmetabolites(26,31)from19781999,apparentlyinspiredby
twocasesofpyrrolizidinepoisoningofinfantsin1977and1978inhishomestateofArizona(27).

Table1:Plantsthatcontainpyrrolizidinealkaloids(PAs).
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SpeciesEvaluated ToxicityandConstituents
BORAGINACEAEFAMILY
Popularlyknownasalkannettherootyieldsaredtopurple
Alkannatinctoria
dyefromtherind.Usedintreatmentofskindiseases,
akaLithospermum
internallyandtopicallyalsofortreatingdiarrhea.Contains
tinctorium
triangularine.Alkaloidcontentis0.250.3%.
Commonlycalledfiddleneckhorsesgrazeontheplantand
Amsinckiaintermedia aresusceptibletopoisoningbyit.Alkaloidcontentrange
fromlessthan0.5%to1.2%.
Knownalsoasalkannet(seeabove)orasbugloss.Usedto
treatskinailments,alsousedasanexpectorantandadiuretic
Anchusaofficinalis
appliedtopicallyfortreatmentofinjuriesandulcers.Total
alkaloidcontentisabout0.12%.
BorageisacommonlyusedWesternherbusedasablood
purifieranddiuretic,indicatedforinflammatorydiseasesand
cough.TheGermanCommissionEputthisonits
Boragoofficinalis
"unapprovedlist"duetopresenceofPAsandlackofproofof
efficacy.Containsintermedineandlycopsamine.Total
alkaloidcontentisverylow,lessthan0.001%.
Commonlycalled"hound'stongue"andalsobugloss,itis
usedtotreatdiarrheausedtopicallyforbruises.Usedin
Cynoglossumofficinale Africaasmedicinalherbblamedforlivercancerthere.
Containsheliosupine,echinatine,lasiocarpine,and
cynoglossophine.Totalalkaloidcontentis0.71.5%.
Heliotropium Knownaswhiteheliotrope(nottobeconfusedwithvalerian).
arborescens Livestockfeedonheliotropiumspecies.UsedinAfricaas
also:H.popovii,H. medicinalherbblamedforlivercancer.Contaminatedcereal
lasiocarpumH. cropsleadingtohumanpoisoning.Containsheliotrineand
eichwaldii,H.bacciferum indicine.Totalalkaloidcontentisabout0.01%.
Commonlycalledstickseed,theseedscanbeeatentheplant
Lappulaintermedia
ismainlyusedtopicallyforsoresandswellings.
Commonlycalledgromwell,ithasbeenusedfor
contraceptivepurposesandfoundtohavesomeeffectson
hormones.Alsousedasantipyreticandtreatmentforgout,
Lithospermumofficinale kidneystones,anddiarrhea.Containslithosenine.Total
alkaloidconcentrationis0.003%.TheChineseherb
Lithospermumerythrorhizonisusedinthetreatmentofskin
diseases.
Commonlycalledforgetmenot.Usedasasedativeand
Myosotisscorpioides tonicexternallyasaneyewash.Containsmyoscorpine,
scropioidine,andsymphytine.Totalalkaloidconentis0.08%.
Calledlungwortorcowslip,thisherbistraditionallyusedfor
Pulmonariaofficinalis
treatingcoughs.P.A.contentisquestionable.
Commonlycalledcomfrey(S.officinale),thisherbhasbeen
Symphytumofficinale extensivelyusedasan"alterative."Ithasbeenblamedfor
also:S.asperum,S. liverdamageinhumans.Containsintermedine,lycopsamine,
caucasicum,S. symphytine,echimidine,symglandine.TotalcontentofPAsis
tuberosum,andS. nearly0.5%inS.caucasicum,butlowerinS.officinale
peregrinum
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(leaves:0.020.18%roots:0.250.29%)S.peregrinumwas
foundtocontainabout0.2%alkaloidsinthetops.
Trichodesmaafricana Contaminatedcerealcropsblamedforhumanpoisoning.Not
also:T.incanum usedasmedicine.
ASTERACEAFAMILY
UsedintheAlpstotreatlungdisorders.Containssenecionine,
seneciphylline,andspartioidine.Totalalkaloidcontentis
Adenostylesalliariae
about0.02%.Venoocclusivediseaseinaninfantwasblamed
onerroneousingestionofthisherbinplaceoftussilago.
Itisaforagecropforlivestock,toxictohorses,causing
Brachyglottisrepens
paralysisofthelimbs.
Commonlycalledredtasselflowerorsimplyemiliaherb,itis
anantipyreticandremedyforinfluenza,cough,and
Emiliasonchifolia
bronchitis.Containssenkirkineanddoroninetotalalkaloid
contentof0.2%.
E.perforatumiscommonlycalledboneset,E.purpreumis
commonlycalledJoePyeWeed,andE.cannabinumiscalled
hempagrimonytheseherbsareusedtoinducesweatingto
Eupatoriumcannabinum alleviatefeveralsodiuretic(modernuse:lowering
also,E.perforatum,E. cholesterol).Containssupinine,rinderine,echinatine,and
rugosum lycopsamine.InChina,E.fortunii,isusedasanaromaticherb
toremovemoisture,especiallyintreatmentofsummerheat
syndrome.
Knownaspestilencewortorbutterbur,usedinEuropefor
numerousdiseases,especiallywhencomplicatedby
abdominalpain.Containssenecionine,integerrimine,
Petasiteshybridus
retrosine,seneciphylline,jacobine,senkirkine,andothers.
also:P.spurius.
Totalalkaloidcontentvariesmarkedly:inrootsitislessthan
0.01%andintheleafitisnegligible.P.spuriuscontains
senkirkineataconcentrationof0.007%.
Commonlycalledgoldenragwortusedasatreatmentfor
injuriesalsoadiaphoreticanddiuretichighdosesmay
induceabortion.S.bicolorhasbeenusedineyedropstotreat
cataractsandconjunctivitis.Livestockoftenfeedontansy
ragwort(S.jacobea),usedmedicinallyasanantispasmodic.S.
longilobuswasmistakenlyusedasanherbremedyandcaused
Senecioaureus
liverfailure.OneormorespeciesofSenecioisusedin
also:S.bicolor,S.
Africanherbalmedicineandisblamedforhighincidenceof
doronicum,S.jacobaea,
livercancer.Contaminatedcerealcropsblamedforhuman
S.nemorensis,S.
poisoning.Containssenecionine,riddelline,retrorsine,
vulgaris,S.Illiciformis,
floridanine,monocrotaline,andotosenine.Totalconcentration
S.longilobus,S.
ofalkaloidsinS.aureusisabout0.02%inS.bicolorabout
douglasii
0.9%inS.jacobaeaabout0.20.3%inS.vulgarisabout
0.16%.S.longilobusingestion(threadleafgroundsel,
substitutedforanintendedherb,gordolobo)wasblamedfor
deathofinfantsintheU.S.SeveralspeciesofSenecioare
usedinChinesemedicinetotreatfebrilediseases,dysuria,
inflammation,diarrhea,and,cataracts.
CommonlycalledcoltsfootwidelyusedinEuropetotreat
lungdisordersandgastrointestinalorders(e.g.,diarrhea)
Tussilagofarfara alsousedinChineseherbalmedicineforthesamepurposes.

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Containssenkirkineinamountsrangingfromnegligibleto
0.015%.Alsocontainssenecionine.
FABACAEAFAMILY
Commonlycalledrattlebox.Contaminatedcerealcrops
Crotalariasp.
blamedforhumanpoisoning.Containscrotananine,
also:C.juncea,C.nana,
monocrotaline,andcronaburmine.C.sessilifloraisusedin
C.retusa,C.fulva
Chinesemedicinetodispelheatandpromoteurination.

Asidefromingestingtheplantsdirectly,PAsmaybeconsumedbyeatinghoneycollectedbybeesthat
visit PAcontaining plants (mainly species of Senecio) and by drinking milk or eating eggs produced by
animals that have consumed PAcontaining plants. In honey originating from species of Senecio, the total
concentrationofPAswas0.33.2microgramsperkilogram.PAscouldbedetectedintheconcentrationrange
of 3070 micrograms per kilogram in honey from the Alpine foothills of Switzerland. No cases of PA
poisoning have been attributed to ingestion of tainted honey or milk (7). Eggs have been implicated as a
sourceofPAtoxicityinacaseinvolvinguseofunregulatedgrainfeedcontainingsomeHeliotropium(32).

THEPHYSICALREACTIONTOPYRROLIZIDINEALKALOIDS
ThetoxicPAsmaycausethefollowingliverreactionswheningestedindosesof1020mg:enlargementof
livercellsandtheirnuclei,disturbancesoflivercellmetabolismresultinginfunctionallosses,areasofcell
destruction, and fatty degeneration. Longterm administration of smaller doses, 10 micrograms or less per
day, may cause liver cirrhosis with exposure to the most toxic of the PAs. In both acute and longterm
responses,venoocclusiveliverdiseasemayoccur.AlthoughthemainsiteoftoxicreactiontothePAsisthe
liver,afewPAsactonotherorgansystemsorthenervoussystemthismaybetheresultoftheirlonghalf
life,allowingthemtomigratetotheotherpartsofthebodypriortofurthermetabolism.

The PAs, which have minimal toxicity in their original form, are metabolized in the liver and can
become toxic metabolites, depending on the PA and on the particular condition of the liver enzymes (31).
Thetoxicmetabolites,highlyreactivesmallerpyrroles(thedehydroformofthealkaloids)resultingfrom
action of microsomal enzymes in the liver, can act locally within the liver cells to cause damage at the
chromosomelevel.Iftheliverbecomesdamaged,thepyrrolizidinemetabolitescanoverflowandinfiltrate
the lung fluids and cause damage there. Pulmonary edema and pleural effusions have been observed,
sometimesresultinginfatalitieswithveryhighlevelsofPAcontaminationoffood.

ThediagnosisthatmostoftenisobservedwhentherehasbeenexcessiveorprolongedexposuretoPAs
isvenoocculusiveliverdisease,involvingobstructionofthesmallveinsbringingbloodfromtheliverback
totheheart.Earlyclinicalsignsofvenoocclusiveliverdiseaseincludenauseaandacuteuppergastricpain,
acute abdominal distension with prominent dilated veins on the abdominal wall, fever, and elevated liver
enzymes. Jaundice may be present and the gallbladder may be distended and full. Chronic illness from
ingestion of small amounts of the alkaloids over a long period proceeds through fibrosis of the liver to
cirrhosis, which is indistinguishable from cirrhosis of other causes. Removal of PA exposure will usually
alleviatethedisorder,butlivercirrhosisisonlymarginallyreversible.Youngchildrenaremostsusceptibleto
theeffectsofthePAs,yetaremorelikelythanadultstocompletelyrecover.

HISTORYOFHUMANTOXICRESPONSES
ReportsofhumantoxicreactionstoPAsaremostlylimitedtocaseswheregrainhasbeencontaminatedby
seedsofPAcontainingplants,causingacutereactionsinasubstantialnumberofpeople.Thishasoccurred,
forexample,inUzbekistanandAfghanistanin1948andagainin1976,inJamaicain1954,andinIndiain
1975(droughtconditionsduringthoseyearsencouragedgrowthoftheweeds,mainlySenecio,Crotalaria,
and Heliotropium, and led to high PA content of flour). Agricultural controls have prevented further
occurrences,exceptintimesofdisruptionbywars:therewasasmalloutbreakofliverdisease,with2deaths,
innorthernIraqin1994.Duringthepastcentury,thousandswerepoisonedcentralAsia,andothercaseshave
been reported around the world in countries with poorly developed agricultural systems. It has been
suggestedthattheKwashiorkhordisease,frequentlyobservedwithchildreninCentralAfrica,isalsorelated
to a damage of liver cells by PAs taken in with foods, characterized by the liver losing its ability to
synthesizeessentialproteins.

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Anextensivereviewofthemedicalliteratureconductedforthecurrentarticlerevealsthattherehave
beenonlyaboutadozenformalreports(afewofthemthenrepeatedindifferentjournalsorwithdiffering
details)involvingabout20peoplewithPArelatedtoxicreactionsfromtakingexcessivedosesofherbsor
takingincorrectherbs.Eachofthesereportsarementionedhere.Someresearchershavesuggestedthatthe
problemismorewidespreadincertainareasoftheworld,suchasAfricaandSouthAmerica,andsimplynot
reported.

Pyrrolizidinealkaloidsbecameanissueofsafetyconcerninrelationtoherbalmedicineabout20years
ago,whenanherbenthusiastconsumedcomfrey(Symphytumofficinale)onadailybasisandsufferedliver
damage(2).Threeadditionalcasesofhumantoxicresponsetocomfreywereeventuallyreported(apossible
fifthonehasbeenmentioned,seereference31),includingonedeathattributedtotheeffectsoftheherb.The
four widelyreported cases, all occurring in the 1980s, were outlined in a presentation by the National
InstituteofMedicalHerbalists(London),totheDepartmentofHealthinJanuary1993(29):
Case1(11):A49yearoldwomanintheU.S.wasadmittedtoahospitalwithprogressive
swellingoftheabdomenandextremitiesovertheprecedingfourmonths.Venoocclusivedisease
waseventuallydiagnosed,allegedlycausedbychronicexposuretoPAsconsumedinacomfrey
powder,estimatedataminimumof85mgofPAsperdayovertheprevioussixmonthperiod.
Shewasaheavyconsumerofherbs,vitaminsandnaturalfoodsupplements,andshedrankthree
cupsofchamomileteaperweekandforthesixmonthsbeforeadmissionhadconsumedonequart
adayofaherbalteaknownasMu16.Inaddition,forthe4monthsbeforeadmission,shehad
takentwocapsulesof"comfeypepsinpills"witheachmeal.Theauthorsconclude"Toour
knowledge,thisisthefirstreportofvenoocclusivediseaseinanyhumanaftertheuseofa
preparationclaimingtobemadefromcomfrey."
Case2(12):A13yearoldboyinEnglandwasadmittedtoahospitalwithsymptomsthatwere
foundtobecausedbyvenoocclusivedisease.HehadbeensufferingfromCrohn'sdiseasefor
threeyearsandhadbeentreatedwithprednisoloneandsulphasalazine,whichremoved
symptoms.Athisparents'request,thedrugswerediscontinuedandhewastreatedwith
acupunctureandcomfreyrootprescribedbyanaturopath.Exactquantitiesandfrequencyare
unknown.Whenadmittedtothehospitalhewastakingprednisoloneandsulphasalazine.The
authorsconcludedthat"theonlypossiblecausalfactorinthispatientwascomfrey."
Case3(13):A47yearoldwhitenonalcoholicwomanintheU.S.begantofeelunwellin1978
withvagueabdominalpain,fatigueandallergies.Ahomeopathicdoctorrecommendedcomfrey
tea.Sheconsumedasmanyastencupsperdayinadditiontotakingcomfreypillsbythehandful,
whichcontinuedformorethanoneyear.Fouryearslater,serumaminotransferaselevelswere
twicetheupperlimitofthenormalrange,andfouryearsafterthatshehadfurthersignsofliver
disease.
Case4(14):A23yearoldmaninNewZealandpresentedwithvenoocclusivediseaseand
severeportalhypertensionandsubsequentlydiedfromliverfailure.Hehadeatencomfreyleaves
forsometimebeforehisillness.Themanpresentedwithathreemonthhistoryofinitial
influenzalikesymptomsfollowedbycontinuedmalaiseandnightsweats.Threeweeksbefore
admissionhenoticedperipheraledemaandabdominaldistension.Forfouryearspriortothis
illnesshehadbeenlivinginacommuneandhadeatenapredominantlyvegetariandiet.Hehada
strikingbingetypeeatingpatternwherebyhewouldeatlargequantitiesofaparticularfoodfor
daysandweeksonend.Intheonetotwoweeksbeforetheonsetofsymptomsheatefourtofive
steamedyoungcomfreyleavesasavegetableeveryday.Theauthorssuggestthatthepatient's
proteindeficientdietcouldhaveplayedacontributoryroletheyattributedcomfreyasapossible
causeduetothetemporalsequenceofevents.Inaseparatereviewofpotentialrisktoconsuming
comfreypublishedintheAustralianMedicalJournal(15),theauthordeclinedtoconsiderthis
caseinhisreportbecause"thereissomecontroversysurroundingthiscase."

Though not of special notice at the time, because the herbs were not so widely used, cases of veno
occlusivediseaseassociatedwithmedicinalherbshadbeenreportedjustafewyearsearlier.IntheU.S.,a
twomontholdinfantinArizonaexperiencedvenoocclusiveliverdiseaseafterbeingtreatedwithgordolobo
yerba, one of the most popular of Mexican herbs, usually obtained from Gnaphalium, but sometimes
substituted by the similarly appearing Senecio longilobus. The case, involving portal hypertension and
extensivehepaticfibrosis,wasfirstreportedin1977(19)thechilddiedofthedisease.Anadditionalcaseof
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an infant administered Senecio longilobus as gordolobo yerba, used to make herbal cough medicine,
involveda6montholdfemale.Shehadacutehepatocellulardisease,ascites,portalhypertension,andaright
pleural effusion in 1978. She improved with treatment. However, after 6 months, a liver biopsy revealed
extensivehepaticfibrosis,progressingtocirrhosisover6months(27).Itwasfoundthatonesupplyhousein
Arizona routinely stocked Senecio as the source of gordolobo. The U.S. FDA provided the following
additionalreportfromthesametimeperiodwithoutreferencestodocumentation:anAmericanwomanwho
had used a medicinal tea for 6 months while visiting Ecuador developed typical hepatic venoocclusive
disease, with voluminous ascites, centrilobular congestion of the liver, and increased portal vein pressure.
Thepatientcompletelyrecoveredwithinoneyearafterceasingtoconsumethetea.

In England, venoocclusive disease was blamed on longterm consumption of large amounts of

Paraguay tea (yerba mate, Ilex paraguensis), from which small amounts of pyrrolizidine alkaloids were
reportedlyisolated(18).However,laterstudiesdidnotfindthesealkaloidsinIlexthepatientmayhavehad
a contaminated source. Venoocclusive disease was said to be caused by medicinal herb use in India in a
report published in 1978 (16). Three patients with the disease had taken Heliotropium eichwaldii. The
authorsofthemedicalreportsuggestedthat:"Themedicinaluseoftheherbmaypossiblyberesponsiblefor
a significant proportion of acute and chronic liver disease in India." However, such a conclusion seems
unjustifiedinIndia,Heliotropiumspeciesaremainlyusedinexternaltherapies,andonlyrarelybeingtaken
inteasorotherinternalforms.In1985,thereappearedareportlinkingingestionofanunidentifiedherbfrom
India,usedasatreatmentforpsoriasis,tothreecasesofliverdamage,withonedeath.Pyrrolizidinealkaloids
wereidentified,withmeandoseestimatedat30mg/day.TheherbmayhavebeenaspeciesofHeliotropium,
as these species are used as remedies for various skin diseases. A case of Heliotropium induced veno
occlusivediseasewasreportedinEnglandin1986(17)thespeciesingestedwasH.lasiocarpum.

A new concern arose with use of another popular herb: coltsfoot (Tussilago farfara). Coltsfoot was
widelyusedforcoughsinEuropeandAmerica,andhasalsobeenusedbytheChineseforthesamepurpose.
There was a report from Switzerland in 1988 of liver damage leading to death of a newborn due to
consumptionofcoltsfootteabythemotherduringpregnancy(20).Theadversereactionwasattributedtothe
herb's pyrrolizidine alkaloids, and that herb was then withdrawn from the market in Europe in 1992.
However,laterinvestigationindicatedthatthecoltsfootwasprobablynotacontributortotheinfant'sdeath
(23).Still,otherPAsmayhavebeenresponsibleinthiscase:theteamixtureincludedPetasites (pestilence
wort),asourceoftoxicPAs.

In1995,threemorereportsappearedinthemedicalliteratureindicatingliverdamagefromingestionof
PAcontainingherbs.AninfantinAustriawhowasgivenateathatwasunderstoodtocontainpeppermint
andcoltsfoot(notacommercialproduct)developedvenoocclusivediseasethatwas,fortunately,reversible
(5). An analysis showed that the coltsfoot was again a substitute, this time from Adenostyles xalliariae
(common name alpendost). It was estimated that the child consumed at least 60 micrograms PAs per
kilogramofbodyweighteachdayovera15monthperiod.Itwasnotedthatanelderlypatienttakingateaof
Senecio vulgaris for two years continuously suffered from venoocclusive liver disease (3) and that a
youngerwomantakingSeneciotephrosioidesasacoughremedyonanoccasionalbasisbutformanyyears
alsosufferedfromthisliverdisease(4).

To sum up the cases reported thus far: there are four (possibly five) incidents related to comfrey
ingestioninadults,twoincidentsofSenecioingestionininfantsandtwoincidentsofSenecioingestionin
adultsfourcasesofHeliotropiumingestioninadults,twocasesinvolvingcoltsfootsubstitutionbyotherPA
containingherbsininfants,andfiveothercasesinvolvingadultswithunknownPAcontainingherbs(threein
China,oneduringavisittoEcuador,andoneusingateaproductfromSouthAmerica).Althoughsomecases
ofliverdamagemayhavebeenduetosomethingotherthantheherbs,inmostinstances,othersourcesofthe
disorderwerenotevidentorweredeemedimprobable.

DOSEANDDURATIONOFUSETOCAUSEHEPATOTOXICREACTIONS
ThedoseanddurationofexposuretothetoxicPAsthathavebeenassociatedwithliverdamageinhumans
wasestimatedbyCulvenor(22).Forheliotrine,anintakeof410mg/kgperdayfor37weeksledtoliver
necrosisandvenoocclusionthecombinationofcrotanineandcronaburnimeatadoseoflessthan1mg/kg
perdayforseveralmonthsledtothesamedisorders.Retrorsineandriddelline,amongthemosttoxicofthe
PAscausedlivernecrosis,liverfibrosis,andcirrhosiswithin2weeksofintakefrom0.71.5mg/kgperday.
InoneofthereportsofanunidentifiedherbfromIndia,thePAingestionratewas30mg/day,andinoneof
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theinfants,thereportedPAintakewas0.06mg/kgperday.Thus,therangeoftoxicdosesinhumansappears
tobeintherangeofabout0.110mg/kgperday.InmostinstancesofPAlivertoxicityinadults,thedaily
intake was several milligrams or hundreds of milligrams per day. However, it has been suggested by the
WorldHealthOrganizationin1989thatthelowestintakerateofPAsthatreportedlycausedvenoocclusive
diseaseinahumanwasjust0.015mg/kgofbodyweightperday,basedonuseofcomfrey.Fora70kgadult,
thatwouldcorrespondto1mgtotalperday.

ExposuretoPAscanvarymarkedlywhenusinganygivenherb.DeterminationwasmadeofPAcontent
ofcomfreyrootsandleavesbyCouetandhiscolleagues(21)therootshadarangeof14008300ppm,while
theleaveshadfrom1555ppm.Inanevaluationof300comfreyrootsamplesinGermany,thePArangewas
found to be 4505990 ppm (30). An evaluation of commercial comfrey products (10), showed that the PA
contentvariedmarkedly:nonedetectedin2products,toarange0.2220ppmamong8otherproductstested
withdetectablelevels,andonewith1520ppm(acomfreyrootproduct).Toreacha1mgperdaydose,just
0.7gramsofherbat1,520ppmwouldbeneeded,abouttheamountthatwouldbefoundin3ofthe250mg
capsules,indicatingthatthisproductwouldbetootoxictoconsumeonaregularbasis.Ontheotherhand,
productswithnodetectablePAsandthosewithlessthan1ppmmightbeentirelysafe.Further,methodof
preparationisalsoimportant.AdecoctionofrootandleafsamplesofcomfreyloweredtheavailablePAsby
7595%.DifferentspeciesofcomfreycontaindifferenttypesandamountsoftoxicPAs.

POTENTIALCARCINOGENICITYWITHLONGTERMEXPOSURETOPAS
A concern that has arisen during the past two decades is that persons who take an herbal preparation
regularly for many months or years might experience a cumulative effect from the PAs. Although these
ingredientsdonotaccumulateintheliverorelsewhereinthebody,theprolongeduseofamountsthatcause
noacutereactionsmayincreasethechancesfordevelopingliverdisease,includinglivercancer.Laboratory
studiesindicatethatsomeofthePAshaveahighmutageniccapacity.This determination is made through
testsinbacteriaorfruitflies,buttheresultsmayimplyacarcinogenicpotentialforhumans.According to
onestudyusingfruitflies,themutagenicpotentialof16PAscanberatedasfollows(7):
senkirkine>monocrotaline>seneciphylline>senecionine>7acetylintermedine>
heliotrine>retrorsine>7acetyllycopsamine>symphytine>jacoline>symlandine>
intermedine>indicine>lycopsamine>indicineNoxide>supinine

That is, senkirkine has the highest mutagenic potential in the test system, while supinine had no
detectablemutagenicactivity.IndicineNoxide(fromheliotrope)isanantitumoragentcurrentlyinvestigated
for treatment of brain tumors formerly it was found useful in treating leukemia in infants, except that it
produced liver damage as a side effect in some cases (thus, it was withdrawn from further consideration).
Senkirkineisfoundincoltsfoot,petasites,andotherherbsthatwereroutinelyrecommendedinSwitzerland
andGermanyasremediessuitedforlongtermadministration.

Despite the findings in laboratory studies, including mutagenic activity, adducts of pyrrolizidine
alkaloidsandtheirmetabolitesintissueoftestanimals,andinductionofcancerinanimals(somePAscause
hemangioendothelialsarcomasinrats),thepotentialcarcinogeniceffectsonhumanshavebeenquestioned.
Ontheonehand,thefrequentoccurrenceofprimarylivertumorsinthenativesofCentralAfricaandSouth
Africa has been ascribed to the consumption of traditional medicinal plants of the genera Crotalaria,
Cynoglossum,HeliotropiumandSenecio.Ontheotherhand,inarecentreviewofPAsinthehumandiet(2),
theauthorsconcludedthat"whilehumansfacetheriskofvenoocclusivediseasesandchildhoodcirrhosis,
PAsarenotcarcinogenictohumans."

RESPONSEOFGOVERNMENTANDINDUSTRYAGENCIES
Asrecentstudiesrevealedthepresenceofpyrrolizidinealkaloidsinseveralplantsusedinherbalmedicines,
concernhasarisenaboutexposuretothesecompoundsandhowtolimitthatexposure.Bulletinshavebeen
issued by the U.S. Food and Drug Administration (FDA) and Centers for Disease Control (CDC) on this
subject.InBelgiumitisproposedthatthelimitforpyrrolizidinealkaloidsinherbsbesetat1ppm,avery
smallamount(1microgrampergramofherb).TheGermanHealthAdministrationhassetastandardforuse
oftheherbPetasitessuchthatthedailydoseshouldnotcontainmorethan1microgramofPAs,withlimited
duration of administration of six weeks total per year for tea mixtures including PAs, a total limit of 10
microgramsperdayispermittedforuptosixweeks.TheAmericanHerbProductsAssociation(AHPA)has
issued the following recommendation (adopted July 1996): "AHPA recommends that all products with
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botanicalingredientswhichcontaintoxicpyrrolizidinealkaloidsbearthefollowingcautionarystatementon
the label: For external use only. Do not apply to broken or abraded skin. Do not use when nursing." The
ConsumerHealthcareProductsAssociationestablishedavoluntaryprogramformanufacturerswiththesame
recommendation(adoptedMarch2001).

Based on the Belgium recommended limit for PAs in herbs at 1 ppm, it would require ingestion of 1
kilogram (2.2 pounds) of an allowed herb to yield 1 mg (the smallest amount cited as toxic for comfrey
ingestion), so the limit set would appear to be quite safe, in terms of any potential for acute reactions.
Normaldailyintakeofherbsisusuallyonlyafewgrams,sothereisalargemarginofsafetya10gramdose
wouldyieldamaximumof10microgramsofPAsfromanallowedherb.TheGermanrecommendedlimit,
just1to10microgramsperday,isconsistentwiththeBelgiumproposalbasedonPAcontent.InEurope,
effortsareunderwaytodevelopcoltsfootandotherdesirablemedicinalplantsthatarenaturallylowinPAs
andwillthenmeetthestandardsthathavebeenset.Inaddition,extractmanufacturershavesoughtmethods
ofremovingthePAsfromtheirfinishedproducts.

Drastic restriction of PAs, such as avoidance of any amount in an herb intended for internal use as
suggested by AHPA, may not be justified. There is a great diversity of alkaloid structures among the
pyrrolizidinegroup.Some of the pyrrolizidine alkaloids, such as farfugine and tussilagine, are considered
nontoxic.AlthoughtheAHPArecommendationspecificallymentions"toxicPAs,"theburdenofproofasto
whetherthePAsaretobeconsideredtoxicwouldfallontheselleroftheherbmaterial,aburdenunlikelyto
beundertaken.The range of amounts of PAs in plants (and different parts of the same plant) is also quite
large:fromlessthan0.001%to0.1.2%,morethana1,000foldrangeamongsampleswithreportedlevels.
This variability in amounts and toxicity makes it difficult to rationally suggest that no pyrrolizidines,
including the toxic ones, are acceptable in herbs used medicinally as internal remedies. As test methods
improve, tiny amounts of these compounds may be found in very popular herbs. Thus, for example,
echinacea(intheAsteraceafamily),oneofthemostcommonlyusedherbsinAmericaandEurope,hasbeen
showntocontainsmallamountsofPAs.Thesearethoughttobenontoxic(basedonthechemicalstructure),
buttheyremainsuspectsinpotentiallivertoxicityfromlongtermuse(over8weeks)oftheherb(33).

Itispotentiallyproblematictodeemanyamountofanysuchalkaloidacontraindicationforusingthe
herbatall,especiallyastestmethodsimproveandminisculeamountsofawiderrangeofPAsarerevealed.
PAshavebeendetectedinplantfamiliesotherthanthethreementionedabove,includingtheApocynaceae,
Celastraceae, Euphorbiaceae, Orchidaceae, Poaceae, Ranunculaceae, Rhiophoraceae, Santalaceae,
Sapotaceae, and Scrophulariaceae, and have been suggested to be present in up to 3% of the species of
floweringplants(24).Therefore,numerousmedicinalherbsmayfallunderrestrictionfromoralconsumption
if there is zero tolerance for presence of PAs. Further, the implications of such a restrictive policy for the
future are that any time a natural compound is found to have some level of toxicity, all medicinal herbs
containing that compound could be eliminated from use, greatly limiting the ability to rely on a natural
healthcareapproach.

PYRROLIZIDINEALKALOIDSINCHINESEHERBS
ThecommonlyusedChineseherbsthatarecurrentlyknowntocontainpyrrolizidinealkaloidsarethese(24):
Zicao:obtainedfromLithospermumerythrorhizonandArnebiaeuchromaoftheBoraginaceae.
TotalPAyieldofLithospermumerythrorhizonewas0.02%,consistingmainlyofintermedine,
andmyoscorpinefromArnebiaeuchromathetotalPAyieldisonly0.0006%,comprisedmainly
ofangeloylretronecine.
Kuandonghua:obtainedfromTussilagofarfaraoftheAsteracea.Itcontainstussilagine,
isotussilagine,senecionine,andsenkirkine.InJapan,Petasitesjaponicushasbeenusedas
kuandonghua.
Qianliguang:obtainedfromSenecioscandensoftheAsteracea.Senecioscandensandtablets
fromitsextractwereofficiallylistedintheChinesePharmacopoeia1977,indicatedforbacterial
diarrhea,enteritis,conjunctivitis,andrespiratorytractinfections.Itisstillusedincomposition
formulasfortreatmentofrhinitis,ulcerativecolitis,andburns.ItcontainsthePAssenecionine
andseneciphylline.
Peilan:obtainedfromEupatoriumfortuniiandE.japonicumoftheAsteracea.

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In an evaluation of 20 herbs of the Asteracea, only species of Eupatoreum were found to contain
pyrrolizidinealkaloids(1),withcontentrangingfromlessthan5ppmforE.chinensis,to6595ppmforE.
fortunei, and 172422 ppm for E. japonicum. The PAfree herbs (less than 1 ppm) included species of
Arctium, Artemisia, Aster, Atractylodes, Carthamus, Centipeda, Chrysanthemum, Circium, Eclipta, Inula,
Saussurea, Taraxacum, Tussilago, and Xanthium. The reported absence of PAs in Chinese samples of
TussilagoisconsistentwithfindingsofnegligibleamountsinsomeEuropeansamples.Inastudyofthree
Chineseherbs,twospeciesofEupatoreum(E.japonicumandE.cannabinum) were shown to contain PAs
andaspeciesofCrotalaria(C.assamica)wasfoundtocontainonePA,monocrotaline(6).Other Chinese
herbs with PAs include various species of Senecio used in folk medicine (e.g., S. argunensis and S.
integrifolius), Emilia sonchifolia (Asteraceae), and Crotalaria sessiliflora. Heliotropium indicum
(Boraginaceae)isafolkremedyinTaiwan,usedfortreatmentoflungdiseasesandsorethroat.

InordertomeettheBelgiumstandardforPAs,thealkaloidcontentofanherbwouldhavetobenomore
than0.0001%,whichislowerbyfarthanthatforArnebiaeuchromaaChineseherbwithverylowlevelsof
PAs.TomeettheGermanstandardofamaximumdailydoseof10mgofPAs,anherbcontaining0.02%of
thesecompounds(asreportedforLithospermumerythrothrizone)wouldbelimitedtojust50mgperday,an
amountfarlessthanislikelytobeusedinChineseherbalformulas.Therefore,eliminationoftheherbswith
establishedPAcontentfromChineseherbprescribingwouldbenecessarytomeetWesternstandards.

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November2001

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Figure1:ChemicalstructuresofvariousPAs.

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