Am J Clin Nutr-1965-MONTGOMERY-103-13

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					Perspectives                                                                                                      in                             Nutrition

            The                                    Medical                                                             Significance                                                                                  of                    Cyanogen                                                                           in
                                                                                                      Plant                                          Foodstuffs

                                                                                                R.           D.        MONTGOMERY,                                      M.D.,             M.R.c.P.*

                                       I      T IS hoped
                                                  pret           it
                                                                                                                                                                                      of        ideas
                                                                                                                                                                                                      the         literature
                                                                                                                                                                                                                    that            will
                                                                                                                                                                                                                                                   serve             as        a
                                    stimulation                         to      nutritional                    research                     applied                to     medical                 problems.

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I       T       HAS         been                known                        for        150          years                  that         a wide gen-containing               neurotoxins             in Lathyrus          and
            variety                      of          plants                     contain        potentially                                  toxic  Vicia     peas,7      and     the     evidence          that  detoxication
amounts                            of           prussic                        acid             (HCN)                             which       may of     ingested          cyanide           may        depend        upon                                                                                                    ade-
be              released                            by                hydrolysis.                    These                        “cyano-         quate           supplies           of      sulfur-containing       amino
genetic’               ‘     plants                        commonly                       eaten                by                man                or            acids8”                  and               of
domestic                               animals                          include                       cassava                          (manioc),
                                                                                                                                                                                                      STUDIES                  OF           CYANOGENESIS
yam,                  maize,                         sugar                     cane,                  sorghum,                               linseed,
pulses                 and              cycads.                                                                                                                          A         century                           ago                   the               transport                            animals                            of
      Assays                       of         the              cyanide                    content                           of       plants                     areGeneral                            Kitchener’s                           army                          in              the                Sudan
subject                       to              errors                    of          interpretation,                         and              the                  suffered                     heavily                      from                 poisoning                           by          the          herbage
content                       varies                      in           different                       parts            the of         plant                      of         the           Upper                     Nile.                        Prompted                               by         this             threat
and               within                       the               species                   according            to               climatic                         to         Imperial                            logistics                        and                by             similar                   episodes
conditions,                             ripeness                         and              methods                 of             storage.                         in      the         Boer                   War,                  the            staff              of        the              Imperial                        In-
In              the          case                   of           pulses,                   study                       is         made                    more stitute                    in         London                        first          identified                         cyanogen                            corn-
diflicult                    by           the            confused                         classification                                    of       many pounds                                in     Lotus                       (Irabicus                   (Egyptian                               vetch)
hundreds                          of           varieties,                       which                   are                 sometimes                             and         Sorghum                         vulgare                (great                  millet,                  guinea                  corn)
traded                     under                   the               wrong                names.                                                                  and              later                    undertook                                   a         systematic                                 study                    of
      Although                          many                   instances                       of       acute                     poisoning                       cyanogenesis                                in                                  126                The                  release                        of
as        a result                  of         ingested                         plant               cyanides                        have                been prussic                           acid         by             crushing                           and                  wetting                     of         the
quoted                       both                   in          veterinary                            and                   human                       medi- bitter                  almond                            had                been                recognized                              for           a        cen-
cine,                 few               are               vell                documented.                         Chronic                           ill           tury              before                        this.                    Davidson                                and
effects                    have               been                  postulated                         but              never                    proved.          in         P*4           published                               one              of         the             earliest                      descrip-
      A           reassessment                                 of        this           subject                        is         timely                    in tions                 of          human                cyanide                           poisoning                           due              to          the
view                   of              four                    (possibly                        unrelated)                  develop-                              ingestion                       of          the                  pois                     d’Achery                  (Phaseolus
ments--the                               increasing                                exploitation                         of           pulses                       lllfl(1llLs,                 lima                 bean)                     in             Mauritius,                                and                also
as          a     source                      ofdietary                      protein,            ‘    the              continuing                                 reported                            estimates                             of              the            HCN                      yield                     from
efforts                to          solve                 the           problems                       of       tropical                      amblyo-              varieties                      of           this             species.                             The               toxic                 glucoside
pea,             neurolathyrism                                       and           other                  obscure                     neuro-                      (phaseolunatin)                                   and            its          hydrolytic                           enzyme                        were
logic              disorders,26                                the             identification                    of                cyano-                         isolated                       by                Dunstan                               and               Henry                       in            1903.12
                                                                                                                                                                  Phaseolunatin,                                      the                   13-glucoside                                   of            acetone
   From      The                         East Birmingham                                  Hospital,                         Birmingham,
England.                                                                                                                                                          cyanohydrin,                                    has                 since                       been                    studied                             ex-
   4 Physician.
                                                                                                                                                                  tensively.’5’82’                                            It             is              identical                            with                    the

..1 merica             n     Jon           rnal            Cl:
                                                          of          n ical       ?‘.Tutrztion                                                           103                                                                                                     Vol.         17,        August                  1965
104                                                                                                                                          Montgomery

                                                                                                                                                                              EXTRACTION                                     AND            ASSAY                 OF          HYDROCYANIC                                     ACID
glucoside                               found                         in           cassava                            and               linseed.                          It
differs                    from                           the                glucoside                                of           sorghum (p-                                  Ph.           lunatus                       crushed                    and              soaked                    in      cold               water
oxymandelonitrile8)                                                    and             the              various                        glycosides                        yields               HCN,                          acetone                    and               glucose.                            Viehoever#{176}
of                                 22      and                   from                  amygdalin                                   in         almonds                    found                  that                   the           HCN                    yield              was              maximal                        within
which                    is          also                     present                            in          the            seeds                   of          many 2          hours                   at              23#{176}c. or                  45             minutes                       at
                                                                                                                                                                                                                                                                                                  37#{176}c.,          but
common                             fruits.23’24                                                                                                                          Winkler2’                               found                  a         yield                 to       be             greater                  after                24
       Phaseolunatin                                            was                also                  identified                               in            the      hours                   exposure                               to             cold.                    This      may                           depend,
seeds                 of           Vicia                      saliva  (akta,                                  wild                vetch)                        by       among                    other                      things,                    upon                  the    degree                           of crush-
Bertrand2                             and                     is probably                                 the              same               glucoside                  ing.                   Early                        observations                         that                autolysis                              does
reported                             by                  Cugudda                                 et           al.26         Vicia
                                                                                                                              in                  faba                   not            occur                          with                 whole                       beans,                    or           with                 beans
( broad                    bean)               .           Viehoever#{176}                              found                    no           cyano-                     boiled                   immediately                                after                    crushing,                         have                 been
genesis                       in     Phaseolus                                   vuigaris                 (haricot                          or kid-                      confirmed                           repeatedly.                                    Physical                        disruption                                 is
ney            bean)                           or             related                       species                        and               considered                  necessary                                to          bring                   the             heat-labile                              glucosidase
that            in             beans                          this               was              a          specific                   property                         into
                                                                                                                                                                          of           contact                          with            the            glucoside.                           The              latter               in        the
Ph.           lunatus.                             However,                                 small                   but            measurable                            intact             bean                       is      stable                  after                  several                     hours’                  boil-
amounts                         of cyanogen                                        have                   since   been                          found                  in
                                                                                                                                                                        ing           or          dry                  autoclaving                                 at          160#{176}c.-HCN                                    being

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at least                       eight   other                                     species                    of pulse,                          including                 released                      subsequently                               by            maceration                              with             addi-
Ph.           vulgaris                         and              Pisum                        sativum                  (common                              or            tional                 beans,                       with            dilute                     acid           or         with              yeast.

garden                   pea).24’27’28                                                                                                                                          In         all          other                    plants                     also,              preliminary                               soaking
       The               HCN                             yield               of         cassava                            was               studied                     in
                                                                                                                                                                         is          necessary                          to           release                      free               HCN                      from                  the
the            West                                Indies                        by               Carmody,2’                     CousinsM                                glucoside.                                     The             process                         may                be          rapid            ;         in         the
and            Collens3’                                      and            in             West                    Africa                    by              Clark8 case                  of          linseed                        cake,                  half              the              available                         HCN
who            also                 referred                          to         cyanogenesis                                      in        rice,              cane, may                be           released                         in         15        minutes.33                                   On           the          other
millet              and                  other                   grasses.                                                                                                hand,                   in          more                     intact                     material,                            such             as           slices
       Whereas                        in grasses                                  HCN                    is only                   found                   in the of                 cassava                            root,                its                completion                               may                  require
immature                           plant,    in Ph.                                   lunatus                  it      occurs                     in          all        days                   of               continuous                           soaking.2’                                 Bruising                              of
parts               of              the                  plant                throughout                                    life             as          well            as
                                                                                                                                                                         the          intact                      root               leads                 to         slow            autolysis,                            and             the
in      the           seed.                          Although                               it        tends                to      be         lost             in        harmful
                                                                                                                                                                       the                                   nature                          of             injured                         cassava                          is             well
white                  varieties                              after                      systematic                                     cultivation,                     known                    in             the          tropics.
probably                      no                         variety                        of    this                         species               can                    be Winkler21                                        found                 that                  hydrolysis                             by            boiling
produced                                which                        is      entirely                           free              of         cyanogen.                  acid    yielded                                      more                HCN                     than               autolysis                         in            the
Native                     American                                       strains                       tend               to           contain                          cold.
                                                                                                                                                                      less                        On              the           other                  hand,                   acid             hydrolysis                             may
than            Eastern                                  strains.                                                                                                        be          incomplete                                  in          7        to          9      hours                   at          100#{176}c., does
       This           bean                     was              first            found                  in prehistoric                                   graves          not           occur                      at           all          at         less              than                   60#{176}c.and                     is         in-
in        Peru.                           It             was                known                       to          Spanish                        explorers             complete                                with                 hydrochloric                                         or          sulfuric                        acid
there               in             the               fifteenth                              century                        and               was                intro- stronger                       than                   5 per                cent,                 through                         oxidation                           to
duced                 progressively                                       into              California,                               Madagas-                                                          20.28

car           and                  the               Far                  East               for              cultivation.                  Other                               The               boiling                       point                  of             HCN                  is         26#{176}c. (80#{176}F.).
varieties                           possibly                                were                      indigenous                               to              India Storage                           in          hot               humid                      conditions                            leads             to             some
and           Africa.                                    In          this             century,                            white               Madagas-                   formation                               of          HCN                  which                  is      gradually                            lost             from
car            beans                            have                      been                    grown                         extensively              in              the           bean,                      but            with                  either                    or
                                                                                                                                                                                                                                                                                dry         cold               storage
Burma                      in             preference                                   to             local               varieties                           which the                potential                               HCN                     yield                   may                be           maintained
have              a           higher                           cyanogen                                content.32                                 Only                thefor                                20         Expression                                    of      fluid                         from       the
large                 white                              variety                            is           now                    imported                              intowet          cassava                     pulp     in the                               preparation                               of African
Britain                       as               “butter”                               beans                    or           distributed              for                 “gari”                        or                   West                      Indian                         “farine”                            removes
human           consumption                                                             in              the                United                         States. most         but                                     not             necessarily                                   all           the              cyanogen,
In    contrast,          the                                              highest                        HCN                   yield                     in      thisdepending                                    on          the           time                 available                        for          hydrolysis.
species                    has                 been                  in      a        black                   strain                   of      uncertain                 HCN                     is         evaporated                                      from                the              expressed                              fluid
origin              found                           in         Puerto                   Rico.
                                                                                           #{176}                                                                        in the                  preparation                                     of
                                                                                                              Cyanogen                                   in       Plant                  Foodstuffs                                                                                                         105

      The              method                       of      HCN                        assay                         most                commonly                                                                                   TABLE               I
                                                                                                                                                                    The                Highest                    Reported                      Figures                   of           Cyanide                    Vield              in
used                  after                 hydrolysis                                     is              a           modification                  of
                                                                                                                                                                                                       Cassava,                    Sorghum                    and            Pulses
Liebig’s                      iodine                  titration                            in             alkaline                        solution,3’
but            a       more                 sensitive                         colorimetric                                          method                        has
                                                                                                                                                                                                                                                                               HCN      (mg.                     per
been                described.24                         The             maximal                                     reported                        yield                                                     Plant
of         HCN                     from               various                          foodstuffs                                   is         indicated
in        Table             I.                                                                                                                                          Bitter    cassava
                                                                                                                                                                            Whole      root’3’                                                                                               55
                            MECHANISM                           OF           ACUTE                        TOXICITY                                                          Stem3’                                                                                                         113
                                                                                                                                                                             Root             cortex’#{176}                                                                                 65
       There                 are         many               toxins                    in plants                              in addition                           to    Dried root         cortex”                                                                                        245
cyanogen.                                 Several                     pulses                              contain                        hemagglu-                   Sorghum
                                                                                                                                                                         Dried      root pulp3’                                                                                             111
tinins,                     antitrypsins                        and                   toxic                         saponins                           and,              Whole        plant      (immature)’3                                                                              25()
unless                    thoroughly                               cooked,                                    may                 be           lethal                to
                                                                                                                                                                     Vicia     sativa       seed”                                                                                               52
experimental                                animals.                     ‘   28   .   36         38             It           is           signifi-                   Phaseolus          lunatus      bean
                                                                                                                                                                             J ava,            coloured”                                                                                   312
cant,                 however,                           that                in            all                those                 species                     now          Puerto               Rico, black’#{176}                                                                       3(X)

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known                        to           be          cyanogenetic,                                  poisonous                                 prop-                         Burma,                 white”                                                                                 210
erties                 have                      been                 recognized                                            traditionally,                                   Jamaica,                 speckled      white”                                                                   17
                                                                                                                                                                             Arizona,                Lima,     coloured28                                                                    17
and                 there                are            long-established                                       practices                            and                      American                       Lima,                white’#{176}                                                1()
taboos                    which                   effect
                                                 in                  serve                      to            reduce                   the           HCN             Other               peas            and           beans’4,’7’28                                                        <3
       With                 regard                  to Ph.              lunatus,                               numerous                              ex-
amples                      are          cited             in        the               older                        literature      of       fatal
or         serious                       poisoning                           of            horses,                           sheep,                      cattle, HCN                       content.                               According                             to         this          investigator
pigs                and            fowl,              in         circumstances                                  in          which                    the             many                      deaths                       also              occurred                            in        Europe                        as              a
agency                      of           the          bean                   could                            not            be          questioned                 result                    of         large                scale             importation                                 of          this              bean
seriously.’2’420.394’                                              In             many                         cases              the           beans                during                     the            first             world                war.
had             been                   soaked               or          boiled                       ;         Dunbar4’                             induced                  There                    was               no          hesitation                               in         ascribing                       these
acute                 poisoning                          experimentally                                                by         the               feeding          outbreaks                                 to             cyanogenetic                                         glucosides,                             and
of          whole                       beans               after                     they                          were                 boiled                     legislation
                                                                                                                                                                  and                                       was              introduced                            in         several                   European
strained.                               Auld34                  referred                                 to          many                    deaths                  countries
                                                                                                                                                                     in                                  and            in        the          United                    States                   limiting                     the
animals                   throughout                             Britain                         caused                      by          the              feed-      permissible                               cyanide                       content                     of            edible               beans               to
ing            of         imported                 Java               beans.                                   He            also              demon-                   10        or           20          mg.              HCN                 per               100             gm.                  Since              then,
strated                     cyanide                       poisoning                                  in         sheep                    fed           freshly       no   cases     have     been     reported                                                         in those       countries.
soaked                    linseed                  cake            with                    a         potential             HCN                 yield                          1936
                                                                                                                                                                             In         Clark8      reported                                                          that       many       deaths
of        53        ing.          per          I 00        gm.                                                                                                       in Trinidad,            Ugunda          and                                                        Northern          Nigeria
       There                  are          several                 early                   reports                      Ph.
                                                                                                                          of           lunalus                       were    caused       by the prussic                                                            acid     in cassava          root
poisoning                          in          man,’7”40’42                                    but                   the            only                  de-        and            in         Nigeria                      by       unripe                  sorghum,                           and            that            the
tailed                    description                              is             that                         of           Davidson                                dangers
                                                                                                                                                                  and                                    s’ere                well               known                            to         the                 natives.
          vn’7                              The            clinical                        features                          were               similar              Although                               no          clinical                   details                        were                 given,               the
to         those                   of       acute                HCN                            poisoning,                               except                    for
                                                                                                                                                                     features                         of         acute                  cassava                     poisoning                               were            de-
the             delayed                          onset                of              confusion,                                    paresis                       andscribed                   by           Nicholls.23                           Nonfatal                             cassava                   poison-
respiratory                             distress                      which                               was                preceded               by               ing          used              to         be        common                         in         Trinidad.29                    It        is     of
severe                      abdominal                      pains                      and                      vomiting.                       The                      interest                    that                the             poisonous                             nature                   of         cassava
beans                 had               been           boiled,                    strained                                 and           re-boiled.                  root                in           the           West                     Indies                 and                 South                    America
       Sporadic                                deaths                        were                              caused                          by               localwas               recorded                        by         Clusius                    in         l605.
varieties                         in      Burma,43                       and                    Viehoever#{176} recorded                                                     In          all          instances                         in       which                   it        has            been                 meas-
a         series                  of        family                    outbreaks                                        in         Puerto                        Ricoured,                 the            HCN                     content                    of      the                suspected                       plant
in        1917-1925,                             with            seven                     deaths,                          due           to         a black has                         correlated                           with                its               observed                                effects.
Ph.             lUfl(IIUS,                     apparently                                       imported,                                 high                  in There                      can            be         no          doubt                   that              if precautions                                   are
106                                                                                                                                         Montgomery

not             taken                  a        dose                  of          HCN                          (about                     150               to            involves
                                                                                                                                                                        400                            cystine                         and              methionine,                                     either                    directly
mg.),                lethal                     to          man,                    can                  be           released                            by           hy-
                                                                                                                                                                         or             indirectly,                             as           sulfur                           donors.8’9                         Isotope
drolysis                       from                  highly                   cyanogenetic                            plants,                        and                    studies                 indicate                           that                     some              of        the              carbon                        of       the
subsequently                                    eaten                  at         one               sitting.                                                                cyanogen                             radicle                      may                      be           lost                    as         carbon                           di-
        The          toxicity                        of          the intact                   glucoside,                         however,                                                  10          It            is also                  known                         that                 hydroxocobala-
has              never                      been                      established                        by             experiment.                                         mm            takes                      up           cyanide                         as          cyanocobalamin,                                   and
Auld34                   fed          isolated                         phaseolunatin                             and             amgyda-                                    readily                liberates                           it     on                exposure                         to         light it
                                                                                                                                                                                                                                                                                                               47                has
lin        to          guinea                    pigs                  in         amounts                              equivalent                                    to been
                                                                                                                                                                          a               suggested                                  that          the thiocyanate                                             radicle                          may
yield             of            12         lethal                     doses                    of         HCN                       per              day                  also
                                                                                                                                                                       (for               be carried                                   by          cobalamin.9                                              Urinary                             thio-
an             unstated                          period)                            without                             ill          effects.                            cyanate
                                                                                                                                                                        He                             excretion                             is         increased                               not              only                 by           the
demonstrated                                 that                 the             hydrolytic                                  enzyme                            was         ingestion                            of             cyanide48                                but                    also              by                  vitamin
inactivated                                at          the              pH                of             human                       saliva                      or         B12 deficiency.49
gastric                    juice,                    as            well                  as             by            the             presence                               of Hydroxocobalamin                                                      has              been                 shown                          to          pro-
cellulose                       or         glucose,                         and               concluded                              that                  condi- tect                    mice                    against                         cyanide                           poisoning                                   to          a       re-
tions                would                       seldom                            permit                            hydrolysis                                   after markable                                 extent,                      which                       is           difficult                       to             explain
ingestion.                                 The                    failure                           of               saliva                         at                   in
                                                                                                                                                                     37#{176}c.quantitative                                  terms,’#{176} and                              Wokes                       and                Picard9

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to       hydrolyze                              boiled Ph.                    lunatus                          was            confirmed                                     discuss                 the                possible                         nature                          a
                                                                                                                                                                                                                                                                                    of sulfur
                                                                                                                                                                                                                                                                                          ‘ ‘                              trans-
by        Montgomery.28                                                                                                                                                     fer         cycle”                       involving                           cobalamin                                     in        cyanide                           de-
        The            ultimate                            fate              of           the             ingested                          cyanogen                        toxication.
radicle                   remains                           unknown                                 ;        that              it         is             not            ab- It           cannot                        be            assumed                           that              the            metabolism                                      of
sorbed                      as              such,                      cannot                             be               assumed.                                      cyanide
                                                                                                                                                                       The                             invariably                                 involves                          detoxication.                                               The
undoubtedly                                  poisonous                                        potential                              of                  boiled             presence                        of            trace               amounts                               of           cyanogen                                  in      the
Ph.            lUfl(IIUS             remains                      to         be          explained.                           Nicholls23                                    body              in        a            form                  other                   than                  cyanocobalamin                               is
outlined                        some                  of          the              precautions                                      necessary                               in
                                                                                                                                                                            probably                             a          “normal”                                   phenomenon;                               it          may
preparing                              cyanogen-containing                                                       food.                         It               is          possibly                        perform                                a             physiologic                                     function                                as
obvious                         that                  minor                        lapses,                           such                 as               boiling a brake                             in            cellular                     oxidative                              processes.
with             a        lid          on            or          mixing                         the             cooked                      food                     with         Large                     doses                      of              free               cyanide                                cause                      acute
other                 uncooked                                    vegetables,                                        may                   contribute                       generalized                                   depression                                of            cellular                        respiration,
to       an       increasing                               intake                   of free                      cyanide.                                                   resulting                       in             “histotoxic’                     ‘     anoxia.”                                  Long-term
        Consumption                                        of           beans                       in          parts                 of             tropical               effects                of repeated                                  sublethal                                doses                    have                     been
Africa                    may                    amount                                  to              30()              grn              per                      day.’ demonstrated                                           but                 only                  with                      difficulty.                                 Ex-
In        some                   regions                         of          the               East                   Indies,                        the              con-perimental                                  cyanide                          encephalopathies                                      with                 de-
sumption                              of             cassava                         may                       be             equally                            high; myelination                                        have               been                 described                             in            monkeys,’2
it        is         a          staple                      item                    throughout                       the             tropics.                               rats,’3’                             dogs”                        and                      cats.”                                The                      damage
It        is,          therefore,                                reasonable                                     to            conclude                               that mainly                 was             to         the             cerebral                          white                    matter,                        oligo-
such            populations                                 tend               over-all                         to         have                a greater                    dendroglial                               proliferation                                      apparently                                    preceding
cyanide                         “load”                      than                    is          the              average                             in          other demyelination                                       54         but               histologic                               lesions                        in          the
parts                of the                  world.                           A               possible                        exception                                 inspinal                   cord                    and               optic                     nerve                     were                  also                     men-
colder                 latitudes                            is         the               heavy                       smoker.                               It          can
                                                                                                                                                                         tioned.                    The                      lesions                            were                produced                                     by               ad-
be          calculated                                    that                one                       infrequently                        puffed ministering                                                       daily                   injections                                  of             doses                         which
cigarette                       may              yield                 at         least                  2.5         mg.            of HCN         habitually
                                                                                                                                                 gas                                                             caused                      prostration                      ,    convulsions                                  and

in      the          puffs,4’                   but              how               much                      of this                is absorbed    near        death,                                                       over                  a             period                    of            several                            weeks.
in      normal                       smoking                          remains                           unknown.                                                            The           animals                               were                  previously                                  well                 nourished.
                                                                                                                                                                            Little               can                 be           assumed                               from                    all           these                    experi-
                          METABOLIC                               EFFECTS                       OF           CYANIDE
                                                                                                                                                                            ments                beyond                           the             fact                 that              repeated                               episodes
      The            fate            of cyanide                              in the                      body               is only                      under-             of       severe                 cerebral                         anoxia                      induced                            by         the             intake
stood             in           general                     terms.                              An             enzyme                       rhodanase                        of     cyanide                       may,                  in       a small                           minority                            of        animals,
(trans-sulfurase)                                     which                    is         widespread                                   in            living                 result            in       demyelination.
tissues                   converts                              free               cyanide                            to            thiocyanate,                                  Wawzonek                                   et         al.’7            failed                    to           induce                      any                  per-
which                is excreted                                 in          the              urine.                            This                     process            manent                     effects                        in        rats                given                       injections                             of          ap-
                                                                                                    Cyanogen                                 in         Plant             Foodstuffs                                                                                                           107

proximately                                half-lethal                           doses               of          KCN                   daily           fortreated            with                             yeast                 or       liver,             but   the                                impor-
four          weeks.                         Recently,                            however,                           Smith                 et        al.Mtance           of animal                              protein                   foods              was noted.
observed                        some                histologic                         changes                         in      the            brains              The          features                          in          these              cases                 were                similar                   to
of three                rats               given               similar                  injections                          for        twenty-             those               found                      in          prisoners                        of         war                   in       the               Far
two         weeks.                                                                                                                                         East           in     whom                       there                 was    a marked                                    lack                  of      re-
       No        syndrome                               other               than acute                    poisoning                        has             sponse              to any                    known                  vitamins ;63 trials                              suggested
ever           been             demonstrated                            clearly                    in        experimental                                  that          the             addition                       of      beans                  to     the                diet          was              inef-
animals                    fed              for          long               periods                       on         whole                   cyano- fective,                            and          extra                   rice             might               be             harmful,                        but
genetic                 plants,                         with               the           possible                         exception                        that
                                                                                                                                                           of            animal               protein        was                                of          value     both                          in          pro-
liver            damage                              due               to             cycads.                             (See               section phylaxis                             and     therapy.2”3                                               In    Singapore,                                     the
on        Cvcadaceae.)                                                                                                                                     incidence                      of         amblyopia                                reached                      its          peak               when
                                                                                                                                                           other             deficiency                             disorders                    were             declining.                  The
          AMBLVO                  PIA,             TROPICAL                       NEUROPATHIES                                         AND
                                                                                                                                                           diet,         which                      was              being                supplemented                                       with               leaf
                                                                                                                                                           extracts,                          contained                              large                   amounts                             of              rice,
       Moore’                    in         934
                                            I            advanced                         the           theory                    that            the      sweet               potato,                          cassava                        and            green                         (Ph.
high            incidence                            of          amblyopia                                  and              frank                  optic mungo),

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                                                                                                                                                                                        and              had                 been                gravely                          deficient                         in
atrophy               in West                       Africa                 was           related                     to       the            con-          animal                 protein                      for       six         months.64                               When                    prison-
sumj)tion                  0!         cassava,                  and              Clark’                 suggested                            that         ers        already                       suffering                        from             amblyopia                               were               sent
the           noxious                      agent                in         cassava                      was               prussic                   acid. to        work                 on          the              Siam                railway,                     where                    the             diet
The            evidence                           was           dubious                      because                        undernutri-                    consisted           almost       exclusively                                                               of           rice              low                in
tion            ‘as             rife               and               the              amblyopia                     was           often                    total     calories,        there was        no                                                   deterioration                           in
associated                            with               deficiency                           states,                       particularly                   their               vision.’3                               These                    syndromes                                    were                  not
pellagra.                         Clark                       confirmed                             the              high                 cyanide          evident                       under                       starvation                             conditions                                in           the
content                    of              Nigerian                        cassava                          and              emphasized                    concentration                                      camps                 of         Europe.
that           an          adequate                             supply                   of         sulfur-donors                                    was          The          evidence                             suggests                    that              a        dietary                    imbal-
necessary                             for               its            detoxication.                           In            feeding                    ance     rather        than   a total   deficiency                                                                       may            be     more
experinients                            w’ith                 cassava                       and                  inorganic                          cy- productive             of certain     syndromes.                                                                              The              detri-
anide,                he              produced                             a         number                          of           chronic                ill
                                                                                                                                                        mental         effects      of a carbohydrate                                                                              load              in thi-
effects,               including                              photophobia                     in          rats,              but             the           amine                  deficiency                    and             a        maize               load                 in         pellagra
results               were                  not            clear-cut                        and              almost                     certainly          are          cases                 in          point.                         In       addition,                             unbalanced
complicated                                 by          deficiencies.                                                                                      deficiencies                        can              be      expected                       to     increase                        suscepti-
       This         form               of amblyopia,                                 often                associated                         with          bility            to          noxious                      agents.
other            neuropathies,                                is still            rife          and              has          been                the          The             subject                        should                 be        viewed                  in          a fresh                  light
subject                 of            many                     studies.                           Fresh                   concern                       was
                                                                                                                                                          following                           the               isolation                       and               identification                    of
aroused                 by                  its            frequency                                and                   severity                       in
                                                                                                                                                          vitamin                  B12.                  It      is now                  known                that                administra-
Eastern                      prison                      camps                    the
                                                                                   in              last              war.                    The           tion         of        this          vitamin                         may              bring                 about                   improve-
subject                 was                 fully              reviewed                       in            1947             by           Denny-          ment                 in             some                    early                   cases               of             tropical                        am-
Brown2                     and                    Spillane.3                            A          full              discussion                           of                      666         that              in      some                  patients                  with   tropical
these            diverse                          neurologic                            syndromes                                 is      beyond           neuropathies                                   the           serum                   levels                 of vitamin                                 B,2
the           scope               of          this              review,                     but              some                 aspects                  of
                                                                                                                                                           are          low”                  and               that                amblyopia                               may                 occur                    in
the         optic               disorder                       may               be         relevant.                           Addisonian         anemia.67        A diet     low     in     animal
       Retrobulbar                                   neuropathy                                 with         central       and proteins      can lead        to a measurable        depletion          of
paracentral                           scotoma,                           often                 associated             at    its vitamin      B,2 without         anemia.”        The       observed
onset               with                   photophobia                         and            conjunctival           in-        efficacy   of liver,     eggs and meat       in the treatment
jection               and                  with                mucocutaneous                          lesions,         pe-      of wartime       cases      of amblyopia       may     thus       have
ripheral                   neuropathy,                           ataxia                  and                deafness,                         was          been              related                           to         their                 vitamin                            B,2           content.
described                       in Jamaica,’#{176}                    Africa”                               and             Malaya.62                      From               what                  is         known                     of     combined                                system                   dis-
There                appeared                            to       be             a close                    association                        with ease   vitamin        B12 deficiency                                                                could            be suspected
pellagra.                             In           later               reports,                         a             improve-
                                                                                                                    slow                            to influence         the    susceptibility                                                                        of the    nervous
ment            in           vision                 was              observed                               in         mild                cases system        to  other      deficiencies                                                                  and              toxins.                        The
 108                                                                                                                                Montgomery

relationship                              of        cyanide,                       vitamin                            B,2         and            retro- no                   investigator                                       has                 succeeded                                 in              inducing
bulbar                 neuropathy                                   may                be          even                 more              specific.            symptoms                       in              the                laboratory                                     by           feeding L.
Whereas                        a       number        of                           cobalamin                                analogs                          aresativus,    with     the                               single                exception                                of Stockman,74
effective                     in        the   treatment                                  and                           prevention                             of
                                                                                                                                                               who      was     able                                to           induce                     flaccid                    weakness                            and
megaloblastic                              anemia,                          it         is         possible                         that                hy- episodic                         spasms                              in          monkeys.                                        He            also              iso-
droxocobalamin                                   alone                       is  specific                                   for         main-                  lated              extracts                                which                     had                    neurotoxic                               effects
taming       the                          integrity                         of the     nervous                                       system;”                 on injection,                                   not              only               fromLathyrus                              but          from
its          involvement                                       in        cyanide                             metabolism                                    hasvarious       other                                pulses                     including      Pisurn                            sativum,
already                     been                    discussed.                    Heaton                          et          al.6’              ob-           Lens            esculenta                 and        Cajanus                            cajan.    The                               signifi-
served                 that                patients                           with                tobacco                          amblyopia                   cance             of        these                findings                            is doubtful.
could               be         treated                         effectively                             with                 vitamin                         B,2,       Two            other                   species                      of
                                                                                                                                                                                                                                            Lathyrus,                           however,                       are
even            when     they     continued                                                      to      smoke,      and                               con- known                      to            be              toxic                   to            domestic                               animals,L.
cluded              also     that      amblyopia                                                          in    vitamin                                   B,2
                                                                                                                                                            sylvestris                      Wagneri                        and             L.            latifolius,                    and              frac-
deficiency                         occurred                            only             in            smokers.                             Smith”              tions           have                been                   isolated                       from                   them               which                  are
suggested                          that              this              was             due              to            the          cyanide                     neurotoxic
                                                                                                                                                               in                                  to         rodents.75’76
tobacco                      which                       is         specifically                               inactivated                                   by Lathyrus                                  seeds                       are                 not                   cyanogenetic                  on

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hydroxocobalamin.                                                                                                                                                                           328                 Nevertheless,                                        it         was               the            iso-
       Diets               deficient                      in        vitamin                       B,2          tend                also          to         belation             from                    them                   of cyanogen-containing                                                  corn-
low            in           thiol-containing                                     amino                       acids             ;          these                pounds                  which                    opened                          a        new               phase                  in      these                 in-
observations                              recall                       Clark’s                         early                   work                        on vestigations.                               The                    first               discovered                                   substance
cassava                    and             tropical                      amblyopia.8                         It         may               also                 was                3-aminopropionitrile                                                                    (fl-cyanoethyl-
be         relevant                       to         this              question                         that                some             3()            per
                                                                                                                                                              amine),                 identified                                in L.               odoratus                      (sweet                  pea)
cent  of the                        subjects                      with     idiopathic                                     neuropathy                           and        L.     pusillus                     (singletary                                pea).77                       This proved
in Jamacia                            have                    histamine-fast                                          achlorhydria.’                           to       have           dramatic                                 effects                  on           the            rat,          inducing                          a
These               problems                          may              be        further                     elucidated                           when systemic                             mesodermal                                   lesion                      which                    has               been
differential                           assay                     procedures                                  have                  been                    per- studied                     intensively                                      as               “osteolathyrism”                                 or
fected               for         the           cobalamin                               analogs.                                                                ‘   ‘odoratism                . ‘   ‘72    .78       .79         The               features                        include                     bony
                                                                                                                                                               deformity,                          slipped                       epiphyses,                                dental                  anomalies,
                    LATHYRUS,                             VICIA               AND            CYCADACEAE
                                                                                                                                             hernias                                and     dissecting                                                   aneurysm                      : the                         path-
       A      condition                             of         spastic                      paraplegia                          in     young ologic                               condition          bears                                               some                     resemblance                                   to
adults                in         time                of         famine                       has             been              recognized    various                                   bone                   diseases                       in           man                and             to         Marlan’s
for        many                  centuries                          and            attributed                                to a poison syndrome.                                                  The                        skeletal                         lesions                       are               under
in         pulses.                        The                 reference                            by             Hippocrates               is                 strong              endocrine                                   influence,                                 being               accentuated
well         known                  : “At                     Amos               all        men              and            women                      who by            thyroidectomy                                     and              suppressed                                  by              the          ad-
ate            peas                 continuously                            became                           impotent                                 in      ministration                           of             thyroxine                                   or          steroids,                          or         by
the        legs,            and            that                state             persisted.”7#{176}                                                           denervation                                of          bone.72’79                                 This              condition                          offers
       The               lathyrus                             species                       of          vetch                      has                been fresh               avenues                          of         investigation,                            although                           direct
incriminated                           specifically                              since                 the             seventeenth                            applications                               to           clinical                       medicine                           have                  not           yet
century                    and Lathyrus                                 sativus              (chickling                            vetch,                     been            demonstrated.
dog-tooth                          pea,       khesari)                                        has    been                               accepted                 A           number         of                        related                       nitriles                      have                 now               been
widely                as         the    toxic      agent                                    in outbreaks                                  in man synthesized,                                       two                   of          which                     are             experimentally
and            animals                         in           India,                 Southern                               Europe                           and neurotoxic                          to         rats.                        Aminodipropionitrile                                         (bis-
North                 Africa.                            There                   were                 claims            the in past                           f3-cyanoethylamine)                                                gives                   rise              to         cerebral                       ex-
that            similar                        symptoms                                 could                     be           induced                         citment,
                                                                                                                                                                in                          choreiform                                  and                  circling       movements
man            by Lathyrus                                    cicera        (chick                     pea)       ,     Lathyrus                               and      some                  anterior                                horn                 cell     derangement.72’M
climenum                         (Spanish                               vetchling)                        and                Ervum                             The             other,                    -cyano-l-alanine,                                            was               found                       by
ervilia              (bitter                   vetch,                   triputa                       pulse.)                                                  Ressler                et      al.8’             to         induce                    spasticity,                              tremors                     and
       The           subject                        has             been                reviewed                            fully                in         re-convulsions                               when                        fed            at           a          1        per               cent              level.
cent         years.2’6’7’                      ‘              Despite                   many                   early                reports                    This              compound                                        could                     form                      fl-aminopropio-
that           horses,                     cattle                   and                pigs             were                 susceptible,                      nitrile           by         decarboxylation.                                               The               same                 workers
                                                                                                                Cyanogen                                  in        Plant                Foodstuffs                                                                                                                 109

found                  that                   a         similar                     neurotoxin,                                      a,y-diamino-                        ing            in             Australia,                                  Central                       America                                 and              the
butyric                     acid,                       a     reduction                               product                             of         3-cyano-            Caribbean.                                In            addition                            to acute             poisoning,
alanine,                       occurred                                  in          the               two                        Lathyrus
                                                                                                                               toxic                                     there               have              been                reports                      from              Australia          and                                the
species,                L.           latifolius                         and          L.          sylvestris                               Wagneri.                       Dominican                                   Republic                            of          hindquarter                                   paralysis
Finally                  Ressler7                            reported                          the          natural                        occurrence                    in         cattle                   fed              on            cycad                    leaves                  and               roots.89”
of           -cyano-l-alanine                                             itself                     in               the                  seeds                   of The                circumstances                                              giving                     rise             to            these                     fea-
Vicia              SUtiV(1.                                                                                                                                              tures             are           poorly                    understood,                                  and           the             pathologic
        I TiCia             SatiV(l                contains                           a        cyanogenetic                                           gluco-             findings                       in           paralyzed                                animals                    unimpressive.9’
side.22882                                Anderson82                                  in         1925                 foundthat                     sam-                 Longterm                        feeding                    experiments,                                  both                 with              cycad
pies             of L.          S(ltiVus                      seeds                  from                  endemic                             areas               of                    81   and                   isolated      cyanogenetic                                                                                92
human                    neurolathyrism                                       in       India                    were                 invariably                          have              resulted                       in severe      liver                                        disease                      including
contaminated                                            with Vicia                          saliva          .             He              induced                        tumors.                             Chronic                           toxic                  effects                     in           man                  have
an           apparent                     paresis                        in          monkeys                     and              ducks                    by            not            been                   defined,                            but               Whiting22                           has                   drawn
feeding                       I 1C1U               saliva.       That                                this                 might                  be          the         attention                            to          the               fact              that              the           seeds           Cycas
true            cause                    of         neurolathyrism                               was                  not            generally                           circinalis                     are             an         important                            item                 in        the        diet                   of

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accepted                            after                      others                       failed                        to              confirm                         the
                                                                                                                                                                        the          Chamorro                                  people                    of      the            Marianna                                 Islands,
association                              or                 the                experimental                                 results.74”3                                 amongst                         whom                      a         syndrome                            resembling                                    amyo-
In 1939,                    however,                               Shah’”                   described                                an         outbreak                 trophic                   lateral                      sclerosis                      is highly                       endemic.93
of           neurolathyrism                                        attributed                                   to          wheat                      cakes                     None               of the                    neurotoxic                         agents                      isolated     from
vhich                   vere                      contaminated                                 with                   Vicia                    saliva.                   plants                   has              produced                           lesions                    closely                     resembling
The             diet           was                  deficient                         in        protein                         and             vitamins,                those                of             human                          disease,                       although                                the             effect
but             no L.              S(ItiVUS                    had              been                  eaten.                              Minchin8                       of         $-cyano-L-alanine                                              perhaps                        comes                        nearest
and                   Gopalan46                                    reported                               large                       numbers                            to
                                                                                                                                                                          of        neurolathyrism.                                           Dastur6                      tested                      the               effect
cases              apparently                                      in          the              absence                              of         either
                                                                                                                                                     L.                  of       feeding                      rats                on L.         sativus       ‘fortified’ ‘                              ‘        with
s(ltiZ’llS             or          I icia                    sativa-although                                           the             identity                          subtoxic                        doses                     of         iminodipropionitrile                                      and                   of
of        the          disease                          was              necessarily                                  based                    on      clinical          inorganic                          cyanide,                         with              negative                      results.
impressions.                                      Studies                      of          a         recent                      outbreak                           of           Lathyrism                               in        man              occurs                     only           when                   subjects
classic                 lathyrism                                   in          India                     again                      seems                   to          have
                                                                                                                                                                        in-                subsisted                            on            a very                    poor                 diet             for              a long
criminate                      L     .    sativus                   alone.87                                                                                             period.                         In general,                                in all conditions                                      of             dietary
       Ressler’s                          vork                 emphasizes                                  the              need               to      clarify           toxicity,                        the   over-all                                nutritional                                     state                  is              of
the              medical                            importance                         of       Vicia                          saliva               and                  paramount                                 importance.                                  In              particular,                             the
related                        seeds                          other                       than Lathyrus.                                    These                        possible                           implications                            of          a        diet                 deficient                             in
nitrile                 compounds                                        appear                       to             be          intermediates                           cobalamin                                 and                 in          certain                      amino                        acids                  have
or           side-products                                         in          the              biological                                 breakdown                     already                    been                       discussed.                            These                      aspects                            of
of        peptides                  : another                                  subject                      for    investigation                                         toxicology                           may                deserve             further                    attention                           in the
is      the            relationship                                      of        their                  metabolism to that                                             laboratory.
of      the            glycosides.
       Cyanogenetic                                         glycosides                           with                      demonstrable
toxic                 properties                                  have                been                  isolated                           also               from           Several                       plant                        foodstuffs                            in            common                                  use,
the                stems                      and                  leaves                      of               several                         species                  particularly
                                                                                                                                                                          of                                             in         the              tropics,                         contain                           cyanide,
Cvcadaceoe.5                                       These                      plants                   have                      a         wide                dis- either                        in          the               form                     of          glycosides                               or           nitriles.
tribution                          iii            the          tropics                     and              subtropics                                 and         areAcute                       poisoning                            can           occur,                    especially                          in         condi-
used               medicinally,                                    particularly                                      in        Latin                America              tions               of         economic                              stress,                  and              there                  are             cogent
and             the         Far               East,                 and              as        a source                          of        food             starch reasons                             for           continuing                      to          control                      the              cyanide
in      the           Pacific                       Islands.                              Their                  toxicity                       has            been      content                       of    cultivated                              lima              beans,                     and               to         take
reviewed                       recently                            by          Whiting.’2                        Acute                     poison-                       precautions                                    in         the              preparation                   of          yams                        and
ing           in        man                   has                 been               described,                 with                 predomi-                            cassava.
nantly                  gastrointestinal                                      features.                               Similar                       symp-                        Chronic                       ill           effects                 from               cyanogenetic                                          glyco-
toms                  occur                        in             livestock,                                and                  thousands                               sides
                                                                                                                                                                          of               have                    not          been                demonstrated                        in        man,               but
animals                       have                      been              lost              through                             cycad                     poison-        serious                    liver                    disease                     has          been               induced                           experi-
110                                                                                                                   Montgomery

mentally                     by             glycosides                         of         cycads,                   and               these 11.         SMITH,         A.        D.        M.              Retrobulbar                          neuritis in Addison-
plants                have               also               been              incriminated                                in          hind-                ian        pernicious                        anaemia.            Lancet,              1 : 1001,     1961.
                                                                                                                                                  12.   DUNSTAN,                 W.         R. and HENRY,        T.                              A.            Cyanogenesis
quarter      paralysis                                    in        livestock.                        Similarly,                             ni-
                                                                                                                                                           in        plants.               IH.   On phaseolunatiii,                                            the           cyano-
trile   compounds                                      with           potent                    neurotoxic                           prop-                 genetic                  glycoside                      ofPhaseolus                        lunatus.                      Proc.
erties          have                been     isolated       from    Lathyrus                                                         and                   Roy.          Soc.          Med., 72 : 85,                       1903.
Vicia         seeds,               but their      relevance      in human                                                       neuro- 13.               The   investigation                                    of
                                                                                                                                                                                                                poisonous          fodder                            plants             and
lathyrism                    has            not            been         established.                                                                       food grains.      Bull.                              Imp.      Inst., 1 : 12,
                                                                                                                                                 14.     Poisonous                     properties         of     the      beans Phaseolus
      Although                     there                   is little                doubt                 that          hydroxo-
                                                                                                                                                           lunalus.                    Bull.      Imp.  Inst., 3 : 373,     1905.
cobalamin                  plays                       a      part             in      the    detoxication                                       of
                                                                                                                                                  15.    Cyanogenesis                        in plants. Bull.        Imp.      Inst., 4 : 329,
cyanide,                suggestions                             that                cobalamin          deficiency                                          1906.
and         ingested                    cyanide                     may              be         related               factors                  in16.     Cassava:                     its  cultivation                                  and            utilization.           Bull.
the      pathogenesis                                         of            tropical                   neurologic                                or        Imp.         Inst.,         13: 595, 1915.
                                                                                                                                                  17.   DAVIDSON,                   A. and STEVENSON,                                       T.            Poisoning                    by
ophthalmic            disorders                                             remain                   only       plausible
                                                                                                                                                           pois         d’Achery                      (Phaseolus                  lunatus,                Linn.).                     Prac-
theories.                                                                                                                                                  titioner,           32:         436,            1884.
    For           a     more                  complete                        understanding                                     of     this 18.         KOHN-ABREST,                         E.             Etude            chimique                     sur les graines
subject,                more                  work     is                   needed         in                    fields              which                 dites:                Pois                  de Java.             Compt.                    rend.   Acad.    sc.

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involve                 the         biochemist,            agriculturalist      and                                                                        (Paris),              142:            586,        1906.
                                                                                          19.                                                           GUIGNARD,                     L.         Sur               les quantit#{233}s dacide                                          cyan-
veterinary                   surgeon          as well       as the         epidemiolo-
                                                                                                                                                           hydrique                        fournies                      le
                                                                                                                                                                                                                     par Phaseolus       lunatus                                         L.
gist     and             clinician.             Such     work        is desirable        in                                                                cultiv#{233} sous                     le      climat            de          Paris.     Bull.              Sc.       Phar-
view       of           the      increasing          development               of pulses                                                                   niacol.,            14: 556, 1907.
as     a     source                of         dietary                  proteins.                                                                 20.    VIEHOEVER,                A.   Edible                          and          poisonous                 beans                 of the
                                                                                                                                                           Lima          type          (Phaseolus                         lunatus      L.).                Thailand                   Sc.
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