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Ronald G. Leonard, Ph.D., President P.O.

Box 262069
1.. San *Diego, G4iforni.a Q2 196-2069

October 19, 2000

Dockets Management Branch


Food and Drug Administration
HFA-305, Room l-23
12420 Parklawn Drive
Rockville, MD 20857

RE: “POTASSIUM IODIDE RECIP” 65 MG TABLETS


Citizens Petition

Dear Sir/Madame:

The enclosed submission is in reference to Section 505 of the Federal Food, Drug
and Cosmetic Act (21 USC §355), and is a “Citizens Petition” requesting the Food &
Drug Administration to allow the filing of an Abbreviated New Drug Application
(ANDA) for Potassium Iodide 65 mg tablets.

Please do not hesitate to contact me at 858 586-0751 if there are any questions or
you require additional information.

for Recip AB

Enclosure

CC: K. Schullstrom, Recip AB

Advising IL Serving the Phnmaceutical industry


;;on/8~353-(375 1 Fax 858 586- 1108 ieonardi@r-rregistratiorxcom
cfv
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R & R REGISTRATIONS
Ronald G. Leonarcii, Ph.D., President P.O. Box 262069
San Diego, California 92 196-2069
October 19,200O

Dockets Management Branch


Food and Drug Administration
HFA-305, Room l-23
12420 Parklawn Drive
Rockville, MD 20857

CITIZENS PETITION

The undersignedsubmits this Petition under Section 505 of the Federal Food, Drug and
Cosmetic Act (21 USC $355), which authority has been delegatedto the Commissioner
of Food and Drugs under 21 CFR $5.10. Petitioner requeststhe Commissioner of Food
and Drugs to declare that the drug product, hereinafter described, is suitable for
consideration in an abbreviatednew drug application.

A. ACTION REQUIRED

By this petition, the undersignedrequestspermission of the Commissioner of Food and


Drugs to file an abbreviatednew drug application for a Potassium Iodide tablet dosage
form containing 65 mg of PotassiumIodide.

B. STATEMENT OF GROUNDS

The Federal Food, Drug and Cosmetic Act as amendedin 1984 provides under Section
505(j)(2)(C) that a petition may be filed with the Secretaryseeking permission to file an
abbreviatedapplication for a new drug which has an active ingredient which differs from
the listed drug in dosageform or strength. Such a petition must be granted unless the
Secretaryfinds that investigations must be conductedto show the safety and effectiveness
of the drug.

The petitioner requestspermission to file an abbreviatednew drug application for


PotassiumIodide, 65 mg tablets. The listed drug is available as a tablet containing 130
mg of PotassiumIodide presently manufactured by ANBEX, Inc. and Carter-Wallace,
Inc., the companiesthat have received FDA new drug application (NDA) approval for
their non-prescription “radiation emergencypotassium iodide” drugs.

It should be noted that the Federal Register (Volume 47, No. 125) dated June 29, 1982,
states“FDA recommendsthat potassium iodide in dosesof 130 milligrams (mg) per day
for adults and children above 1 year and 65 mg per day for children below 1 year of age
be consideredfor thyroid blocking in radiation emergencies...” It would be convenient

Advising & Serving the Pharnxtceuticd Industry


I
Phone 858 586-075 1 Fax 858 586-i 108 leonardi@r-rregistrations,com
R 8c R REGISTRATIONS

to have this potency available so that adults could take two tablets for 130 mg dosage
requirement and children one tablet for the prescribed65 mg/day.

The Agency also states(Federal Register, Vol. 50, No. 142, p. 30258, July 24, 1985) that
risks of side effects, such as allergic reactions, from the short-term use of relatively low
dosesof potassium iodide for thyroid blocking in a radiation emergency, are outweighed
by the risks of radioiodine induced thyroid nodules or cancer,if the projected dose to the

thyroid gland is 25 rems or greater. BecauseFDA has authorized the non-prescription


sale of “radiation emergencypotassium iodide,” it is legally available to organizations or
individuals who, basedon their own corporate or personal analysis, choose to have the
drug immediately available.
Additionally, it states“This recommendation is made in full recognition of the potential
positive effects of the drug, action by the FDA permitting KI over-the-counter sales,and
the authority of State and local health officials to elect to distribute and use the drug
basedon the specific needsof individual sites.

Since the proposedproduct, containing 65 mg PotassiumIodide would be identical in


active ingredient, and route of administration to currently marketed product, the safety
and effectivenessof the proposeddrug product is not expectedto be different from that of
the listed drug. Two tablets of the proposedpotassium iodide tablet will be
therapeutically equivalent to the 130 mg tablet IosatTMmarketed by Anbex. This is based
on the well known solubility, dissolution and absorption of potassium iodide resulting in
an appropriate bioavailability profile for the 65 mg tablet of Potassium Iodide. The
solubility’ of potassium iodide is 1.43g per mL. The dissolution2 profile of the 65 mg
tablet is >85% in 30 minutes. The absorption3of potassium iodide is well documented
and noted to be rapid and high.

To the best of our knowledge, the proposeddosageform will not be violating any patents
relating to the composition of the product or the method of manufacture.

We submit that the criteria of Section 505($(2)(C) are met and that the requested
permission to file an abbreviatednew drug application for the dosageform described
above should be granted,

C. ENVIRONMENTAL IMPACT

The subject matter of this petition is covered in 21 CFR $25.23(c).

2
R & R REGISTRATIONS

D. ECONOMIC IMPACT

The petition will provide this information upon request.

E. CERTIFICATION

The undersignedcertifies, that, to the best of his knowledge and belief, this petition
includes all information and views on which the petition relies, and that it includes
representativedata and information favorable to the
petition.

Signature:

Name of petitioner: Recip AB, c/o R & R Registrations

Mailing Address: P.O. Box 262069


San Diego, CA 92 196

Telephone Number: (858) 586 - 075 1


Fax (858) 586 - 1108

References
1. Solubility - The Merck Index Twelfth edition, p. 1316
2. Dissolution - Recip’s Specification for Potassium Iodide Tablets
3. Absorption -
3.1 Matovinovic J. Iodine. Presentknowledge in nutrition, 5 ed. Washington
DC, The Nutrition Foundation, Inc. 1984587-606
3.2 Zanzonico PB, Becker DV. Effects of time of administration and dietary
iodine levels on potassium iodide (KI) blockade of thyroid irradiation by
131I from radioactive fallout. Health Phys 2000;78(6):660-7.

3
c

7809 '0tarrit

.I m9. -
,
470 EiEMENTS OF GROUP I

stick may he inserted into a section of rubber tubing,, or Stdrege--Preserve in tight. tighr-re&tanr. containers ~1~1 avoid
cessive heat.
wrapped se\:eral times with tin foil, to avoid cautenzmg
the fingers of the operator. In industry it is used in Uses-The therapeutic \.alue of ttle hvpopllosph:
rhe manufacture of soft soap, in electroplating, in paint has been repeatedly questioned in medl’cai literat\
:irld v;irllisil removers. and in many other processes. This Syrup has been proposed as an alt.eTalice, a to?
and a source of phosphonts.
Dose-lisual, 8 ml.
POTASSIUM HYPOPHOSPHITE N. F.
[I’oLassii Hypophosptris: Sp. Hipofosfito PocBsico]

Potassium Hypophosphite, dried at 105’ for 1 hour, POTASSIUM IODIDE U. S. P., B. P., Ph. I.
contains not less than 98 per cent of KPH202 (104.09). [Kalii Iodidum Ph. I.; I’otaIisli Iodidum B. I’.; .Fp. I’oduro Pot&
Caution should be observed in compounding Potassium Potassium Iodide, dried at 105’ for 4 hours, cants
Hypophosphite with other substances, as an explosion not less than 99 per cent of I<1 (166.01).
?nay orcur ij it is triturated or heated with nilrates, chlo-
,a/~, or other oxidizing age&s. Preparation-.4 hot aqueous solut,ion of pot.assi
hydroxide is treated with iodine in slight escess. ‘:
Preparation--When solutions of calcium hypophos- result is the formation of two salt.s, pot,assium iod
phite and potassium carlsonate are mixed, potassium- and potassium iodate.
hypophnsphite and calcium carbonate are produced by
double decomposition, thus: 6KOH + 31s - .jl<I + f\IOs t 3HcJ)
Potassium 10dine I’llrsssl”rn n’alrr
CR(PH~O~)~ + K&O3 - 2KPHs02 + CaCOs I Hydroxide I,,tlide D *
p”IL”d”B’:m
C’di~lUr!l l’<rtaablum I“3tseaiUm Calcium
H~p~lplll,spl,llP C’tirbOliUt~ H,ypophosphlte Carbonate The solut,ion is cutlcclltrated by heating oi’er a 1
The cdal(GumCarl)onat,e is removed by filtration, and flame in an iron kettle. then an escess of powdered ct
the clear sc)lut.ioi> in e\:aporated until a pellicle forms, coal is added and well incorporated. The misturt
aft,er \\.hic,h it is c,onstantly stirred, wit,h continuance evaporated to dryness, then ignit.ed. The chart
of t.he heat, unt.il the salt granulates. The heat em- (carbon) reduces the iodate to iodide and all of
ployed in the evapnrat,ion should be kept considerably iodine is thus obtained as Potassium Iodide. The m
below 100” for fear of explosion. is lixiviated with wat.er, filtered, evaporated to a s
able concentration, and set. aside to crystallize, or i
Description-White, opaque hexagonal plates. crystalline masses, or
a granular powder, and 1s very deliqueacent. It is odorless and has granulated from the hot. solution.
a pungent. reline taste. Its aqueous solution (I in 20) is neutral or Potassium Iodide is also prepared by first form
alkaline fo li~mua. The N. F. provides Gests for Idenlijicalion. ferroso-ferric iodide t.hrough the reaction bet\veen i
Sdubililp-One Cm. IS soluhte in about 0.6 ml. of water and in
about 9 ml. oi alcohol at 25O: it is somewhat more soluble in boiling wire and iodine in the presence of water. A solution
water or boiling alcohol. pure potassium carbonate is then added until
Tesrs for Puriry-The N. F. provides tests and limits for Loss on dry-
irro 15 per relit), .hlkalirtily, Phosphate, Arsenic. Calcium, and Heavy solution is faintly alkaline, boiled for a few mome!
met& (20 p. p. m.). and filtered; the filtrate is concentrated and set as
Assay-The salt is assayed by oxidation with excess standard bromine
solution. The surplus bromine is caused to liberate an equivalent to crystallize.
auantitv of iodine which is titrated with standard sodium thiosulfate. The reactions are expressed separately as follows:
<sing starch as the indicator. See page 1251.
Storage-Preserve in tight containers.
Incomaatibilities-Sodium citrate promntes the solubility of the less
solubld hypophosphices. Most oxidizing age&a con&t them LO
phosohates with simultaneous reduction of the anent. Triturstion of
ihe dry chemical with a strong ozidizinv went may produce an ex- FeJs i- aK&O~ - SKI + Fc&+ i -rc‘O~
plosion. When rubbed with colonel the latter substance is darkened Fer,r~~~~:rric Porasnialttl I’oLsssiuIn Ferr&i;f~rr,c Carbon
due to Its reduction LO metallic mercury. Ferric a&s precipitate from Csrbonste Iodide I)loxide
solution as ferric hypophosphite. Bismuth subnilrale is darkened due
to the producrion or metallic bismuth.
Potassium Iodide is always crystallized from an al
Uses-See Compound Hypophosphiles Syrup below. line solution and to prevent discoloration, due to for:
Dose-l ‘sual, 500 mg. tion of free iodine, a small amount of free alkali is 1
mitted. See also the equations under Po(assi7cm 1
Compound Hypophosphites Syrup N. F. mide.
[S:?.~U~W I~yl,~lpt~osl,hltum Composttus: Sp. Jarsbe de Hipofosfitos Description-Hexahedral crystals. either transparent and colorle
Compurhto) somewhat
%I. > opaque1.1.11
and whitr. or a white. granular powder. h *
staore in ary air. out sllgnrly nyyroscoplc m molsr. au. un proionem
Calcium Hypophosphite 35 Cim. keeping it may become yetlo\s:ish Lhrough the formarion of free rodins
Potassium Hypophosphite 17.5 Gm. by oxidation. The aqueous solution is neutral or slightly alkaline u,
Sodium Hypophosphite litmus, and gradually becomes yellow because of the formacion of frw
Ferric Hypophosphire.. 7: 2 iodine. The addition of small amounts of sodium thiosulfate removw
,$;;f;;ese Hypophosphice 212 Gm: the yell?? color. The U. S. P. provides tests for IdPnti/icotion.
I.1 Gm. ,- -~o%;;bpty-~gne Cm. dissolves in 0.7 ml. of “at;? ian,~2i~~,~f;l~~
Strychnine. 0.1 Gm. t3FernrmTs ml. of acetone at z
Sodium Citrate 3.7 Gm. boiling water. When ‘dissolved in water heat is absorbed. One
Hypophosphorous Acid 5 ml. hundred ml. of its aqueous solution sacuraced at ‘25’ conrains 100 Cm.
Dextrose 250 Gm. of KI.
Glycerin 300 ml. Tests for Purity-The U. S. P. provides Lesrs and limits for .4&z-
Purified Watei, a sufficient qiantity. lint&; Loea on drying (1 per cent); lo&zt.z. nilrile. Lhiosuljatc, and
To make 1000 ml. barium; Nc’tralc. &rile, and nmmonia: and Heavy melda (10 n p. m.).
\Iis the ferric and manganesehypophosphiteuwith the sodium chloroform, Assay-An acidified solution of the salt is titrar.ed. in the presence of
with standard potassium iodate solution. See page 1250.
citrate, add 30 ml. of purified water, warm on a water bath, and Storage-P reserve in well-closed containers.
stir until a rlear solution is obtained. Dissolve the calcium, potus- Incompatibilities-Iodides are water-soluble cxcepr Ihe lead. ailan
sium, and sodium hypophosphites in 400 ml. of purified water, to nercuru, and cuprous m&s. These are soluble in the presence of alksc
\vhich 2 ml. of hypophosphorous Hcid has been added; then die- iodides, the lead and silver iodide* least readily,
solvz rhr quinine and strychnine in 30 ml. of purified water wit.h In the presence of acid. iodides are decomposed rapidly NiLh the
the nid of 3 ml. of hypophosphorous acid, and add the glycerin: liberation of iodine. Sugar retards the reaction Ozidizirw ~9ml,
mis the solutions, and dissolve the dextrose in them by agitation. liberate iodine with simulrancous rcducrion of rhc .saenr. Thus. by
.4dd sufficient l>urifird wst(br to mltke the product measurel&JO reac$?n with cupric sul/ale. ioclillp 1s liberated and cuprous iodide is
precrpltated; with ethyl &rife .s?>irit. iodine and nitric oxide (which
llll., :ind str:1irl forms brown NO, on ronLnrt X~III air) are evolved. Ammonium i+
Reference 2
TEST METHODS AND LIMITS

a) Content of Potassium Iodide


Quantification was performed by titration with silver nitrate
Limits: 61.8 - 68.3 mgtablet
Refer to Method: USP XXII

b) Content of Iodine
In-house calorimetric assay using diethyl-p-phenylendiamin and
detection at 550 run
Limits: c: 1.3 pg I,/tablet

c) Content of Iodate
Titrimettic assay using starch
Limits: < 4ppm
Refer to method: LJSP XX, p. 645

d) Hardness
The strength required to crush a tablet was measured. The mean value of ten
determinations was reported.
Limits: 4.0 - 7.0 kp
Refer to Ph. Eur. 2.9.8.

e) Disintegration Time
Six tablets were examined during disintegration with water. The ma.ximum time
was noted.
Limits: All tablets disintegrated within 15 minutes
Refer to Ph. Eur. 2.9.2.

f) Dissolution
Dissolution medium, apparatus and sample withdrawal according to USP
XXIII, P. 1791-93, Apparatus 2
Quantification of potassium iodide is performed as described above.
Limits: 2 80% of labeled content after 15 minutes

g) General Appearance
Approximately 100 tablets were examined by eye regarding color, surface and
defects. The tablets are white to off-white, round, bevelled, with a cross line on
one side. The diameter is 9 mm.
Limits: Approved

h) Microbiological Control
Limits :
Aerobic bacteria: < 103/g
Fungi: 2 10*/g
E. coli: Absence
Refer to Ph. Eur.
Limits: Approved
41
46 f H Trplon HA Schroeder. H M Perry. Jr and M J Cook Trace Elcrnenfs ,n
Human Trssucs If1 Subfects from Africa Ihe Near and Far East and Europe ~caf,n
Phys 11 403-451. 1965
47 K.M Hambrdge rn The Newer Trace EfemenfS m Nufrrfron W Merlr and W E
Chnp ter JOSIP MATOVINOVIC

Cornatzer. Edrtors. pp 169-194 Marcel Dekker. Inc New York. 1971


48. Y Murakamr, Y Suzukr T Yamagata and N Yamagata Chromrum and Manga.
nese rn Japanese Drers Chem Abswacrs 65 I 1033. 1966
49 A Walker and L Page NutnlrveContentot CoffegeMkafs J Am Dle/ ~~~~~ 70
Iodine
260-266. 1977
50 J T Kumpularnen, W R. Wofl. C Verfton and W Mertz Delermrnatron of Chrom,um
rn Selected Unrred States Drets J Agnc Food Chem 27 490.494, lg7g
51 P Korvrstornen Mrneral Element Composriron of Frnnrsh Foods Acfa Ag, stand
supp/ 22. 1980
52 D.H.P Streeten. M M Gerstern. G M Marmor and R J Dorsy Reduced Glucose
Tolerance rn Elderly Human Subjects. Drabefes 14 579-583. 1965
53. H.A Schroeder Chromrum Deficiency in Rats A Syndrome Srmulatrng Diabetes
Mellitus with Retarded Growth J. Nufr. 88. 439-445. 1966
54 W.R. Wolf. W. Mertz and R. Masironr: Determrnalron of Chromium rn Refined and The multiple, often cybernetic relationships between disorders in
Unrefined Sugars by Oxygen Plasma Ashing Ffamefess Atomrc Absorption J. iodine nutriture and thyroid disease are evidence of the complex-
Agric. food Cbem 22. 1037-1042. 1974
55. E.G. Offenbacher and F.X Pi-Sunyer Temperature and pH Effects on the Release
ity of humans and their environment. Our present knowledge
of Chromium from Starntess Steel rnto Wafer and Fruit Juices. J. Agnc. FM about iodine stems from many observations, empirical experiments
Chem. 3 1: 89-92. 1983 and scientific investigations. The nemesis of both understanding
56. W.R. Wolf. Nutrient Trace Element COmpOsrtrOn Of Foods Analytical Needs and and controlling nutritional disorders of iodine metabolism, howev-
Problems Anal Chem 50: 19OA-194A. 1978 er, has been in mistaking the complex for the simple, and the
57 R A. Anderson, J H Brantner and M M Pofansky An tmproved Assay for Biofogi- r
: beginning for the end. This has been true both before and after it
cafly Active Chromrum. J Agnc. Food Chcm 26 1219.1221, 1978
58 D Behne and F Diehl rn Aclivalion Techniques m /he L//e Sciences pp 407.4 14. i became obvious that an environment either deficient or excessive in
tnternatronal Nuclear Atomic Energy Agency, Vienna, 1972 iodine is an important source of ill health. Because of unpredictable
59 t W-F. Davrdson and R L Burt Physiofogrc Changes rn Plasma Chromrum d li1 and perplexing man-made changes in life and environment, simple
Normal and Pregnant Women. Effect of Glucose Load. Am J Ob Gyn 116 6tJl- prevention programs of these two abnormalities are not sufficient.
608. 1973
A national and international policy on iodine nutriture is manda-
60 J Versreck and R Cornelrs Normal Leveis of Trace Elements in Human Blood. ;:
Plasma or Serum Anal Chum. Acra 1 16. 217.254. 1980 tory as an integral part of a world-wide improvement of nutrition in
61 F J Kayne, G Komar. H Laboda and R E Vanderlrnde. Atomrc Absorptron S general.
trophofometry of Chromium tn Serum and Unne wtth a Modified Perkin-Elme An artificial division of the environment into inorganic, organic
Atomic Absorpfron Spectrophotometer C/in Chem 24 2151.2154. 1978 h and human worlds may be helpful in the discussion of the relation-
62 J Versreck. J Hoste. F Barbrer. H Sleyaert. J DeRudder and H Mrchefs: D&3f
ship of iodine and the thyroid gland in health and disease. This
mlnatrOn of Chromium and Cobalt rn Human Serum by Neutron Activalron m
SC ChnChem 24 303.308. 1978 topic will be discussed from these three viewpoints after a brief look
63 R A Anderson, M M Polansky, N A Bryden, E E Rogrnskr. W.H Ghnsmann. K at the history of iodine.
Patterson and C Verffon Urinary Chromrum Excretron of Human Subfects: Effe
of Chromrum Suppfementatron and Glucose Loadrng Am J C/m. Nuff 36: 11.8
1193. 1982
64 R A Anderson, M M Polansky. N A Bryden. E E Rogrnskr. K Y Pattersonm
Reamer Effect ot Exercrse (Runnrng) on Serum Glucose. Insutrn. Gtucfl The sense of taste for iod ine, in contrast to that for chloride, does
Chromrum Excrellon Dabefes 31 212-216 1982 F-4
not regulate the inl ;ake of this nutrient. But, long before history
cameto be written, the Peoples of the Pacific coasts of China and
587
L

588 MATOVINOVIC 589


IODINE

South Amcrlca rmplrtcally learned to tat Iodine-rtch seaweed for


the cure of goiter. ’ The Greeks and probably other ancient maritime bines with iodide to form polyiodides, which accounts for the high
peoples had the same experience. Finally, in the twelfth centurv solubility of iodine in water.
Ruggiero Frugardi (Roger of Salerno) from the great Hlppocratii During the last glaciation period, 18,000 to8000years ago, mature
School of Medrcine at Salerno, Italy, recommended an electruarlum iodine-rich soil was swept away by glaciers and was replaced with
of ashes of sea sponges for the treatment of goiter, and this remedy new crystalline soil, which, lacking humus, could not retain iodine.
has remained in use for centuries.2 According to the medical geographic map, most of Canada and the
Ironically, iodine was born as a stepchild of potassium nitrat<,, a northern regions of the United States are in the goiter belt of the
basic ingredient of gunpowder. Continuous wars and the English northern hemisphere, as are the Pyrenees, the Alps and the Hima-
blockade of Europe forced Napoleon’s chemists to intensify the layan region. In addition, the mountain ranges of Canada, the Unit-
production of salpeter from seaweed (Normanic, varec; Scottish, ed States and Mexico were also depleted of iodine by weathering of
kelp) deposited by the sea on the coasts of Eretagne and the soil during eons of time.
Normandie. The intensity of iodine deficiency reflects the cycle of simulta-
As part of this major undertaking, Bernard Courtois (1777..1838). neous depletion and repletion of soil iodine (from parental rocks to
the son of a salpeter producer and formerly a pharmacist who the sea and back again via wind, rain, snow and flora and fauna).
isolated morphine from opium, was forced by circumstances to take Some variants are also caused by geological and climatic factorsas
over his father’s business in Paris. Late in 1811, while CrystaJlizing noted in the Andes as well as in the tropical areas of South America,
potassium nitrate, he probably added too much sulfuric acid to the Africa and Asia.6 Thus the condition of iodine distribution in the
concentrated cooling mother liquid of the varec ashes. Thus beauti- inorganic world is responsible for a world-wide low iodine content
ful violet fumes were formed and a brownish violet crystalline sub- of the soil in many countries which are inhabited by about one
stance was deposited on the wall of the vat. Impressed by its color, billion people.7
he named the substance “iode,” the Greek word for violet-colored.’ Iodine is a trace element. Its concentration in the inorganic world
In 1816, Prout in England was the first to use iodine in the treat- varies considerably. Approximate values of iodine in the air. so&
ment of goiter.J Francois Coindet (1774-1848) was the individual terrestrial water and sea water are 0.7 pg per cubic meter, 300 pg per
who most promoted iodine as goiter therapy. In 1820, he demon- kilogram, 5 pg per liter and SOpg per liter, respectively (Figure 1).
strated to the Swiss Society of Natural Sciences the results of such Combustion of coal and gasoline enriches the air with iodine.
goiter treatment. He was the first to observe iodine-hyperth, .-._ Iodine is returned to the earth in the rain in concentrations of 1.8 to
ism in goitrous patients given large doses of iodine. He warned, “I 8.5 kg per liter (Figure 1). The given value for terrestrial waters
cannot sufficiently emphasize the well-known axiom of Boerhaave: represents an average with very wide variations. Sea water contains
At prudenter a prudente medico, si methodum nescis, abstine.. .“5 the largest total amount of iodine, mostly in the form of iodates.
Solar light with the wavelength of 560 pm can oxidize iodide to
iodine, and about 400,000 tons of iodine escape each year from the
ocean into the air. The highest concentration of this halogen (about
lodrne and the Inorganic World 0.5 to 2.0 g per kilogram) is found in the deposits of Chilean nitrate,
Iodine, like chlorine, silica and bromine, was present in the pri- j-’ where it was brought by the Antarctic anticyclonic air flow from the
mordial waters of the earth. In the inorganic world of small particles i Pacific Ocean. The brine of rock salt and especially fossil oil are
and large energies, the uneven distribution of iodine in water, sl important industrial sources of iodine.”
and air has been determined by the second law of thtrmodyna
The atomic number of iodine is 53, and its atomic wei( Iodine and the Organic World
126 91. It is poorly soluble in water, but molecular 1r~11nc(12)
In the organic world of macromolecules, iodine became a perma-
nent pat‘t oi diverse structures in most living organisms. %C iodine
590 MAKWIN~VI(;

rred to bc>the ong:ln of vcrtc+ratcs 111sweet, offcn iodine-dthcltnt ..


water. Accordingly, the thyroid has been engaged 111accumulation *
of iodine and in synthesis and storage of iodotyrosine and iodnthy-
ronines. lodotyrosinc represents the reserves of Iodine in the thy-
roid. The iodothyronine hormones are secreted in the bloodstream
as messengers with different functions (regulators of metamorpho-
sis and homeothermy, stimulators of protein synthesis and of sex-
ual development) in various groups of organisms.
Surprisingly, marine fish do not undergo metamorphosis, and
are poikilothermal, but have retained the thyroid gland. The same
is true for poikilotherm frogs and lizards. They need the thyroid
hormone only for larval metamorphosis; in the adult organism, the
thyroid has no evident endocrine function.
These observations, and especially the exceptional persistence of
the thyroid without adaptative value to some organisms, prompted
Etkin’ to suggest that: 1) iodine is a micronutrient per se, indepen-
dently from being a constituent of thyroid hormone, and 2) the
thyroid gland is also the storage organ for iodine (in the form of
iodotyrosines) in support of its special metabolic and/or structural
,Q
function in various tissues of the body.
The most important phenomenon of the”iodine:organic world” .
relation is the development of goiter. A goiter represents a compen-
.: satory enlargement of the thyroid gland caused by difficulties in
Frgure 1. Simple Model of lodIne Turnover ‘lodIne in ~1 --- secretion and/or utilization of thyroid hormone. Arbitrarily, the
mtlk Golrrogens0sulllde 01hydrocarbonsin sedan.,..,“,y ,, prevalence of sporadic and endemic goiter in the whole population
watef CaSSava. goilrogenlccabbage,soybeanan0 is 5 percent and above 5 to 10 percent, respectively. Endemic goiter
WWoduced by PermissionlromR I. Volghr tn
Hea’th-- CJ c HemPW Echfor. P 303 Unrversrty of Mlssourt rress. LoIumDra.
in humans and animals is the same disease and occurs in the same
1972) .. areas.
r
lonirre Deficiency. Absolute iodine deficiency is the most common
4 world-wide cause of endemic goiter and cretinism. In 1940, about
concentration in plants varies directly with the environment. Mnct ‘gj 200 million people from all continents, races and cultures were
plant iodine is in inorganic form. Terrestrial plants are usuati afflicted by endemic iodine-deficient goiter.‘” Since that time, re-
dine-poor, and their average iodine content is 1 mg per kilogra... duction of goiter prevalence has been accomplished in many areas,
dry weight. The iodine content is higher in marine plants. BrownC and especially in more developed countries. Because of a great
seaweed is very rich in inorganic iodine (0.7 to 4.5 g per kilograF’ increase in population in less developed countries, however, at
dry weight) and is important for production of Iodine in Japan.: Present more than 200 million people have goiter.
In marine animals, such as sponges, and in the skeleton of th Nutltt-nl Coitrogem. Natural goitrogens, usually in combination
corals, iodine is in the form of diiodotyrosine.’ Only vertebra!: with iodine deficiency, are the cause of endemic goiter. The most
developed the thyroid gland, which is mainly concerned with ia Important natural goitrogens are cassava, cabbage, disulfides of
dine metabolism. The cause of this revolutionarv event is coax Saturated and unsaturated hydrocarbons from geological Organic
592 MA rOVlNOvlC:

scdimcnts in drtnking water, bacterial products of Esc/rc,rlc-/r~n c-ct/, in The goitrogenic pharmaceuticals and Industrial chemicals have
drinking water, soybean and iodine CXCC’SS in seaweed and brown great applications in abTriculturc (organocl~lorin~ insecticides and
and green kelp. tungicides releasing ethylenthiourea) and animal husbandry (bac-
tenostatic sulfonamides and antibiotics of the tetracycline group).
The total effect of the goitrogens used in agriculture and animal
iodine and the Human World
husbandry is not yet known.
During the last 60 years, progress in the prevention of endemic For the last fifty years, thechemical industry has produced plasti-
goiter has not been successful everywhere. In less developed coun. cizers of the polychlorinated biphenyls (PC&). Since 1978 the pro-
tries, the protagonists of goiter prophylaxis were confronted by the duction of these compounds has been banned, but 375,000 tons still
phantom of Jod-Basedow and many were exhausted by the power- in use of the total 750,000 tons produced in the United States will
ful obstacles of ignorance, economic difficulties, civil disorders and eventually end up in the rivers, lakes and seas. ” Most contaminat-
war. ed are the Great Lakes and their tributaries. Since 1972 it has been
In contrast, the problems of iodine nutriture in some more indus- documented that PCBs cause severe endemic goiter in predator fish
trialized countries are now of a different nature. Most of these of the Great Lakes waters. I2 In 1972, the PCB content in 45 percent
societies introduced successful iodine prophylaxis about 30 to 55 of the U.S. population was 1 Fg per gram of body fat.”
years ago. In addition, after World War II, many industrialized Fire retardants of the polybrominated biphenyls (PBBs) act like
countries have developed economic and efficient technologies of PCBs. In 1973, a limited, accidental contamination of animal feed
food production paralleled by a large growth of complex chemical with PBBs occurred in Michigan. Biochemical evidence of disor-.
industries. Thereafter, during the last 20 years, an upward trend dered thyroid function was detected in some individuals who ha&
towards high to excessive nutritional iodine intake was noted, and consumed contaminated meat and milk,” but was not confirmed ina
in the last five to ten years several warnings on animal feed and another study.‘8
human food contamination with synthetic goitrogens were pub-
lished.““R The most important cause of these complex changes in
iodine nutriture of animals and humans comes from use of iodine-
rich compounds and various goitrogenic chemicals. iodine in Food
r-3. ‘I
----..- UJCU
4 ;.
IIf uarly tdlllllng dllcl
In areas completely dependent on local food supplies, the iodine,
(ethylenediamine dihydroiodide for therapy and prev, content of water is a reliable indicator of its content in the soil an6
lumpy-jaw. actinomycosis, foot rot necrobaccilosis and iodophor- nutrients. Drinking water, except for some “mineral waters,‘%
antiseptics for udder and teats as well as cleansing agents for dairy : rarely an important source of iodine. Vegetables and fruits supply
equipment and containers) and in the baking industry (iodates as i little iodine. Meat contains more iodine and its content depends on
dough-conditioners in “continuous-vacuumlmix process” and as the feed and food of domestic and wild animals, respectively. IO-
cleansing agents for equipment).12 Milk and dairv dine is concentrated in milk and eggs, which are second only to
as bread and bakery il roducts are th seafood as the richest sources of iodine. Marine salt contains little
human fc,od.’ 2 B:. lodme After crystallization of sodium chloride, the mother liquid,
Pollutic In is another SCburceof iodi ne 1 containing all the iodine, is separated to prevent the precipitation of
pollution of iodine is possibly in the large ind:itriayand ‘pharm: ! the bitter magnesium chloride. With only a few exceptions, crude
ceutical production of iodinated chemical compounds (1.~OO,~k& i rock salt contains little iodine, which has escaped during the eons of
Iodine is used per year by industry in the United States alon i s1ow evaporation of sea water.
which either directly, or via sewage tur Data on the iodine content of food from goiter free Washington,
into the drinking water and food.‘2,‘X h DC and Athens, Greece, as well as from the “Greek Endemic
594 MAroVlNOviC IODINE 595 e
.
Areas” (401 tug, 202 ~g, and 41t~, respectively) illustrate the differ. sines in thyroglobulin. The pivotal factor in this regulatory mecha-
ence in nutritional iodine supply of a country with modern food nism is the quantity of iodine. At a critically low iodine supply, all
technology versus that of a predominantly agricultural, less devel- functions of the thyroid gland are accelerated. inversely, at a fixed
oped country.’ In the industrialized countries, milk and dairy pro. excessive iodine intake, all processes in the thyroid are slowed
ducts, and bread and bakery products are the most important down or chronically modified, depending on the duration of abnor-
nutritional sources of iodine (as discussed later in this chapter). mally high iodine intake.
The younger control system is geared to maintaining a normal
concentration of free thyroid hormones in the bloodstream. The
Iodine Requirements
function of the thyroid is similar to that of a thermostat, for it
As an essential constituent of thyroid hormone, iodine is an in- interrelates the concentration of free thyroid hormone in the serum
dispensable ingredient of human and animal nutrition. The nutri- with a secretion of the pituitary thyroid stimulator (thyrotropin,
tional need of iodine is influenced by growth, body weight, sex, TSH) and the thyrotropin-releasing hormone of the hypothalamus
age, nutrition, climate and disease. The iodine requirement was (TRH).
determined by several methods, and estimates differ considerably. Both control systems, the iodine and the TSH, probably regulate
‘ In many individuals living in a goiter-free area, the average urinary the intermediate metabolism of the thyroid cell mostly via the
excretion of iodine was about 150 tJ.gper day.19 The mean thyroidal adenyl-cyclase-cyclic adenosine monophosphate (AMP) system.
uptake of stabile iodine was 72 r?:48 pg per 24 hours as determined Their effects are complementary under physiological conditions.2’
by neutron activation analysis.2” Absorptiot? of loditw from Food. After ingestion, iodine is reduced to
The daily requirement in adults is placed at about I to 2 pg per iodide, and within an hour it is quantitatively absorbed from the
kilogram of body weight. An iodine intake between “a minimum of small bowel. Iodotyrosines, iodothyronines, some short-chain io-
50 kg and a maximum of 1000 pg” is considered to be safe.” The dopeptides and radiographic iodinated compounds are absorbed
i980 U.S. recommended daily allowance (RDA) for iodine is in the without deiodination. Iodine in all inorganic compounds and many
range of 40 to 120 pg for children up to age ten, and 150 kg for older organic compounds is bioavailable.
children and adults. An additional 25 pg and 50 Kg are recommend- Utilization of Iodine by the Thyroid. The utilization of iodine for.
ed during pregnancy and lactation, respectively.22 secretion of thyroid hormone proceeds by three steps. First, fromi
the plasma across the cell membrane is an active process against+
electrical and mass gradients. The normal concentration of iodide in
The Thyroid Gland: Structure and Function the thyroid cell is 30 to 40 times higher than that in the serum.
The normal human thyroid weighs about 0.3 g per kilogram of Second, at the interface of the cell and the colloid, a peroxidase
. -. is
1 instrumental in oxidizing iodide into an “iodine-intermediate.” the
body weight, or 20 to 25 g in adults. The thyroid, a storage gland,. ’
has an iodine content of about 8.0 to 10.0 mg per 20 g gland. enzyme also facilitates the formation of monoiodotyrosines and
Approximately 95 percent of thyroid iodine is bound to thyroglobu- diiodotyrosines by incorporating iodine into the tyrosyl residues of
Iin. About 45 percent of thyroidal iodine is in the form of thyroxine, thyroglobulin. The subsequent oxidative coupling of iodotyrosines
and 3 percent is in the form of triiodothyronine; approximateIy42. into the thyroid hormones, thyroxine (T4) and triiodothyrnnine
:; (TX),is also carried out by the same peroxidase, possibly in coopera-
percent is in iodotyrosines.
The thyroid structure and function are regulated bv two inted! tion with another enzyme. Finally, thyroglobulin is engulfed by the
lated systems. The phylogeneticaliy older regulator 16iodine itself{ Cytoplasm of the thyroid cells. The digestion of thyroglobulin is
lts purposes are the homeostasis of thyroid hormone sc.cretion a$ accomplished by proteolysis. The secretory phase ends by diffusion
the prc%Y’vation of optimal iodine reserves in the f(lrm of the hormones into the capillaries via extracellular space.2”
SYb MA r OVlNOVrC IOOlNf 597 *

Thyrord Hormones cspcxxally with rodlne inlak, the avcrag:e is about 30 ml per mlnutc.
About 80 to 90 pg of T., and 10 to 20 pg oil‘, are bccreted daily into Therefore, in adults, the dally thyroidal uptake IS about 70 ~g and
the bloodstream The simultaneously liberated iodotyrosineb are the urinary clearance is 144 pg. Finally, about 55 kg I per 24 hours
dc-iodinated rn the thyroid, and iodine is returned to the thyroIdal enters into this compartment after degradation oi thyroid hormone
pool for reutilrzalron. in the tissue. Thus, the I - input and output of this compartment are
Most T, in the serum is bound to thyroxine-bindlng globulin. The well-balanced.
normal serum levels of T, and T3 are 8.6 t- 0.5 pg and 128 L 6.7 ng T/lqroidn/ Or<qorriclodrrw (TI. The iodine concentration is about 400
for 100 ml, respectively. During the passage in blood through the Fg per gram wet thyroid tissue; a 20-g thyroid contains about 8 mg
liver, about 50 percent of T, is deiodinated to T,, and a very small iodine. A small fraction of iodide (1 to 2 percent) is not accounted
amount is deiodinated to physiologically inactive reverse T, (rTJ). for. The thyroidat fractional uptake from the inorganic iodide pool
Significant amounts of T4 and T, are also enzymatically bound to is measured with “‘I and varies with the pool size of inorganic
glucuronate and sulfate, respectively, and thus are excreted in the iodide and thyroid activity. In this modei, it represents 32.7 percent
bile. The T, glucuronate and Tj sulfate are hydrolyzed in the intes- of the iodide pool. The absolute iodine uptake (AIU) can be calculat-
tine, and most of the T4 is reabsorbed into the blood. After metabol- ed from the urinary iodide specific activity and the plasma radioac-
ic degradations of thyroid hormones, a large fraction of iodine is tivity: AIU = UE/(l -U), where U is thyroidal 13’1uptake per 24
reutilized by the thyroid. hours as a fraction, and E is urinary iodide (12’1)excretion per 24
The primary function of the thyroid hormone is to stimulate heat hours. In this model, AIU = 70 pg per 24 hours or 2.9 pg per hour.
production (by increased oxygen utilization) for the preservation of The thyroid secretes about 70 pg iodine in the form of thyroid
a constant body temperature. In addition, the hormone influences hormone per 24 hours.
Exfrnthyroidnl Orpuic lodirw (B). All thyroid hormones ih tHe .-
the synthesis of protein; during embryonal life and childhood, it
promotes physical and mental growth and development. blood, tissues and enterohepatic circulation belong in this compart-
ment. The average serum thyroxine iodine is accepted as the con--
centration of iodine in this compartment. Because its volume is
Normal Iodine Metabolism about 9.41 liters in adults, the organic iodine pool is about 470 pg.”
The complex multicompartmental system of iodine metabolism Approximately 55 pg of organic iodine (in the form of thyroid hor-
mones) is utilized by the tissue and thereafter is released as iodide
was conveniently simplified and divided into three compartments
by Riggs. I9 4 into the inorganic iodide pool. About 3.1 percent (15 kg) of the
extrathyroidal iodine is excreted per day via bile in the feces.
~~lor&‘fl~~ic~
/CX?I!IC
Corr~~nr~nrcrrt (1-J. After absorption, iodide is dis- ’iI
tributed in the I- compartment, which represents about 35 percent
of body weight (25.5 titers per 70 kg) and consists of plasma, cxtra-
cellular space, ahmentary tract secretions, red cells and the thyroid
gland. The concentration of plasma iodide is considered representa- Endemic and Sporadic Goiter
tive of this compartment (mean, 0.18 pg per deciliter; range, from Clnssific~tio~~ of Thyroid E~llnrgcrrrc~~~f. The Pan American Health
0.04 to 0.57 pg per deciliter). Therefore, the Inorganic iodine pool 19 Organization classification is retained for estimation of thyroid
.,L size.
. .
approximately 98 to 120 Fg. Very little iodide is excreted in It is a slight modification of the system of Perez et at.‘” and 1s
air, perspiration and feces. A little more, 4.5 to 9 ~g per delineated as follows:
excreted In milk. The renal clearance of iodide (40 ml per minute),
Stage O-A: Normal thyroid.
constant over a wide range of plasma iodide concentration. In C
Stage O-B: Goiter detectable only by palpation and not visi-
trast, thyroldal iodide clearance varies with t/lyrolcj activity, a
ble, even when the neck IS fully extended.
Stag! I:
Adaptatton to iodine deficiency is a dynamic process that starts
after a few weeks of negative iodine balance. At first, an increase in
glands, even If not enlarged (see below). all thyroid functions and a slight, diffuseenlargement of the thyroid
Stage II: Goiter visible with neck in normal pasition; Pal- gland, due to hypertrophy and hyperplasia of thyroid cells, repre-
pation is not needed for diagnosis. sent an increased response to the stimulation by the normal amount
Stage III: Very large goiter which can be recognizecl at a of TSH. If that mechanism fails to preserve the normal serum level
considerable distance. of T,, and T’,, an Increase in secretion of TSH wtll further augment
In case of doubt between any two stages, the lower one should be the above compensatory mechanisms. Thereafter, chronic high
recorded. stimulation by TSH will cause a relative increase In secretion of T,
The diffuse or noduiar structure of the thyroid should be record- over Tq, accompanied by continuous, at first patchy and later overt,
ed, because nodules develop in areas of chronic severe Iodine defi- nodular thyroidal hyperplasia in one area, as well as degenerative
ciency. This estimation is independent of the thyroid size, except exhaustion and atrophy of thyroid tissue in another area. The ad-
when nodules are found in a gland of normal size. Then it is record- vantages of relatively higher secretion of T, over TJ are that: 1) T,
ed as Stage 1, because nodules imply a significant change in the contains 25 percent less iodine than does T.+ 2) T, is three to four
thyroid structure.” times more potent than T, and 3) the half-lives of T3 and T, are one
and seven days, respectively. Therefore, the relative increase in
secretion of T, represents a further modality of adaptation to severe
iodine deficiency.
The beginning of iodine deficiency is characterized by a compen-
Endemic Goiter satory increase in excretion of stored thyroid hormone and a normal
AI~~lutc lodirl~ DC~~CW/ICJ/.
Absolute iodine deficiency is the domi- excretion of urinary iodide. As the stores of thyroid hormone con-
nant cause of endemic goiter in the world. The measurement‘of tinue to deplete, the thyroidal clearance of plasma inorganic iodide
iodine in food is difficult, and the 24-hour collection of urine isoften increases, with a commensurate decrease of iodide excretion in the
unreliable. Therefore, the severity of endemic, iodine-deficient goj- urine. After that, the thyroidal uptake of stabile iodide is equal to
ter is classified according to the urinary excretion of iodide in micro- the amount of iodine excreted in the form of thyroid hormone. The
grams per gram creatinine in a casual s ecimen of a representative plasma inorganic iodide Concentration is decreased, as is the thyroi-
sample of the population in the area.2r da1 iodine content. At this time, iodine deficiency either may be
relieved or may progress into a chronic stage. It is during the chron-
Grade I. Coiterendemias with an average of more th?n ic iodine deficiency that the metabolism of iodine is greatly altered.
r*g I- per g creatlnine in the urine. The th) According to the model of Riggs, I9 under conditions of severe io-
hormone supply is adequate for normal phvsical dine deficiency only one-third or less of iodine requirement is sup-
and mental development. plied m food; the major fraction of iodine in the iodide pool is
Grade II. Goiter endemias with urinary excretion bctwe derived from catabolism of thyroid hormone. Therefore, the plasma
an average of 25 to 50 pg iodide per gram crea inorganic iodide Concentration is less than 4.7 pg per liter, and the
nine. The secretion of thyroid hormone may IJ inorganic iodide pool is very small. Because the renal Clearance of
be adequate, and these individuals are at risk iodide is cunstant, the urinary excretion of iodide, under conditions
hypothyroidism, but not of overt cretinism. of low serum iodide Concentration, is also very low.
Grade 111. Goiter endemias with an average urinary exa
tion of iodide below 25 pg per g creatinine. fi Conditioned Iodine Deficiency
population is at serious risk of crctinisni.27 .’
Under c(jndltlons of equal iodine suppty or action of goilrogens.
.theage, sex, hodv build and functions, ‘,\swellas geneticnbnormali-
600 601 .
MlilOVlNOv~c IOOINF

tics or acquired disorders, can contribute to a higher prevalence and Furthermore, natural goitrogens arc probably the dominant
larger size of goiter in certain individuals. The most important are
causeof goiter in some localitres where iodine intake ISabundant. In
increased requirement for thyroid hormone and mild genetic drsor- 1963-64, Indian Creek, Kentucky had a goiter prevalence of 33.1
ders of the thyroid.
percent. Simrlarly, in Richmond County, Virginia, goiter preva-
Some fast-growing children, as well as some pregnant and lactat-
lence in school children was 29.0 percent; the average daily iodine
ing women, develop goiter due to a relative iodine deficiency pro
intake was 165 to 384 vg per day. Goiter prevalence in children
duced by an increased requirement of thyroid hormone.
drinking artesian waters was 9.8 F 2 percent. In contrast, 28.4 -C
Statistical studies of the prevalence of and freedom from goiter in
2.8 percent of children drinking water from surface springs and
homozygous and heterozygous twins, respectively, suggest that
shallow wells were goitrous. Endemic goiter in school children in 37
genetic factors do affect goiter development. The higher prevalence
communities in the Cauca Valley in Western Colombia belongs in a
of goiter in some families may be partly due to a “lower biological
similar category. After ten to 20 years of goiter prophylaxis with
efficiency” of the thyroid. About 3 to 4 percent of otherwise healthy
iodized salt, the goiter prevalence in school children was 1 to 42
individuals with persistent Wolff-Chaikoff effect manifest an over-
percent, and the average daily urinary iodine excretion was in the
sensitivity to the goitrogenic action of excessive pharmacological
range of 65 to 295 pg. In a prospective study started in 1959, goiter
doses of iodine (discussed later in this chapter). About 30 percent of
prevalence in school children decreased from 82 percent to 30 per-
humans and chimpanzees lack the taste for bitter phenyithiocarba-
cent in Candellaria, but had remained at that level for 15 years; in
mates. In the white race, this taste deficiency can also extend to
Zarza, Colombia only 80 km away, goiter prevalence had decreased
some antithyroid compounds such as methylthiouracil. This anom-
from 16 percent to less than 9 percent.29
aly occurs more frequently in some individuals with either sporadic
Natural goitrogens vary by origin and by their adverse mecha-
nodular non-toxic goiter or with endemic goiter of any type.2n Indi-
nism of action. The most important goitrogenic substances of natu-
viduals with latent Hashimoto’s thyroiditis can develop goiter
ral origin will be briefly mentioned.
when exposed to either mild iodine deficiency or iodine excessI
The tubera and leaves of cassava are the staple source of carbohy-
drates for about 300 million people in tropical countries. During
Processing of cassava, the plant enzyme, linamarase, liberates hy-
Natural Goitrogens drocyanic acid (HCN) from the cyanogenic glucoside Imamartn.
The consumer’s procedures for removal of the HCN from the cas-
Recently Gaitan2 observed a great disparity in goiter prevalence sava dishes are relatively effective. The body’s impressive number
in several neighboring communities in various countries, despite of detoxifying mechanisms change HCN into thiocyanate (SCN - ),
the fact that the severe iodine deficiency was the same (that is, goitrogen under conditions of moderate to severe
urinary iodine excretion of less than 25 pgpergram creatinine). The . SCN- can cross the placenta and can disturb the
<. 1. ~. .L-- -:,,, 1.
fObwing are examples of this phenomenon with respective goiter ‘nsPo rt ot..iodine
.. to tne
” tetus. ir reacnes ~nrrn. *row-
prevdence: I) Alto Ventuary and Bailadores, Venezuela, 5 and 55.8 usion The ratio of urinary SCN - (mg) to It71(Fg) is
percent; 2) Tiom and Mulia, Western New Guinea, 5 and 58.04 ,lable indicator of this goitrogen.
percent; 3) South-West Idjwi Island and North Lake Kivu, Zaire, 5.3 rape and mustard, which belong to the genus Brnssicn
and 54.0 percent; 4) Guangaje, Cumbaya and Pisiculla, 12.4. 16.3 d the fXmi]y of Cruc+rne, are important as foods, feed and condi-
and 26.1 percent, versus Penipe, La Esperanza and Tucachi, :nts. Today these plants are enormously important sources of
51.0 and 54.4 percent in Ecuador. These observations suggest Peseedmea] for animal feed and purified proteins in food, as we]]
iodine deficiency in some areas is only the permissive factor, s rapeseed oil in the food industry.
the natural goitrogens in feed and food are the significant dete The major technical and nutritional problem with roots, leaves
nants in the prevalence and severity of endemic goiter. nd especially seeds of domesticated and wild Crrtcifcrcle is their
602 IOUlNl
603
MATOVIN\IOVI~

high contc~nt of glucosinolatcs, which during processrng of the of the rat, blood-biliary turnover In humans 15generally too small
plant are hydrolyzed by their myrosinase (thloglucohydro!asc EC for such a pathogc’nic mechanism.
3.2.3.2). This reaction releases glucose, sulfate and an aglucon Ino/. Rats fed peanuts develop goiter.. ‘7 Phenolic dcrivates are active
eculc which is further converted into thiocyanatr, nitriles, sulfur goitrogens 111the peanut and in se\,cral similar nuts. An unknown
and isothiocyanates. The allyl-, 3-butenyl, 4-pentenyl-, benzvl., compound in the Persian walnut. similar to soybean, produces a
phenylethyl and 4-methyl-3-butenyl glucosinalates are converic‘i waste of thyroxine in the feces ni the rat.
into isothiocyanates (that is, steam-volatile mustard oils). Some Of The small, seed-pine nuts of the female cones of the pinon are
these isothiocyanates degrade further to thiocyanate ion. More jm. important in the diets of Indians in southwestern United States and
portantly, some isothiocyanate intermediates, also called progoi- South America, The unknown goitrogenic substance inhibits thy-
trins, by spontaneous cyclation form 5-vinyl-2-thiooxazolidones, roidal uptake and organification of “‘1 in the rat. Administration of
also known as goitrins.“OJ The latter compounds are by action and iodine does not reverse the effects.
potency similar to the synthetic thionamide antithyroid drugs.
‘They inhibit both the iodination and coupling processes in the svn-
thesis of thyroid hormone, and addition of iodine to food does &t
relieve their goitrogenic effect.
Disuliides of saturated and unsaturated aliphatic hydrocarbons -.
from sedimentary rock drained by waters into deep wells were iodine Excess in Food and Feed as Goitrogen
identified as the cause for an unsatisfactory reduction of endemic In contrast to all other goitrogens, iodine in large amounts dis-
goiter in Candellaria, in the Cauca Valley, Colombia. Experimcntal- turbs all thyroid functions, starting from the transport of iodine and
ly, the ether-methanol extracts from the charcoal filters kept at the continuing to the synthesis and secretion of the thyroid hormone.
outlets of those wells caused inhibition in rats of thyroidal ra’l up- Iodide in large doses (that is, usually more than 50 mg per day, or
take and synthesis of thyroid hormone; enlargement of the thyroid at serum iodide concentration of 20 t~.gper deciliter) inhibits the thy-
also occurred. roidal transport of ‘3’I-iodide. The thyroid hormone synthesis attall
High goiter prevalence with abundant iodine intake was ob- steps, starting with iodination of tyrosyl residues up to the forma-
I ._ n
serveo In eastern Kentucky.” and northern Virginia,“’ where the tion of TJ and T,, is progressively more inhibited by acute and
drinking water came from shallow wells and was bacteriologically chronic intake of large amounts of iodine. This phenomenon,
polluted. The cell-free filtrates of cultures of E. coli from these wa- known as the Wolff-Chaikoff effect, is persistent in only 3 to 4
ters contained a substance with molecular weight 10’ which had an percent of otherwise healthy individuals, for whom iodine in large
inhibitory effect on the thyroid uptake of I311in the rat.“,‘i doses is a goitrogen. In other individuals, an escape from or adapta-
Soybean, which for 5000 years has been the principle crop of the tion to this mechanism occurs after 48 hours, because of a more
warm and tropical areas of the Orient and today is an important 3 efficient hormone synthesis caused by a drop in intrathyroidal io-I
crop in the United States, was first identified as a goitrogen in rat dine concentration,which in turn is due to a persistent reduction of
the 19%. By adding more iodine to the diet, its goitrogenic efl--. iodide transport into the thyroid cell.‘”
could be eliminated:% Iodine in large doses is the only constituent of food which can
Uptake of ‘3’1 increases in the soybean goiter of the rat. inhibit the secretion of thyroid hormone by preventing hydrolysis
MiddlesworthJh injected “‘I-thyroxine intraperitoneally in the of thyroglobulin. Excess iodine acts directly on the thyroid cell, but
and observed that soybean-fed animals wasted large amoun italso inhibits the normal stimulating effect of TSH on the proteoly-
‘“‘I-thyroxine in the stool. The goiter development in soybeal Sisof thyroglobulin, thus interrupting the secretion of thyroid hor-
rats is secondary to a relative iodine deficiency (I mfi .fq conti nes. Whether excess iodide intake can be a goitrogen in man is at
0.68 mg iodine). Although this type ofgoitrogcncsis I$ characterid sent Controversial.39
*
10DlNf: 605
604 MATOVINOVIC

REFERENCES
Synthetic Goitrogens
J J 0 Orr and I Cerlch Iodrne rn Nulrrl~On A &v’ew 01 fxrsl’ng fnfOrrJlaff0~~ U/2 IO
Some of the syntheticgoitrogens are [‘CBS, fire retardants (PBBs),
1927 Specral Reporl No 123 Medrcal Research Councrl. London 1929
organochlorine insecticides (DDT, DDD and Dieldrin), fungicides 2 p Rrchler Wer Hal Zuersi Dre Spongra Usla Gege” Kropl Emphohlen Arch Klrn
(ethylenbidithiocarbamates, EBDCs), bacteriostatic agents (sulfa,,. Ch,’ 82 951 952 1907
amides) and antibiotics (tetracyclines).” 3 J van Schroeder Dre Endeckung des Jods Gba Zfschr 10 4342-4434 1949
The first three groups of goitrogens act mostly by inducln2 the 4 w Proul Chem’sfry Mereorology and /he funcl’on Of D’gesf’on W Prckerrng.
.a _.. . . London. 1934
rnyroxme urldme dlphosphate (UPD) glucoronyi transferase acti\,-
., I .1 1. -. 5 J D Corndet Nouvelles Recherches sur les Eflels de Mode, et sur LeS PreCau-
jr)’ 01 me Ilver. 1 his XtlVity leads to an excessive biliary excretion of rrons a Survre dans le Trarlmenl du Gortre par ce Nouveau Remede Ann de
T,-glucuronate in the bowel which is beyond the capacity of intesti- Ch’m e/ Phys Paw.) 16 2.52-266. 1821
nal reabsorption of thyroxine. The high fecal loss of thyroxine re- 6 J Ma1ovrnovrc. M A Chrld. M Z. Nlchasman and F C Trowbrrdge rn Endem’c
sults in the lowering of serum level of thyroxine. In a servo- Go,/er and Crer’n’sm Con/ruing Threa/s lo World Heal/h J T Dunn and G A
MedcrroS.Neto. Edrtors. Scren(rfrc Publrcairon No 292. pp 67-94 f’an Amercan
mechanism type of reaction, the pituitary, sustained bv the
Health Organrzatron. Washrngton DC, 1974
hypothalamic TRW, augments the excretion of TSH which & turn 7 C Hwmrken and f 0 Wood tn Endemrc Gorier and Endem’c Cre/!‘?‘sm J B.
stimulates simultaneously an increase in function and size of the Stanbury and 6 S Hetzel. Edrlors. pp 497-506 J Wrley and Sons. fnc New York.
thyroid gland. Concurrent severe iodine deficiency or abundant 1980
SUPPIY of iodine, respectively, can increase or prevent the goitro- 8 D Koutras, J Malovinovrc and R Vought rn Endemic Golfer and Endemrc C&rn-
rSm J 8 Stanbury and B S Hetzel. Edrlors. pp 185-195 J Wiley and Sons. 1°C
genie effect of these compounds. In addition, these chemicals in
New York. 1980
larger concentration can directly damage the thyroid gland. g. W Elkrn- The Thyrord-A Gland in Search of a Functron Perspecf Brol Med 22
The fire retardants (PBBs) and the organochlorine insecticides 19-30. 1978
disturb the iodine metabolism and produce goiter in essentially the 10 F C Kelly and W W Snedden in Endem’c Go’rre WHO Monog’wh. Se’ 44. PP
same way as the KBs. The fungicides in question, under the influ- 27.233 World Health Organrzalron. Geneva. 1960
11 H T Suzukr, K Htgucht. K Sawa. S Ohtaki and H Horiuchr. Endemic Coastal
ence of heat, are degraded to ethylenthiourea, which like thiona-
Gorcre rn Hokkardo. Japan Acfa EndOWnO/ (Kbh) 50 161-176. 1965
mide inhibits iodination and coupling of iodotyrosines. The 12. J Malovrnovrc and F L Trowbridge ‘n Endem’c Go’rer and Endemic Cre/‘nkm
sulfonamides are similar to thionamide goitrogens, but are less J B Stanbury and t3 S Hetzel. Edrlors. pp 37-67 J Wiley and Sons. InC New
potent. Their effect, however, is increased in the presence of iodine. York. 1980
The tetracyclines act as antithyroid agents because they specificall 13 w.C Mrller. iodrne M’nera/ Yearbook 1 471-474. 1g65
14, w J wet-,,,(,,-,TowardsCleanerWaterS&dies 1” TO,riCSubStances and Other
disturb the coupling of iodotyrosines. ~~~~~~~~~~~ J Wei, Editor. “01 3. pp 26-33 Research News. University Of
Mtchrgan. Ann Arbor. 1978
15 R Sonsregarda”d J F Leatherland The EPrzoorrologY and Pathoge”es’s Of
Thyrord Hyperplaslarn Coho Salmon (OnoCOrhY”chus KrSu’Ch) ‘” Lake on’a”o
Summary Cancer Res 36 4461.4773. 1976
16. C A[{en.Rowland. V D Castracane and J Serfter rn Programs and AbS’raCfS ”
Iodine is essential for the biosynthesis of the thyroid horm fhe Endmnne Socrery P 301 The Endocrrne SK’elY. Anaheim. 1g7g
The RDA is 2 clg per kg body weight in adults and somewhat 17. I J S&k&f and H A Anderson A Survey Of the Geneva/ POw/a/‘On Of M’ch’gan
for Heallh E&c/s Of POlybrom’naled Bipheny/ ExWsure Ref~ofl lo the Depart-
in children. Endemic goiter caused by iodine deficiency is a ment of p,,b~,~ Health. Sept 30. 1979. Envrronmenlal Scrence Laboratory Mt.
wide problem. Public health policy should ensure optimal i SinaiSchool of Medrcrne. New York. 1979
intake throught the world. The prevention of both iodine d&cl 8. .I K S~ross I A Smokier, J !SbrSler and K R Wrlcox The Human Heaflh Effecls of
and excess, combined with prevention of effects of natural Exposure to Polybromr”a\ed Brphenyls J roxrco/ APP’ Phafmaco’ 58 ’ 45-1 5o.
1981
synthetic goitrogens, should be a continuing public health ga
. D.S Riggs Ouanlrralrve Aspectsof lodrne Melabolrsm rn Many Pha’maco’ Rev 4
264.370. 1952
GOti MATOVINOV~C

42
20 H N Wagner. Jr W l3 Nclp and J H Dowllng Use of Nculron Acllvallorl Arl+s,s
lor Sludyrng Slab& lodrne Mc~abolrsm I” Man J Clrn Invesf 40 1984 !gyz FORHtST H NIELSEN
1961
2 I /oilme Mmfure m lbe Unded Sfafes Summary 01 a Conlcrence Oci 3 i 1970 p
ClIUplCI WALTER MERTZ

51 Food a”d Nulfrllo” Board Nar!o”al Academy of Sciences. Washl”glo” DC


1971
22 Food and Nulrriron Board. Nafronai Research Councti
Allowances
Recommended
Nlrllh Edrlron. PP 14 7- 15 1 Narronal Academy of Sciences
D,elary
Wash,“g.
Other Trace Elements
IO”, DC. 1980
23 S H f”gbar Auforegulalron of Ihe Thyrord The Response lo lodlde Excess a”d
Deplellon Mayo Clrnrc Proc 47 814.823. 1972
24 C J DeGroof and J f3 Slanbury The Thyrordand 11s&eases. Fourth Edlllon pp
37-109 J Wrley and Sons. Inc. New York. 1975
25 S H InQbar ChCal and Physrologrcal Observalrons in a Palrent wrfh ldropafh,c
Decrease rn Thyrosrne~Brndlng Globultn 01 Plasma J Clrn lnvesf 40 2053.2063,
1961
26 C Perez. NJ Scrimshaw and J A Munoz in Endemrc Gortre Pp 369.376 WHO Evidence for the essentiality of molybdenum first appeared
Monograph Ser No 44. Geneva. 1960 in 1953 when xanthine oxidase was identified as a molybdenum
27 A Ouefrdo. F Defange. J Dunn. R Fletro-Bendez. H K. Iberlson. 0.~ KoulraS
metalloenzyme.’ Reports suggesting that arsenic, cadmium, lead,
and H Perinel(l I” Endemrc Golfer and Crelrnrsm Confrnuing Threat to wo,/d
Heaffh J T Dunn and G A Medcrros-Nero. Edllors. Scienrrlrc Publrcafion No 292, nickel, tin and vanadium are essential have appeared since 1970.
p 267 Pan Amerrcan Heallh Organrzafron. Washrnglon. DC. 1974 Those relating to cadmium, lead and tin have come from one labora-
28 D A Koulras In Endemrc Golfer and Endemrc Crelrnism J B Sfanbury and 6 S tory,2 however, and have not been confirmed by others. Dietary
Hefzef. Edrlors. pp 25.5268. J Wiley and Sons. Inc. New York. 1980 supplements of cadmium, lead or tin improved the growth of sub-
79 E Galran in Endemrc Gor/er and Endemic Crerrnrsm J E. Stanbuty and B S.
optimally growing rats slightly, but did not give optimal growth;2
Helzel. Editors. pp 219-236 J Wiley and Sons. Inc New York, 1960
30 C Ii Van Ellen In TOXC ConsWenfs of f’lanl foodsfuffs I E Lrener. Edrlor. pp - the evidence of a growth effect was not confirmed independently.
103.134 Academic Press. New York. 1969 Nielsen critically reviewed those findings and concluded that on the
31 C H Van Etten and I A Wollf in Toxicants Occumng ,n foods Second Edition. basis of present knowledge, cadmium, lead and tin should not be
Publication No 73. pp 210-234 Narronai Academy of Sciences,Washlnglon. included in the list of essential trace elements.3 For those elements,
DC. 1973
the evidence did not fulfill the requirements for essentiality as de-
32 W T London. DA Koulras. A Pressman and R L Vought. Eprdemloloqc and
Metabolrc Sludres of a Gorier Endemic cn Eastern Kentucky J C/in Endocrind.
fined by Mertz4 Thus, the following discussion will be limited to
Mefab 25 1091-1097 1965 aspects of arsenic, molybdenum, nickel and vanadium nutrition.

Virgrnra J Ch Endocrrnol Melab 27 138 I 1389. 1967


34 E Gailan. P Medina. T A De Rouen and M S Zra Gcrfer Prevalence a
r!al COWmflallOfI Of Waler J c/m Endocnnol Melab 51 957-961. Arsenic
35 R L Voughl. f A &own and K H Srbrnovrc Anlrfhyrold Compound(s)
by Escherrchra co/r Prelrmlnarv , Renorf
.r-. .I_ Cfrn
-.. _Fnrfocrrnol
--- Melab 38 Mcfnl~lisrl~. Absorption, retention and excretion of arsenic are
1974 influenced by the chemical form and level in which it is ingested.
36 L-ban MIddlesworth. Re-Evaluation of &tarn Aspects .__01 lodrne
.- Melabdi+j Rats, unlike other mammals, concentrate arsenic in their blood’dnd
Ret Progr Hormone Res 16 405.431, 1960 appear unique in the metabolic management of arsenic. Thus,
37 V Snnrvasan. N R Moudgal and P S Sarma Sfudres on Goltrogenrc Agents ’
metabolic findings from rats may not be applicable lo other species.
Food J Nufr 61 87-95. ?957
_- . . . ,,I
ja J WON loalne-boiler
^
and the Pharmacologrcal Effects of Excess fOa’“e n’rr All forms of arsenic are well-absorbed. Organo-arsenic. however,
Med 47 101-124. 1969 may be less well-absorbed than is inorganic arsenic.
,r Human . sub-.,
39 J Matovlnovx In Annual Revrew of Nufrrfron W J Darby. H P BroQulsf a ingested tissues Of chickens Ited arsanillc-’ *As acid rapidly
Olson. Edllors. vol 3. pp 341.412 Ann@ Revrews Inc Palo- Alto. Ca
607
Paper

EFFECTS OF TIME OF ADMINISTIQiTIQN ,4NP DIETARY


_^.‘ ,-. . ~,.. _~,_
IODINE LEVELS ON POTASSIUM IQIlJIjE (KI) BLOCKADE OF
THYROID IRRADIATION BY 1311FROM
RADIOACTIVE FALLOUT

Pat B. Zanzonico* and David V. Becker1


only when admhistered within 2 d before to -8 h after tadioic+
ti~h7d-Radl0i0din~ padcuhrly V, may be tvkaaed Into the dine intake.
emlmmnent in bmach-of-containment nuclear raactor “.“.,acddents He&h Phys. 78(6):660-667; 2000
and~ioaM1irradiatethethyroidwithPnattendantriskof Key words: “‘1; dosimetry; thyroid; fallout
neoplab growth and other adverse be&b effects. Pbammc+
logkthyrddblodmdebyo potassiumlodlde(Kl)(50-1oOmg
in aduljs) am substantjally uce thyroid uptake of andirtadi-
ationbyin- radi 3 odbxIntbecurrentanalys&cam-
INTRODUCTION
putermoddingoflodinemetabdismhasbe#nusedtosystemat-
&ally eluddam tbe effects of two pm&ally important but bi&ly
vadable facton on the radioprutective ei?ect of KI: tbe time of h~olsarop~s OF ipdine iye, produced in abundancein
zdmh&dbrelativetoexposuretoradldodiwandthe~etary fissionreactions,andsignificantamountsof radioiodinecan
level of iodh In euthyroid adults recelvlng iodim+mMdent diets be releasedinto the environmentin breach-of-containment
(2SOCrgd-‘lnthe current anal@), Kl admMsteredupto4Sb nuclear reactor accidents.The potential adverse health
before uLI expotwe am almost completely block tbyroid uptake effectsof environmentallyreleasedradioiodineslie in the
and therefore greatly reduce the thyroid absorbed dose. HOW- fact that iodine is readily absorbed into the circulation
ever, KI zxdmi&btioo 96 b or more before nlI exposure has no
sign&ant protective effect In contrast, KI admhMration afir
following ingestion or inhalation, rapidly concentratedby
z ~~oi~,L”d”ces a smaller and rapidly decreasing and stored in the thyroid, and only slowly secretedin
dnunishtioo 16 h or later after ulI exposum org@ied form as thyroid hormones resulting in high
will have little effect on thyroid uptake and absorbed dose and thyroid absorbed doses. Thyroid irradiation at sufficiently
therefore little or no protective effect. The 13*1thyroid absorbed high absorbeddosesfrom internally depositedradioiodine
dose is two-fold greater with imuflldent levels of dietary lodine, can causethe late appearanceof thyroid nodules and/or
Zgoo cGyL37 MBq, than with sufficient levels of dietary iodine, cancer(NCRP 1985)and,at higher absorbeddoses,destroy
1,500 cGy/37 MBq. When KI ls adminlsterad 48 h or less before follicular cells and therebyinduce hypothyroidism(Wolff
WI1 intake, tbe thyroid absorbed doses (in cGyB7 MBq) are 1980).Following the Chernobylnuclearreactoraccidentin
comparably low with both suffident and insuffldent dietary 1986,for example,an early and dramatic increasein the
iodine levels. When KI is admhdstered after lJII intake, however,
the protective effect of KI is less and decreasesmore rapidly with
incidenceof pediatricthyroid cancerensuedin Byelorussia
Insufficient thao with stiden$.dietary iodine. For example, KI
and Ukraine, presumably as a result of environmental
. .
adnnmstm tion 2 and 8 h after ‘)‘I intake yields protective effects dispersion and ingestion and inhalation of radioiodine
of 80 and 40%, respectively, with iodlne-suffldent diets, but only and,in particular,r3’I (Astakhovaet al. 1998;Baverstocket
65 and 15% with iodlne-de6cient diets. In concl~on, whether al. 1992;Beckeret al. 1996;Goslings1989;Kazakovet al.
exposed populations receive suifident or insuftldent dietary 1992;Sobolevet al. 1997;Williams 1996).
iodine, oral Kl is an effective means of reducing thyroid lrradi- Radioactivefallout in the immediatevicinity of the
ation from environmentally dlspemed radioiodine but is effective reactor,the so-callednear-field,is introducedinto the body
predominantlythroughinhalationbut alsois depositedupon
vegetation,which is consumeddirectly asfood or indirectly
* Nuclear Medicine Service, Memorial Sloan-Kettering Cancer by consumingmilk from cows that have grazedon radio-
Center, 1275 York Avenue, New York, NY 10021; + Division of actively contaminatedfodder. At later times and greater
Nuclear Medicine, New York Hospital-Cornell Medical Center, New distances,ingestionis the primary pathwayinto the body
York, NY.
For correspondenceor reprints contact: P. B. Zanzonico.Nuclear (Becker 1987;Eisenbudand Wrenn 1963;Holland 1963;
Medicine Service,Memorial Sloan-Ketig CancerCenter, 1275York Zanzonicoand Becker 1993).
Avenue, New Yck. NY 10021,cf email al &wnip@mskcc.org. There are 24 isotopes’of iodine, “‘1 to ‘@I, all of
(Manuscript received 24 August 1999; revised manuscripfre- which except ‘*‘I are radioactive. Although 1321, “‘1, l”41,
ceived 9 December 1999. accepred 3 February 2ooO)
cO17-9078/0010 and i3? are actually producedin greateryields than 1311 in
Copyright0 2ooOHealthPhysicsSociety thermal neutron fission of 23slJ(Holland 1963),thyroidal
Dietary iodine and Kl blockadeof “‘I irradiationof the thyroid 0 P. B. ZANZONICU
ANOD. V. BW.KER 661

II. ‘ation off-site following breach-of-containmentnu- Stemthal et al. 1980; Wolff 1980). The time of admin-
F reactor accidentsis ascribedalmost entirely to 13’1
@ause of its relatively long half-life (Holland 1963).
istration of the KI relative to radioiodine intake is the
critical determinantof effectivenessof blockade,with KI
p current analysis IS therefore restricted to 13’I. administration coinciding with radioiodine intake provid-
Most reactor accident scenarios are envisioned as ing the greatest protective effect, that is, the greatest
&eloping over many hours, providing some time to reduction in thyroid uptake of and irradiation by radio-
hplement protective actions to reduce intake of radio- iodine (Blum and Eisenbud 1967; Il’in et al. 1972;
hlides. Sincethe initial near-field exposureis primarily Lengemannand Thompson 1963; Stanbury 1990; Zan-
bugh inhalation, air filtration, sheltering, and evacua- zonico and Becker 1993).Practically, however, given the
$onare particularly important early protective measures. vagaries of environmental release and dispersion of
$ven minimal respiratory protection with a moistened radioiodine in breach-of-containmentnuclear reactor ac-
&&kerchief can filter out some particles and signifi- cidents, it is probably impossible to time KI administra-
&tly reduce inhalation of radioactivity. Sheltering, tion to coincide exactly with radioiodine intake.
&ich includes closing of windows, doors, and ventila- Besides the time of KI administration relative to
ftonsystems,canprovide non-disruptive protection when radioiodine exposure (Zanzonico and Becker 1993), the
&osure is expectedto be of short duration In high-level effectivenessof KI blockadeis affectedby dietary levelsof
br continuing releases,evacuationof populations in the iodine.For the purposesof the currentanalysis,restrictedto
immediatevicinity of reactor accidentsmay be prudent. euthyroid adults,a dietary intake 100pg d-l lessthan and
Interdiction of contaminatedfoods, particularly milk and greaterthanthe recommendeddietary intakeof 150 pg d-’
water,can be immediately effective in preventing inges- (NRC 1989)was defined as iodine deficiency (50 pg d-l
tion of fallout. Radioiodines can appear in cow’s milk overall) andiodine sufficiency(250 pg d-’ overall), respec-
within 5 to 10 h of ingestion of contaminatedfodder, tively. In the current paper,computermodeling of iodine
with peak concentrationsby 36 to 48 h post-ingestion metabolismhas been used to systematicallyelucidate the
(Becker 1987; Zanzonico and Becker 1993). effectivenessof thyroid blockadeas a function of dietary
In addition to the foregoing physical measures,a iodine statusas well as of the time of Kl administration
numberof biologic measurescaninterferewith the absorp- relative to radioiodineintake,
tion andinternaldepositionof someradionuclides.Phanna-
cologic thyroid blockadeby oral potassiumiodide (KI) is MATERIALS AND METHODS
perhapsthe mostefficient and practicalof theseprotective
measures(Becker 1987;Beckeret al. 1984;NCRP 1977; Compartmental model of iodine metabolism
Robbins1983;Rubery and Smales1990;Stanbury 1990; Whole-bodyiodine metabolismwas simulatedusing
VanMiddlesworth 1987; Zanzonico and Becker 1993). the compartmentalmodel in Fig. 1 and Berman’s SAAM
Iodine is rapidly and completely absorbedby the upper program(Bermanet al. 1%2; Bostonet al. 1981).In Fig. 1,
gastrointestinaltract within 30 to 60 min of ingestion, PBI, or protein-boundiodine, correspondsto circulating
Inhaledradioiodiies reachequilibrium in the blood within thyroid hormone. This standard model is essentially a
about30 min. Iodideis rapidly concentratedby the thyroid simplificationof thedetailedmodelof Bermanet al. (1968).
with maximum accumulationreachedby 36 to 48 h in Using the analytic fit of Blum and Eisenbudto their
euthyroidindividualsreceivingsufficientdietary iodine. In measurementsof suppressionof the 24-h thyroid uptake
iodine deficiency,uptakeis morerapid, and a higher peak of i311as a function of serum concentration of iodide
uptakeis reachedearlier,at 12to 24 h. Intrathyroidaliodine (Adams and Bonnell 1962; Blum and Eisenbud 1967;
is slowly secretedinto the circulationin organicform asthe Ramsdenet al. 1967),the following formula relating the
thyroid hormones,tetra-iodothyronine(T3, thyroxine), and iodide-to-thyroid exchange rate to the serum iodide
tri-iodothyronine(T4). The biologic half-life of the organi- concentration was derived and used in the foregoing
lied thyroidal iodine is 60 to 100 d. Becauseof its rapid compartmentalmodel (Zanzonico and Becker 1993):
uptakeand long retention,the radioiodinethyroid doseis k(thyroid,iodide) = 0.37k(thyroid,iodide),&dide]-0,9
proportionalto theuptake(Bermanet al. 1968;Wolff 1980; (1)
Zanzonicoand Becker 1993;Zanzonicoet al. 1995).
Potassiumiodide, given in adequatequantities (50- where
100 mg in adults) at the appropriatetimes, can almost &thyroid, iodide) = the iodide-to-thyroid exchange
completelyblock thyroidal uptakeof radioiodide (Becker rate (h-l);
1987;Becker et al. 1984; Il’in et al. 1972; NCRP 1977; &thyroid, iodide), = the maximum iodide-to-
Robbins 1983;Rubery and Smales1990;Stanbury 1990; thyroid exchange rate (h-l);
Stemthal et al. 1980; VanMiddlesworth 1987; Wolff that is, the theoretical iodide-
1980; Zanzonico and Becker 1993). Although the pre- to-thyroid exchangerate (h-l)
dominantmodeof action is not well established,several at a serum iodide concentra-
mechanismshavebeenpostulated.Theseinclude isotope tion of zero,
dilution, saturation of the iodide transport mechanism, = 0.0456 h-l; and
interferencewith intrathyroidal organification of iodide, [Iodide] = the concentration of iodide in
and inhibition of hormonerelease(Dumont et al. 1990; serum (PgIl 00 mL).
662 Health Physics June2OGQ.
Volume 78, Number6

D&e Committee (MIRD) of the Society of Nuclear


Sumient: 250ughy Medicine (SNM) (Loevinger et al. 1991; Zanzonico et al.
Deficient:50 q/day 1995). The DOSCAL program (Sgouros et al. 1988). a
I computerizedversion of the MIRD formalism, was used
in the current analysis.
For internal radionuclidesin generaland radioiodine
in the thyroid in particular, self-irradiation accounts for
nearly the entire absorbed dose to any given target region
0.0005h I primarily because of the contribution from particulate
t I
radiations (such as beta-rays).Beta-rays are assumedto
be completely or almost completely absorbed in situ
sincethe dimensionsof humanorgansare typically much
Sufficient: 0.000137htr greaterthan the rangesin tissue of particulate radiations.
Deficient: 0.0013h The thyroid absorbeddosemay be equatedwith the mean
self-irradiation absorbeddose (Zanzonico et al. 1995):

1 D(thy) = b(thy+thy) (2)

O.O071/hr
= AthyS(thy+--thy), (3)
PBZ where
,’ I J &thy) = the meanabsorbeddoseto the thyroid;
@thy+thy) = the mean self-irradiation absorbed
Fig. 1. Simplified whole-body compartmental model of iodine dose to the thyroid;
metabolism. Inter-compamnent exchange rates are indicated. in- &,r = the cumulated activity in the thyroid;
cluding the iodide-to-thyroid and thyroid-to-PBI (protein-bound and
iodine) exchange rates for iodine suffkiency (250 pg d-l) and
deficiency (50 pg d-l). The clearance exchange r&e from the S(thy+thy) = the thyroid-to-thyroid S factor
iodide compartment, 0.08 h-l, corresponds to urinary excretion. = 22 cGy137Mbq h-’ for 13’1in the adult
20-g thyroid.
As noted, an inhaled and/or ingested activity of 37
Using eqn (I), the model is quantitatively adaptable MBq (1 mCi) of “‘I was assumed for the current
to the entire range of dietary iodine levels, from defi- analysis.
ciency (assumedto correspondto 50 pg d-’ ingested)to
sufficiency (assumedto correspondto 250 @gd-’ ingest-
ed), and to KI blockade (correspondingto oral adminis- Protective effect
tration of 100mg of KI). The pertinent concentrationsof The reduction in thyroid irradiation achieved with
iodide in serumwere determinedusing the compartmen- oral KI blockade’was expressedas the “protective ef-
tal model in Fig. 1 to determinethe steady-stateamount fect,” defined below (Il’in et al. 1972):
(in Fg) of iodide for a daily intake of 50 or 250 pg and
a ReferenceMan serum volume of 3,000 n-J+(ICRP Protective effect
1975).
Thyroid absorbeddose without blocking
Thyroid cumulated activity - Thyroid absorbed dose with blocking
The time-dependentradioiodine activity and the E Thyroid absorbeddose without blocking
resulting cumulated activity in the thyroid were esti-
matedusing the foregoing model. The effect of radioac- x 100%. (4)
tive decay was introduced by appending a “clearance” Protective effects were determined and presentedsepa-
exchange rate to each compartment i equal to the rately for sufficient and for deficient dietary levels of
physical decay constant (A,,) of 13’1,k(O,i) = A, = iodine (250 and 50 pg d-l, respectively) and as a
0.00359 h-‘. Assuming an internalized activity of 37 function of time of Kl administration relative to radioio-
MBq (1 mCi), the cumulatedactivity of inhaled/ingested dine intake.
radioiodide in the thyroid was determinedby integrating
the decayed activity in each compartment using the
methodof Sgouroset al. (1987). RESULTS

Thyroid mean absorbed dose In Figs. 2 and 3, thyroid uptake, in decay-corrected


A standard methodology widely used for internal percentageof ingested and/or inhaled activity, is plotted
radionuclide absorbeddose calculations is the “MIRD againstthe time interval between KI administration and
formalism,” developedby the Medical Internal Radiation intake of 13’I; the data in Figs. 2 and 3 have been
Dietary iodine and KI blockadeof ‘“‘I irradiationof the thyroid 0 P. B. ZANZONICO
ANDD. V. BICKER
‘;

: KI administered 24 hr BEFORE **‘I KI administered 2 hr AFTER ()(I


301
9

80%
93%

3. KI administered 8 hr AFTER “‘1


KI administered 72 hr BEFORE *JV

% “‘I 20
Activity
in Thyroid
32% 10

0
KI administered 24 hr AFTER “‘1

KI adminlstered 96 hr BEFORE V
7%
7 Y

1 I Time Relative to ‘“‘1 Exposure (hr)


46 -72 48 -24 a 24 48 72 96
T Fig. 3. Thyroid uptake of radioiodine in percentage of adminis-
1311
tered activity vs. time for different time intervals between a single
Time Relative to 1341Exposure (hr) KI administration (100 mg) and exposure to “‘I for Kl adminis-
tration uj?er “‘I exposure. The top, middle, and bottom graphs
Fig. 2. Thyroid uptake of radioiodine in percentage of adminis- correspond to IU administered 2, 8. and 24 h ujrer exposure to i3’I,
tered activity vs. time for different time intervals between a single respectively. The upper curves (X) correspond to the control, or
KI administration (100 mg) and exposure to ‘“I for Kl adminis- unblocked, time-dependent thyroid uptake; the lower curves (0)
tration before i3iI exposure. The top, middle, and bottom graphs are the corresponding data for Kl blockade. The corresponding
correspond to lU administered 24, 72, and 96 h before exposure to protective effects of KI, related to the crosshatched area between
“‘1, respectively. The upper curves (X) correspond to the control, the two curves in each graph, are specified.
or unblocked, time-dependent thyroid uptake; the lower curves (0)
are the corresponding data for Kl blockade. The corresponding
protective effects of KI, related to the crosshatched area between areas under the blocked and unblocked thyroid time-
the two curves in each graph, are specified. activity curves (representedby the crosshatchedregion
betweenthe curves), are also presented.
Fig. 4 illustrates the differencesbetween sufficient
and deficient dietary levels of iodine in terms of thyroid
calculatedfor euthyroid adultson iodine-sufficient diets. kinetics and the protective effect of KI; in this illustra-
KI administration before i311exposure (Fig. 2) corre- tion, it was assumedthat IU was administered8 h after
sponds to negative time intervals (to the left of the ‘)‘I intake. In iodine deficiency, the model-derived thy-
ordinate axis) and KI administration after i3’I exposure roid uptake rises more rapidly to a higher maximum
(Fig. 3) correspondsto positive time intervals (to the (60%) at an earlier time (12 h) than in iodine sufficiency
right of the ordinate axis). As indicated on the middle (26% at 36 h). As a result of the approximately two-fold
graph in Figs. 2 and 3, the upper curves in each graph higher thyroid uptake, the thyroid absorbed dose is
correspondto the unblocked,or control, time-dependent approximately two-fold greater in iodine deficiency,
thyroid uptake; the lower curves are the corresponding 2,900 cGy/37 MBq, than in iodine sufficiency, 1,400
datafor KI blockade.In Figs. 2 and 3, the corresponding cGy/37 MBq (assumingno significant difference in the
protective effects, related to the difference betweenthe effective half-time of thyroidal radioiodine).
June 2COO. Volume 78. Number6

Fig. 4. Protective effect of KI blocking in iodine sufficiency and


deficiency illustrated for KI administration 8 h ,after exposure to
W. The upper curves (X) correspond to the control, or unblocked.
time-dependent thyroid uptake; the lower curves (0) are the
corresponding data for KI blockade. The protective effect of IU is (W
proportional to the crosshatched area between the two cyrves
expressed aa the fraction of the area under the control thyroid
uptake curve and thus is greater for iodine sufficiency than iodine
deficiency.

Fig. 5 graphically summarizes the effect on “‘I


thyroid uptake (Fig. 5a),,‘absorbeddose (Fig. Sb), and
protective effect (Fig. 5c) of the time interval betweenKI
administration and t311intake and of the level of dietary
iodine. As in Figs. 2 and 3, ICI administration before 13’1
exposure(Fig. 2) correspondsto negative time intervals
(to the left of the ordinate axis), and ICI administration Cc)
after 13’1exposure(Fig. 3) correspondsto positive time
intervals (to the right of the ordinate axis). ICI adminis-
tered up to 48 h before 13’1exposure can almost com-
pletely block thyroid uptake (Fig. 5a) and therefore
greatly reduce the thyroid absorbed dose (Fig. 5b),
regardlessof the dietary iodine level. For example, ICI
administration 24 and 48 h before 13’1exposureyields a
protective effect of 90 and 75%, respectively, in iodine
sufficiency and 95 and 85%, respectively, in iodine
deficiency (Fig. 5~). KI administration even 72 h before Tamsof Kl AdministrationRelative to ‘3’t tntakc (hr)
13’1exposurewill reduce24-h thyroid uptake from 26 to
19% (Fig. 5a) and yield a protective effect of 32% in Fig. 5. Decay-corrected 24-h percent thyroid uptake, thyroid
iodine sufficiency (Fig. 5~). In iodine deficiency, KI absorbed dose per unit activity inhaled and/or ingested (&y/37
administration at this time will reduce 24-h thyroid MBq). and KI protective effect (%) as function of time of Kl
uptake from 60 to 25% (Fig, 5a) and yield a protective administration relative to ‘I’1 exposure for iodine sufficiency ( + )
effect of 55% (Fig. 5~). However,as indicated in Fig. 5c, and iodine deficiency (m). ‘Time “0” represents the time of “‘I
KI administration 96 h or more before ‘“I exposurehas intake.
no significant protective effect (less than 10%).
In contrast, KI administration after exposure to
radioiodine induces still marked but less, and rapidly even less, 15%, in iodine deficiency (Fig. 5~). KI
decreasing,blockade (Fig. 5). Once 13’1is incorporated administration 16 h or later after 13’1exposure will have
into the thyroid, its slow discharge cannot be signifi- little effect on uptake (Fig. 5a) and dose (Fig. 5b) and
cantly acceleratedexcept perhapswith thyroid stimulat- therefore little or no protective effect (Fig. 5~).
ing hormone (TSH), but further accumulation can be Becausethe ‘,*I thyroid absorbeddose is essentially
blocked by ICI. KI administered up to 2 h after 13’1 proportional to ‘the 24-h thyroid uptake, the curves
exposure can almost completely block thyroid uptake representingthe 24-h thyroid uptake(Fig. 5a) and the “‘I
(Fig. 5a) and therefore greatly reduce the thyroid ab- thyroid absorbeddose (Fig. 5b) as functions of the time
sorbed dose (Fig. 5b), yielding protective effects of 80 of KI administrationrelative to 13’1exposureare parallel.
and 65% in iodine sufficiency and iodine deficiency, Note that.the 24-h thyroid uptake (Fig. 5a) and therefore
respectively(Fig. 5~). However, later Kl administration, the 13’1thyroid absorbed dose (Fig. 5b) for iodine
even as soon as 8 h after ‘)‘I intake, will only modestly deficiency are always greater than or equal to the
reduce uptake (Fig. 5a) and dose (Fig, 5b), yielding a correspondingvalues for iodine-sufficient diets. As fur- -
protective effect of only 40% in iodine sufficiency and ther indicated in Fig. SC, for Kl administered before
Dietary iodine and ICI blockade of 9 irradiation of the thyroid 0 P. B. ZANLONICO AND D. V. BW~;EH 665

xposure to 13’1,the protective effect is greater in iodine showed that 10 mg of Kl given in a single dose
eficiency than in iodine sufficiency, and the earlier IU is simultaneouslywith a tracer of radioiodine will decrease
dministered before i3’I intake the greaterthe protective uptakefrom 25 to 16%of control and thus provide a 35%
ffect (as discussedabove). However, when KI is admin- protective effect. However, KI in amountsof 30 mg or
steredafrer Is’1 intake, its protective effect is less and more will reduce the 24-h uptake from 25 to 1% and
&eases more rapidly in iodine deficiency than in provide a 95% protective effect. Although 100mg is only
odine sufficiency. For example,KI administration 2 and slightly more protective than 30 mg, there are substantial
I h after is’1exposureyields protective effects of 80 and pharmacokineticadvantagesto a larger amount: it will
K)%,respectively, in iodine sufficiency, but only 66 and provide an elevatediodide blood level, which is directly
.7%, respectively, in iodine deficiency (Fig. 5~). relatedto both blocking effectivenessand the duration of
effect. The US. Food and Drug Administration has
DISCUSSION recommended100 mg of iodide (130 mg of KI) as the
“standard” adult dose. The recommendeddose for chil-
The results of the current model-basedanalysis are dren is 65 mg. This is the sameorder of magnitude as
lualitatively and quantitatively similar to the experimen- Poland’s selection of 70 mg for children ages 2-16 y;
al results of Il’in et al. (1972) in human subjects.These Polandgavechildren from 3 to 12 y 50 mg of iodine and
esults indicate that KI is more effective in reducing the children under 3 received 25 mg (Nauman 1990, 1991).
absorbeddose of i3’I to the thyroid when it is adminis- By these measures, Poland was able to reduce the
:ered prior to or at the same time as ingestion or projectedthyroid absorbeddosesfrom radioactive Cher-
nhalation of the radioiodine (Figs. 2 and 3), and its nobyl fallout by an estimated40% (Nauman 1990, 1991).
effectivenessin iodine deficiency ‘may be comparableto With continuing exposure, it is desirable to admin-
or somewhatgreaterthan that in iodine sufficiency (Fig. ister ICI daily for the duration of the exposure and
5). Since logistical issuessuch as distribution may make perhapsfor several days longer. Continued administra-
administration of KI before or coincidental with the tion of KI, however, may produce significant physiolog-
radioiodine exposure unlikely, the effectivenessof KI ical effects. In the study of Stemthal et al. (1980), most
given following exposure is of considerable practical individuals who received KI in amountsgreater than 30
importance.Clearly, the earlier the KI is given, the better, mg a day for 8 d had a significant fall in serum thyroid
but it is still useful in reducing thyroid dose if adminis- hormone levels. Three of the five subjectswho received
tered up to 8 h and to a lesserextent even 12 h after a 100 mg a day for 8 d had elevated TSH levels and
single exposure to fallout. Importantly, however, the biochemical hypothyroidism. Also noted was a consid-
protective effect is less and decreasesmore rapidly in erable individual variation in responsewhich potentially
iodine deficiency than in iodine sufficiency when IU is could be a major problem in large populations.
administeredafter 13’1intake (Fig. 5~). The World Health Organization (WHO), in their
It is important to note that in the absenceof KI extensive examination of Kl administration (WHO
blockade the 13’124-h thyroid uptakes and absorbed
doses and, therefore, radiogenic risks are two-fold 1989),concludedthat iodide prophylaxis was not gener-
greater in iodine deficiency than in iodine sufficiency. ally justified in the far-field for adults (except for
Accordingly, in the event of breach-of-containmentnu- pregnancy),where the main route of exposureis inges-
clear reactoraccident,KI administrationand the prompt- tion and where embargo of contaminated food can be
ness of administration are actually more important usedto limit the thyroid dose.In the near field, however,
among iodine-deficient than among iodine-sufficient where thyroid dosesin adults as well as children may be
populations. Endemic iodine deficiency persistsin parts high and inhalation the more likely route of exposure,
of Europe, where nuclear power reactors are rather more rapid action is required. Infants, children, and
numerous, and in other heavily populated areas of the adolescentsup to 16 y should be given ICI in both
world (Delange et al. 1993). near-andfar-fields (as was done in Poland).For pregnant
The results of the current analysisapply to a single women in the first trimester, the fetal thyroid is not yet
blocking doseof KI before or after a single exposureto functioning, but in second and third trimesters stable
“‘I With continuing or subsequentexposure to 13’1, iodine should be given to protect both the fetal and
however,the effectsof even a single administrationof IU maternalthyroids. In all cases,administration should be
may still be significant becauseof its persistentthough determinedby projecteddose estimateswhen such pro-
decreasingblockade of uptake for as long as 72 h. For jections exceedthe intervention level for the country and
example, 48 h after KI, there is still a 75 and 87% community involved. The oral dose for adults is gener-
protective effect in iodine sufficiency and deficiency, ally recommendedto be 100 mg of iodide (130 mg of
respectively,and at 72 h a 32 and 56% protective effect potassiumiodide). Neonatesshould have dosesprefera-
in iodine sufficiency anddeficiency, respectively,against bly not to exceed 12.5 mg and children not to exceed50
“new” 13iIexposures(Fig. 5~). mg (NCRP 1977; WHO 1989).
The issue of the optimum oral dosage of KI for Considerableattention has been given to the possi-
thyroid blockade has been addressedby a number of bility of adversereactions to KI, but wide experience
different investigators(Blum and Eisenbud 1967;Stem- prior to Chernobyl has beenli’nited (Becker et al. 1984;
thal et al. 1980; WHO 1989). Stemthal et al. (1980) NCRP 1977; Robbins 1983; Wolff 1985). The primary
666 Health Physics June2000,Volume 78. Numhcr 6

reactionsfrom single or severaldosesof KI given over a Baverstock,K.; Egloff. B.: Pinchera.A.; Ruchti. C.: Williams,
short period have been dose-dependentnon-thyroidal D. Thyroid cancer after Chernobyl. Nature 359:21-22;
effects (Wolff 1985). The greatestconcern, therefore,is 1992.
related to iodine sensitivity, where a small dose may Becker,D.; Robbins,J.; Beebe,G.; Bouville, A.; Wachholz, B.
possibly trigger a pronouncedresponse.Although rare, Childhood thyroid cancerfollowing the Chernobyl accident.
sucheffectshavebeenreportedand include dermatologic Endocrinol. Metab. Clin. North Am. 25197-211; 1996.
reactions (eczema) and sensitivity reactions (edema of Becker, D. V. Reactor accidents. Public health strategiesand
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The experiencein Poland, where 10.5 million chil- Becker,D. V.; Braverman,L. E.; Dunn, J. T.; Gaitan. E.;
German, C.; Maxon, H.; Schneider, A. B.; Van Middles-
dren and adolescentswere given a single doesof 70 mg WOOL L.; Wolff. J. The use of iodine as a thyroidal
of KI, showed reactions to be uncommon (overall blocking agent in the event of a reactoraccident. Report of
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Somewhat surprisingly, the most common reaction in Thyroid Association.JAMA 252:659-661; 1984.
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