ble standards, amnesia, confusion and altered state of

consciousness. Medical iodophobia has reached pan-

The Historical demic proportion, and it is highly contagious (iatrogenic
iodophobia). A century ago, non-radioactive forms of
Background of the inorganic iodine were considered a panacea for all hu-
man ills,2 but today, they are avoided by physicians like
Iodine Project leprosy. Who or what killed iodine?

The first nail in the iodine coffin was the publication by

by Guy E. Abraham, MD
Wolff and Chaikoff from UC Berkley in 1948,3 describ-
ing their finding in rats administered iodide in increasing
amounts by intraperitoneal injection. When serum inor-
The goal of this article is to provide the background on ganic iodide levels reached 0.2 mg/L, that is 10-6M, ra-
the Iodine Project which started five years ago and reac- dioiodide uptake by the thyroid gland became undetect-
quaint the reader with the concept of orthoiodosupple- able. The correct interpretation would be: that iodide
mentation — the amount of iodine required for whole sufficiency of the thyroid gland was achieved when se-
body sufficiency based on an iodine/iodide loading test rum inorganic iodide levels reach 10-6M, as we previ-
recently developed by the author.1 ously discussed.4 But Wolff and Chaikoff concluded
that serum inorganic iodide levels at a concentration of
During the first half of the 20th century, almost every US 10-6M blocks the synthesis of thyroid hormones, result-
physician used Lugol solution for iodine supplementa- ing in hypothyroidism and goiter. These authors did not
tion in his/her practice for both hypo- and hyperthyroid- measure thyroid hormones in the rats studied. Hypothy-
ism,1 and for many other medical conditions.2 In the old roidism and goiter were not observed in those rats. This
pharmacopeias, Lugol solution was called Liquor Iodi fictitious phenomenon became known as the Wolff-
Compositus. The minimum dose, called minim, was one Chaikoff effect.5 Because these law-abiding rats refused
drop containing 6.25 mg of elemental iodine, with 40% to become hypothyroid and instead followed their nor-
iodine and 60% iodide as the potassium salt. The rec- mal physiological response to the iodide load, they were
ommended daily intake for iodine supplementation was unjustly accused of escaping from the law of the Wolff-
2-6 minims (drops) containing 12.5-37.5 mg elemental Chaikoff effect. Labeling these innocent rats as fugitives
iodine. During the second half of the 20th century, iodo- was a great injustice against these rodents.
phobic misinformation, disseminated progressively and
deceitfully among the medical profession, resulted in a The second and final nail in the iodine coffin was ham-
decreased use of Lugol, with iodized salt becoming the mered in by Dr. Wolff in 1969.5 By 1969, Wolff had
standard for iodine supplementation.1 The bioavailable moved to the National Institute of Health from UC Berk-
iodide from iodized salt is only 10%, and the daily ley. Wolff arbitrarily defined four levels of “iodine ex-
amount of iodide absorbed from iodized salt is 200-500 cess.” The first level of excess started with intake above
times less than the amount of iodine/iodide previously 0.2 mg/day, and iodide intake of 2 mg or more was con-
recommended by US physicians. After World War II, sidered “excessive and potentially harmful.” In the next
US physicians were educated early in their medical ca- issue of this journal, this author discusses the Wolff-
reer to believe that inorganic, non-radioactive forms of Chaikoff effect and presents evidence that the data re-
iodine were toxic. Adverse reactions to radiographic ported in the rats by Wolff and Chaikoff3 did not justify
contrast media and other iodine-containing drugs were the interpretation of these data as applied to rats. Even
blamed on iodine. If a patient told his/her physician that worse, extrapolation of these findings to human subjects
he/she could not tolerate seafood, the physician told him/ by Wolff5 was inappropriate, and unscientific. By the
her that he/she was allergic to iodine. 1970s, physicians concluded that one must avoid inor-
ganic, non-radioactive iodine like leprosy, unless it was
Several forms of iodine prescribed by US physicians are incorporated into the toxic, organic iodine-containing
listed in Table 1. The manmade organic forms of iodine drugs. Then iodine could be tolerated because iodine
are extremely toxic, whereas the inorganic non- could be blamed for the toxicity of these drugs.
radioactive forms are extremely safe.1 However, the
safe, inorganic, non-radioactive forms were blamed for Against this background, a 1993 publication by Ghent, et
the severe side effects of the organic iodine-containing al,6 reported the beneficial effects of 5 mg iodine in-
drugs. A new syndrome, medical iodophobia, was re- gested daily for approximately one year in 1,368 patients
cently reported1 with symptoms of split personality, dou- (Continued on next page)

THE ORIGINAL INTERNIST Summer 2005 57

 as previously mentioned, was from 2-6 drops containing
Table 1 12.5-37.5 mg elemental iodine with 40% iodine and 60%
Various Forms of Iodine/Iodide Used in iodide as the potassium salt. As late as 1995, it was still
Clinical Medicine and Their Toxicity Levels the recommended amount in the 19th Edition of Reming-
ton’s Science and Practice of Pharmacy. For hyperthy-
FORMS TOXICITY roidism, physicians then used Lugol solution in daily
amounts ranging from 6-180 mg, with the most common
1) Non-radioactive dose of 90 mg resulting in success rates as high as 90%.1
A) Iodides (i.e., SSKI)
Extremely safe Radioiodide and goitrogens called antithyroid drugs were
INORGANIC

B) Tincture of iodine
C) Lugol solution not available to US physicians until the late 1940s, after
World War II.
2) Radioactive iodides for
diagnostic and therapeutic Carcinogenic,
Cytotoxic With the advent of radioiodide and goitrogens as alterna-
purposes tives to Lugol solution in patients with hyperthyroidism,
1) Naturally occurring thyroidologists became very destructive, causing hypo-
Safe within
A) Thyroid hormones physiologic thyroidism in 90% of these unfortunate patients.1 It is of
B) Thyroidal iodolipids ranges interest to mention that both radioiodide and goitrogens
ORGANIC

were introduced by the same group of investigators as a

2) Man-made replacement to Lugol in the treatment of hyperthyroid-
A) Radiographic contrast ism, at about the same time iodophobic misinformation
media Extremely toxic started appearing in the medical literature again authored
B) Iodine-containing drugs
by the same investigators.1 How strange!
(i.e., amiodarone)
Thyroidologists suffer from selective iodophobia for the
with fibrocystic disease of the breast (FDB). This author inorganic, non-radioactive forms of iodine combined
became aware of Ghent’s publication in 1997. Ghent’s with paradoxical iodophylia for radioactive iodide and
study did not confirm Wolff’s prediction that daily io- the toxic, organic iodine-containing drugs. As an exam-
dine intake of 2,000 µg (2 mg) was “excessive and po- ple, some thyroidologists recommend radioiodide abla-
tentially harmful.” Based on academic credentials and tion of the thyroid gland in order to allow the reintroduc-
reputation, the opinion of thyroidologist Wolff from the tion of the organic iodine-containing drug amiodarone in
National Institute of Health, would prevail over the find- patients with a prior history of amiodarone-induced thy-
ings of Ghent, et al. However, being interested in facts rotoxicosis.8 Amiodarone is a toxic form of sustained-
only, not in preconceived opinions of famous thyroidolo- release iodine. The author has previously discussed the
gists, an extensive search of the literature on iodine in interesting observation that this antiarrhythmic drug be-
medicine was initiated seven years ago by the author, comes effective when the body has accumulated ap-
combined with some original clinical research. proximately 1.5 g of iodine.8 This is exactly the amount
of iodine retained by the human body when iodine suffi-
The literature search revealed that 60 million mainland ciency is achieved following orthoiodosupplementation.7
Japanese consume a daily average of 13.8 mg of elemen- Whole body sufficiency for inorganic, non-radioactive
tal iodine, and Japan is one of the healthiest nations, based iodine/iodide results in optimal cardiac functions. Inor-
on overall well-being and cancer statistics.4 Japanese ganic, non-radioactive iodine was never tested in clinical
women do not stop consuming iodine-rich foods during conditions for which physicians prescribe amiodarone.
pregnancy, and Japanese fetuses are exposed to maternal However, inorganic iodide is blamed for the severe side
peripheral levels of iodide at concentrations of 10-5M to effects of this drug. Unbelievable, but true!
10-6M.1,4 Either the Japanese are mutants, capable of
thriving on toxic levels of iodine or we have been A review of the iodine literature revealed that British phy-
grossly deceived, and the human body needs at least 100 sicians recommended a similar range of daily intake of
times the RDA, which was established very recently in iodine in the form of hydrogen iodide as the ranges of
1980 and confirmed in 1989!7 iodine recommended by US physicians in the form of
Lugol solution. The recommended daily intake of hydri-
The literature search also revealed that US physicians odic acid syrup was 2-4 ml.9 The syrup is prepared by
over the past century used Lugol solution extensively in the British apothecary from a stock solution containing
their practice for both hypo- and hyperthyroidism.1 The 10% hydrogen iodide (HI), which is diluted 10-fold with
recommended daily amount for iodine supplementation, (Continued on next page)

58 THE ORIGINAL INTERNIST Summer 2005

syrups of different flavors. The syrup would contain 1% using daily amounts of 12.5-50.0 mg of elemental iodine
hydrogen iodide. This would compute to 10 mg iodide (See page 89). In 2003, Dr. David Brownstein joined
per ml. So, the recommended daily amount of elemental the Iodine Project and became a very efficient spokes-
iodine was 20-40 mg. man for the orthoiodosupplementation program. He
wrote a booklet published in 2004,11 describing his ex-
After overcoming the delusion that inorganic, non- periences with this approach in his practice. Dr. Brown-
radioactive forms of iodine are toxic and becoming stein was invited to outline some key recommendations
aware that the inorganic, non-radioactive forms of iodine for the benefit of other health care practitioners based on
were extremely safe and used extensively by US physi- his and his partners’ experience so far in 3,000 patients.
cians for many medical conditions, the author initiated His article will be in next month’s issue.
the Iodine Project. Clinical studies were performed five
years ago to confirm Ghent’s findings,6 combined with Five years ago, urine samples were sent to local laborato-
some original research. The clinical aspects of this re- ries for the measurement of iodide levels before and after
search were performed under contract at the Flechas orthoiodosupplementation. The iodophobic mentality
Family Practice Clinic in Hendersonville, North Caro- became evident immediately. The reports came back with
lina under the supervision of Jorge D. Flechas, MD, and statements like “Greater than 500 µg iodide/24 hr., check
funded with grants from Optimox Corporation. The au- for contamination.” The author then switched to a large
thor designed the protocols and monitored the progress commercial laboratory catering to some 30,000 health
and completion of each project. Informed consent was care practitioners. The normal range of urine iodide lev-
obtained from all subjects participating in these projects. els for that laboratory was: 0.02-0.50 mg/24 hr. Together
with urine iodide levels, this laboratory also performed
Because administration of iodine in liquid solution is not urine levels of minerals, trace elements, and toxic metals.
very accurate, may stain clothing, has an unpleasant
taste, and causes gastric irritation, we decided to use a The bioavailability of a Lugol tablet (Iodoral®) contain-
precisely quantified tablet form of Lugol. To prevent ing 12.5 mg elemental iodine was evaluated by measur-
gastric irritation, the iodine/iodide preparation was ab- ing 24-hour urine levels of iodide together with the min-
sorbed unto a colloidal silica excipient; to eliminate the erals, trace elements, and toxic metals before and after
unpleasant taste of iodine, the tablets were coated with a administration of this preparation. The results obtained
thin film of pharmaceutical glaze. John C. Hakala from following iodine supplementation revealed that in some
Hakala Apothecaries, in Lakewood, Colorado, com- subjects, the urine levels of mercury, lead, and cadmium
pounded the tablets.10 increased by several times after just one day of supple-
mentation. For aluminum, this increased excretion was
To confirm the safety of the Lugol tablets, pilot studies not observed usually until after one month or more on
were performed with tablets of Lugol containing 1.0- the iodine supplementation.
12.5 mg of elemental iodine. Following the pilot stud-
ies, 10 female subjects, seven with breast symptomatol- Based on data available in the medical literature, urinary
ogy, were studied for three months at 12.5 mg/day. Pre- iodide levels are considered the best index of iodine in-
and post-supplementation evaluation of blood chemistry, take.12 The initial results of the bioavailability study
hematology, thyroid function tests, and ultrasonometry suggested that the Lugol tablets were not well absorbed
of the thyroid gland were performed. The results ob- since only 20-30% of the administered amount was re-
tained in these female subjects using a tablet form of covered in the 24-hour urine collection of five subjects
Lugol solution (Iodoral®, Optimox Corporation, Tor- tested.12 Just in case medical textbooks were wrong, and
rance, CA) at 12.5 mg/day for three months confirmed the explanation for the low recovery of iodide is body
Ghent’s observations, and the safety of the Lugol tablets. retention of iodine/iodide, the supplementation was con-
This was reported in The Original Internist in 2002.10 tinued for one month and then urine iodide levels were
measured again in the 24-hour urine collection. Medical
In order to build a database that could be used to develop textbooks were wrong. The subjects excreted a mean of
a protocol for the implementation of iodine supplemen- 50% of the amount ingested, with one subject excreting
tation in FDB and other clinical conditions, a long-term 96% of the ingested amount.12
study of Lugol tablets in female patients with FDB, us-
ing Ghent’s scoring of FDB, was initiated four years ago The implication of such observation was that an iodine/
at Dr. Flechas’ clinic, supported by grants from Optimox iodide-loading test could be developed to assess not just
Corporation. Dr. Flechas will present a preliminary re- thyroid sufficiency for iodine but requirement of the
port of his results on the use of Lugol tablets in FDB, (Continued on next page)

THE ORIGINAL INTERNIST Summer 2005 59

 mentation, the loading test was repeated. All six sub-
Figure 1 jects showed a significant drop of the iodide concentra-
Effect of Increasing Intake of tion in the 24-hour urine collection. In all five subjects
Iodine/Iodide on Percentage Urinary who had reached sufficiency, the percentage of the oral
Excretion of Ingested Amounts amount excreted in the 24-hour urine collection was be-
low 90%, ranging from 64-82%. This drop in percent-
age excretion has been observed in some subjects after
Mean percentage dose excreted

Mean SD ( ) = Range
in 24-hour urine collection

60
(14.2-66) they have achieved whole body sufficiency for iodine,
even though they continued to ingest 50 mg iodine/day
50
regularly. Increased exposure to goitrogens may be the
(14-37)
40 explanation. In some of these cases, the author has ob-
(22-25)
30
(20-26)
served increased urine bromide excretion as high as 20-
20 fold baseline levels following the loading test, concomi-
10
tant with a drop in percentage iodide excreted.
0
Whole body sufficiency for iodine correlated well with
1 2 3 4
overall well-being, and some subjects could tell when
Quantity of Iodoral® tablets used in loading test they achieved sufficiency even before knowing the re-
(From Abraham reference 1)
sults of the test. Iodine sufficiency was associated with
a sense of overall well-being, lifting of a brain fog, feel-
whole human body for that essential element. However, ing warmer in cold environments, increased energy,
instead of a one-month loading test, further studies were needing less sleep, achieving more in less time, experi-
performed to shorten this test to a single ingestion of the encing regular bowel movements and improved skin
preparation. Another group of six subjects, (three male complexion. In some subjects with overweight or obe-
and three female) were evaluated with 24-hour urinary sity, orthoiodosupplementation resulted in weight loss,
iodide levels after ingesting one, two, and three tablets decreased percentage body fat and increased muscle
of the same preparation. The mean percentage excre- mass. Following orthoiodosupplementation, increased
tions (± SD) were 22±1.2% for one tablet, 23±2.8% for urinary excretion of the goitrogens fluoride and bromide
two tablets, and 25±12.3% for three tablets. In a third and the toxic metals mercury, lead, cadium, and alumi-
group of six subjects, urine iodide levels were evaluated num was observed; marked improvement of fibrocystic
following four tablets of the same preparation. The disease of the breast occurred following three months of
mean pecentage excretion was 39±17.2%. (See Figure iodine supplementation at 50 mg/day. In three patients
1.) For the loading test, a single ingestion of four tablets with polycystic ovary syndrome with olygomenorrhea,
was chosen, because this dose resulted in the highest orthoiodosupplementation resulted in regularization of
mean percentage iodide excreted with the widest interin- the menstrual cycle. In patients on thyroid hormones,
dividual variations. orthoiodosupplementation resulted in a decreased re-
quirement to much lower levels of thyroxine and in
Because of the improved overall well-being reported by some cases, resulted in the complete discontinuation of
the subjects who achieved 90% or more iodide excreted, this hormone. This decreased requirement for thyroid
sufficiency was arbitrarily set as 90%. Implementation hormones following orthoiodosupplementation was ob-
of orthoiodosupplementation based on the loading test served in a female patient with total thyroidectomy, sug-
revealed that sufficiency was not achieved in some sub- gesting that iodine not only improves thyroid function
jects even after two years of iodine supplementation at 1- but also has an effect at the target organ level. In dia-
2 tablets/day. To achieve sufficiency within three months, betic patients on insulin, orthoiodosupplementation re-
most subjects required 3-4 tablets/day (37.5-50.0 mg), and sulted in better control of this condition, and in some
some obese and diabetic subjects required even more than cases alleviated this condition without the need for insu-
50 mg/day to achieve and maintain sufficiency. lin. In hypertensive patients, whole body iodine suffi-
ciency resulted in normalization of blood pressure with-
Six normal subjects with normal body weight (three men out medications. Similar observations were reported by
and three women) ingested four tablets of Iodoral® other physicians using this program. Best results were
(50mg)/day for three months and were followed with achieved when orthoiodosupplementation was combined
monthly loading tests. After three months on orthoiodo- with a complete nutritional program emphasizing mag-
supplementation, only one female subject did not reach nesium instead of calcium.1 The occurrence of side ef-
sufficiency. Following one month off orthoiodosupple- (Continued on next page)

60 THE ORIGINAL INTERNIST Summer 2005

fects was rare and this topic will be discussed by Drs. dure and set it up in his own clinical laboratory. At first,
Flechas and Brownstein in other articles. The Wolff- the loading test was performed on his patients only, but
Chaikoff effect was not observed in some 4,000 patients eventually, he made this service available to other clini-
on orthoiodosupplementation for as long as three years cians. Packets containing four tablets of Iodoral® were
with daily intake ranging from 12.5-50.0 mg. This is the made available for the loading test. In another article in
combined experience of Drs. Flechas and Brownstein. this issue, Dr. Flechas will present the results of the
loading tests he gathered during the previous two years
The serum level of inorganic iodide supposedly causing and his experience with the implementation of orthoio-
hypothyroidism and simple goiter by the Wolff- dosupplementation in his practice.
Chaikoff effect is 0.2 mg/L.3 The author previously cal-
culated that in an adult, this level would be achieved In order to test the reliability of commercial laboratories
with a daily ingestion of 12.5 mg elemental iodine.1 in the performance of urine iodide assay at the levels
Since this amount of Lugol solution was used safely by observed following the loading test, Optimox Corpora-
three generations of US physicians for iodine supple- tion financed a pilot study on five subjects who under-
mentation, and since we have observed that patients re- went the loading test. Samples were sent to two com-
ported optimal mental and physical performances on 3-4 mercial laboratories for iodide measurement. These
times that amount, we would like to propose a redefini- laboratories used the ICP-MS method. The same sam-
tion of the Wolff-Chaikoff effect as optimal mental and ples were also measured by the author in situ (Table 3).
physical performances. This seems to be the most con- Lab #1 consistently underestimated and Lab #2 consis-
genial solution to the Wolff-Chaikoff forgery. In this tently overestimated the levels measured in the potenti-
way, the names of Wolff and Chaikoff would continue to ometric laboratory of the author. Physicians using the
be mentioned in the medical literature, but associated iodine/iodide loading test to follow their patients on or-
with the real and pleasant outcome of orthoiodosupple- thoiodosupplementation will depend on the results of
mentation, that is optimal mental and physical perform- these tests for evaluation of whole body iodine suffi-
ances, not the gloomy, fictitious outcome proposed by ciency and clinical response. Therefore, the measure-
Wolff,5 that is goiter and hypothyroidism. ment of urine iodide levels must be accurate at concen-
trations two orders of magnitude greater than the normal
Three years ago, the author decided to set up the iodide range of these laboratories, that is 0.02-0.50 mg/24 hr.
assay in situ, using the ion-selective electrode procedure.
To improve specificity, chromatography separation of The supervisor of Lab #1 was contacted. He was very
the halides was performed on anion-exchange resins.12 helpful and explained that his equipment was calibrated
Halides and other substances interfered in the assay of to measure the range of urine iodide levels expected in
iodide (Table 2). One full year was required to optimize the US population, that is 0.02-0.50 mg/24 hr, and there-
the assay for iodide. In January 2003, Dr. Flechas and fore, it would not be reliable at levels 100 times higher.
John C. Hakala were invited as guests of Optimox Cor- He performed recovery experiments and confirmed that
poration to attend a two-day workshop in order to learn his equipment underestimated the true value by 50%
this technology. Dr. Flechas quickly learned this proce- (Continued on next page)

Table 2
Interferences in the Ion-Selective Electrode Assay of Halides and
Procedures for Preventing These Interferences
Halides Interferences* Procedures for preventing interference
-
Chloride OH = 80 1) Acidification
Br- = 3 x 10-3 2) Chromatographic separation from other halides
I- = 5 x 10-7
Fluoride OH- Acidification with Orion spcial ISA: TISAB, added to urine samples at equal volumes
- 4
Bromide OH = 3 x 10 Chromatographic separation from other halides
Cl- = 400
I- = 2 x 10-4
Iodide Cl- = 10-6 Chromatographic separation from other halides
Br- = 5 x 103
* The maximum allowable concentrations of interfering substances express as the molar ratio of the interfering ion concentration to the
sample halide concentration. If the ratio is exceeded, the data generated by electrode will become unreliable. Information supplied by
Thermo Orion Corporation.
within the range of iodide levels expected for the loading dide-selective electrode, no matter the expected iodide
test. He showed great interest in offering this service to levels.
his clients, and the author supplied him with the details
of the technique using ion-selective electrode, following Orthoiodosupplementation resulted in marked increase
chromatography on strong anion exchangers. in bromide excretion, and to a lesser extent in fluoride
also. The results obtained in the first five subjects stud-
The chromatographic system was modified in order to ied are displayed in Table 4. The results observed for
measure accurately the other halides: chloride, fluoride, bromide in subject #5 were so surprising that they were
and bromide, using a positive displacement manifold published as a letter to the editor of Townsend Letter.13
designed by the author.8 The flowchart for this chroma- These findings have since been replicated in a large
tographic separation is displayed in Figure 2. Compari- number of tests. Female patients with breast cancer
son of results obtained before and after chromatographic seem to retain more iodine on the loading test than nor-
purification of the halides chloride, fluoride, bromide, mal subjects and excrete more bromide than normal sub-
and iodide revealed the following. In 24 urine samples jects. This needs to be confirmed using a well-designed
analyzed, the values obtained for chloride and fluoride protocol since this observation is anecdotal on a small
by the direct assay, using Thermo Orion reagents and the number of patients.
values obtained after chromatography were not signifi-
cantly different. However, for bromide and iodide, the Recently, the author extended the ion-selective electrode
direct assay overestimated significantly the values ob- assay to serum samples.8 Evidence for an enterohepatic
tained following chromatography. For iodide, the direct circulation of inorganic iodine was observed for the first
assay overestimated by two-fold on the average, the lev- time. Serum iodide levels reached peak values of 1.5-
els obtained following chromatography in urine samples 2.2 mg/L between two and four hours post ingestion of
obtained prior to iodine supplementation. Even after Iodoral® in subjects ingesting 3-4 tab/day. A second
iodine supplementation, significant differences were ob- peak of serum iodide after eight hours following the first
served in the iodide levels of some samples measured by peak was observed in some subjects suggesting that se-
these two procedures. It was decided to perform chro- rum iodide undergoes an enterohepatic circulation. Se-
matography on all samples prior to analysis by the io- (Continued on next page)

Figure 2
Flowchart Describing the Combined Measurement of Chloride, Fluoride, Bromide, and
Iodide in the Same Urine or Serum Sample by Prior Chromatography on Anion-Exchange Resin
Cartridges Fitted with the 10 ml Plastic Syringes in a Positive Displacement Manifold (PMD).11
Sample
IN 10 ml of 10 ml of 10 ml of 10 ml of
urine/serum 0.05N NaNO 3 0.1N NaNO 3 5N NaNO 3
SEQUENCE 1 2 3 4
OF ELUTION

S A X SAX
c column
o l u m n
Altech #21907 600 mg

In 10 ml
HALIDES In 10 ml of In 10 ml of In 10 ml of
- Chloride of urine/ - Fluoride - Bromide - Iodide
ELUTED 0.05N NaNO 3 0.1N NaNO 3 5N NaNO 3
serum
+ + + +

5 ml of 5N NaNO 3 10 ml of TISAB 5 ml of 5N NaNO 3 20 ml H 2O

ISE assay ISE assay ISE assay ISE assay

of chloride of fluoride of bromide of iodide

ORION
#9617 BN #9609 BN #9635 BN #9653 BN
ELECTRODE #
rum iodide levels were still elevated 24 hours after the after the first peak. Apparently, iodine is not reduced to
loading dose, ranging from 0.3-0.6 mg/L.3,7 iodide by the liver during enterohepatic circulation.
There was no significant difference in the iodide meas-
In order to assess the presence of iodine and iodate (the ured following the addition of reductant to serum for the
oxidized forms) in serum following orthoiodosupple- conversion of iodine to iodide or following the addition
mentation, serum iodide levels (the reduced form) were of 10 times more reductant for the conversion of iodate
measured by ion-selective electrode before and after to iodide. Therefore, there was no evidence of iodate in
reduction with sodium metabisulfate. The three inor- the serum samples analyzed. The oxidation of iodine to
ganic forms of the element iodine consumed by human iodate in biological systems has not been reported and
subjects are 1) the negatively charged reduced iodide; 2) this metabolic pathway of iodine probably does not oc-
the negatively charged highly oxidized iodate IO-3; and cur in vivo. The only source of peripheral iodates would
3) the neutral oxidized iodine I2. The iodide selective be from ingested food and drink. The author has not
electrode is influenced only by negatively charged been able to locate a publication dealing with the meas-
forms of this element, that is, iodide I- and iodate IO-3. urements of serum iodate following ingestion of iodate.
Experiments performed by It is an easy experiment to
the author with sodium Table 3 carry out.
iodate revealed that the Iodide Levels Measured in 24-hour Urine
iodate molecule, because Collections of 5 Subjects Following the Serum inorganic iodide
it is larger in size than io- Iodine/Iodide Loading Test: A Comparison of Results levels are a good index of
dide, did not have any ap- Obtained from 3 Different Laboratories the bioavailability of in-
preciable effect on the gested iodine/iodide. Se-
electromotive force (EMF) Commercial Commercial Optimox rum inorganic iodide is
of the electrode, even at Lab 1 Lab 2 R&D Lab cleared rapidly by the kid-
concentrations 10,000 Subject Sex (mg/24h) (mg/24h) (mg/24h) neys with a daily clearance
times higher than the rate of 43.5 L.7 At steady
amount of iodide influenc- 1 F 14.0 37.8 23.1 state condition, the serum
ing significantly the EMF iodide levels expected for
of the selective electrode. 2 F 12.0 20.8 19.0 patients receiving 50 mg
3 M 7.0 23.8 12.5 iodine/day should be ap-
Pilot studies were per- proximately: serum io-
formed in order to quan- 4 M 11.0 99.0 34.7 dide (mg/L) = daily intake
tify the amount of the re- (mg)/43.5 L = 50 mg/43.5
ductant needed for the re- 5 M 12.0 41.9 19.0 = 1.15 mg/L.7 If patients
duction of iodine and io- * Urine iodide levels measured by Induction-Coupled Plasma — Mass continue to excrete low
date to iodide. Almost 10 Spectrometry. levels of iodide after or-
times more reductant was ** Urine iodide levels measured by Ion Selective Electrode Assay. thoiodosupplementation
required for the reduction for three months, serum
of iodate to iodide than iodine to iodide. The reduction inorganic iodide levels are indicated to assess whether
of iodate resulted in the formation of iodine first, then this is due to decreased absorption or increased demand.
iodide. When this procedure was applied to urine sam- Malabsorption of iodine/iodide would result in very low
ples, no significant difference was observed between serum inorganic iodide levels (10-8M) in the presence of
pre- and post-reduction levels, suggesting that only io- low urinary excretion. We have not observed a case of
dide, the reduced form, was present in urine. However, malabsorption of iodine yet, when iodine supplementa-
serial serum samples obtained for 24 hours following tion was in the range of 12.5-50.0 mg/day. However,
the loading test, showed a significant difference in the the author has previously reported low absorption of
serum iodide levels between pre- and post-reduced sam- sodium iodide from salt.7 On a molar basis, there is
ples within the first two hours in a female subject, with 30,000 times more chloride than iodide in iodized salt.
post-reduction levels 5-10% higher. This suggests the Due to competition for absorption by the halide chlo-
presence of serum iodine early after ingestion of the ride, only 10% of iodide in iodized salt is absorbed.
Lugol tablets. Iodine obviously is not completely re-
duced to iodide in the intestinal tract during absorption Obesity increases the requirement for iodine7 and up to
as mentioned in medical textbooks. In another female 100 mg elemental iodine/day may be required to
subject post-orthoiodosupplementation for one month, a achieve and maintain sufficiency. Another factor in-
second peak of serum iodine was observed eight hours (Continued on next page)

THE ORIGINAL INTERNIST Summer 2005 63

volved in the increased demand for iodine is the pres- obese female patients with poor clinical response to or-
ence of excessive amounts of goitrogens from the diet thoiodosupplementation, high urinary iodide excretion
and lifestyle. For example, smoking increases serum was associated with serum inorganic iodide levels below
thiocyanate levels, interfering with the sodium/iodide 10-6M (0.13 mg/L). The expected serum levels associ-
symporter function. Sources of goitrogens are available ated with high urinary iodide excretion should be be-
from medical textbooks,14 although the halides fluoride tween 5 × 10-6M to 10-5M.7
and bromide are not listed as goitrogens. Fluoride inter-
feres with the uptake of iodide by the thyroid gland sym- Although congenital hypothyroidism due to sodium/
porter system, but it is itself not transported inside the iodide symporter defect is extremely rare, milder forms
thyrocyte,15 suggesting that fluoride causes oxidative of iodine/iodide transport defect/damage throughout the
damage to the halide-binding site of the symporter. The whole body may be more common and undetected. As
author previously discussed the goitrogenic effect of of 1997, only 38 cases of congenital hypothyroidism due
bromide even at low concentrations.1 Patients who used to sodium/iodide symporter defect were reported. Of
water from wells and municipal plants may be exposed interest is that in one of these cases,18 a male Japanese
to potassium perchlorate, a very powerful goitrogen that subject, the diagnosis was not made until he was 30
behaves like fluoride, binding to the halide-binding site years old. At the time of evaluation, he was euthyroid
of the symporter without itself being symported. A re- with a goiter while on the high iodine Japanese diet, but
cent Internet publication by Kirk, et al,16 reported the he got hypothyroidism on a Western diet. Administra-
presence of high concentrations of perchlorate in dairy tion of 50 mg iodide restored euthyroidism. An active
milk sold in grocery stores and in human milk. The transport system for iodide by a sodium/iodide sym-
mean levels of perchlorate were five times higher in porter has been demonstrated in several organs besides
breast milk than dairy milk. Perchlorate has a selectivity the thyroid gland, capable of concentrating peripheral
factor of at least 30 over iodide. To compete effectively inorganic iodide 20- to 40-fold against a gradient.19 The
against this goitrogen, the peripheral concentration of cellular uptake of iodide in some tissues may involve
inorganic iodide must be at least 100 times higher than other mechanisms than the symporter system. Inorganic
the concentration of perchlorate. Kirk, et al,16 observed iodine/iodide has been detected in every organ and tissue
that breast and dairy iodide levels were inversely corre- examined, with relatively high levels in the thyroid
lated with the levels of perchlorate. Perchlorate and gland, liver, lung, heart, and adrenal glands. The highest
fluoride, due to their high redox potential, may cause quantity of iodine was found in fat tissue and muscle.8
oxidative damage to the halide-binding site, decreasing Exposure to fluoride and perchlorate can cause oxidative
its efficiency for iodide transport. damage to the halide-binding site of the sodium/iodide
symport system, due to their high redox potential. In
If the pre-orthoiodosupplementation loading test report such cases, more than 50 mg iodine/day may be required
shows 90% or more of the ingested iodine in the 24- to overcome the low efficiency of the iodine transport
hour urine collection of patients on a Western diet, se- system. If the high iodide excretion prior to orthoiodo-
rum inorganic iodide levels are indicated to rule out an supplementation is due to significant amount of iodine in
iodide transport defect or damage not just in the thyroid the diet of the patient, such as the diet of mainland Japa-
gland but throughout the whole body. In our experience, nese, or if due to ingestion of medications containing
this is very rare and was observed in only two cases. iodine, fasting serum inorganic iodide levels will be
The intestinal absorption of iodine/iodide involves a dif- between 5 x 10-6 and 10-5M (0.65-1.30 mg/L). This is
ferent mechanism than the uptake of iodide by target the range of serum iodide levels observed by the author
cells via the sodium/iodide symporter. For example, when sufficiency is achieved.7
chloride competes with iodide in the intestinal tract7 but
chloride has no detectable effect on the iodide symporter As mentioned previously, medical iodophobia has
system.17 This explains why a patient with iodide trans- reached pandemic proportion, is highly contagious, and
port damage is able to absorb iodine/iodide efficiently has wreaked havoc in the practice of medicine and on
but unable to transfer peripheral iodine/iodide into the the US population. More misery and death in the US
cells. Peripheral iodide is cleared very rapidly by the may have resulted from the Wolff-Chaikoff effect than
kidneys, resulting in quantitative recovery of ingested both World Wars combined. Due to thyroid fixation,
iodine/iodide in the urine in a patient who is very iodine- thyroidologists dictate the need for iodine. However,
deficient, if the cellular transport system is defective. In thyroidologists suffer from selective iodophobia for the
those cases, serum inorganic iodide levels 24 hours after inorganic, non-radioactive forms of iodine combined
the loading test will be low, even though the loading test with a paradoxical iodophylia for radioiodide. In a sur-
suggests whole body sufficiency for iodine. In two (Continued on next page)

64 THE ORIGINAL INTERNIST Summer 2005

vey of US thyroidologists, some 70% used radioiodide and two with hyperthyroidism), the iodine content of the
to treat hyperthyroidism1 instead of the Lugol solution thyroid gland was very low, being 4-10 times lower.
used previously to treat this condition safely and effec- The author previously calculated that the theoretical
tively with a success rate as high as 90%, compared to a maximum of thyroidal iodine in the adult is 50 mg.7 In
thyroid destruction rate of 90% with radioiodide. The the 12 patients on amiodarone therapy, the mean ± SD
love affair of thyroidologist for radioiodide is not limited was 30.5±9.2 mg, giving a 95% confidence limit ranging
to its therapeutic application. Radioiodide is used exten- from 12.0-48.9 mg/thyroid. The upper limit of measured
sively for diagnostic purposes although safer methods iodine in the thyroid gland of these patients, 48.9 mg is
exist to obtain the same information. Fluorescence scan- very close to the theoretical maximum of 50 mg/thyroid.
ning of the thyroid gland gives more useful information
than isotope scanning.19 Okerlund commented, “The Why don’t thyroidologists use fluorescent scanning of
types of images obtained from fluorescent thyroid scan- the thyroid instead of isotope scanning? One possible
ning are indistinguishable from those of isotope scan- reason is the fact that this procedure exposed the harmful
ning, since the same electronics and data presentation effect of thyroid hormone therapy and radioiodide in
systems are used. The size, shape, and positional rela- depleting the thyroid gland of iodine. Low thyroid io-
tionships of the thyroid lobes are therefore comparable dine is associated with thyroid hyperplasia and cancer.1
to isotope scanning, with the right lobe larger in the ma- Could thyroid hormones cause the same iodine depletion
jority of normal cases, the two lobes of equal size in a in breast tissue? The prevalence of breast cancer is higher
smaller number, and the presence of a larger left lobe in in women on thyroid hormones.4 Thyroidologists use
a still smaller number.” Fluorescent scanning gives ad- thyroid hormones extensively in their practice without
ditional information on the amount of stable iodine in supplementing their patients with iodine. Fluorescence
the thyroid gland. scanning of the thyroid gland should be implemented.
Thyroidologists would then have to face the damages
Okerlund20 reported that thyroid hormone therapy and they are causing to the thyroid gland and consequently to
irradiation of the thyroid gland cause a depletion of io- their patients.
dine from the thyroid gland. Ingestion of thyroid hor-
mones for three months or more resulted in very low Medical iodophobia resulted in the removal of iodate
levels of thyroidal stable iodine reaching the detection from bread 20 years ago, replacing it with the goitrogen
limit of the equipment. “The finding that previously bromate. This was associated with an increased preva-
irradiated thyroid glands are sometimes iodide depleted, lence of obesity, diabetes, and hypertension, as well as
coupled with the observation that the iodide depleted thyroid and breast cancer.1 A recent publication reported
gland in experimental animals is physiologically more an association between low iodine intake in women dur-
sensitive to the effects of pituitary thyrotropin (TSH), ing pregnancy and attention deficit and hyperactivity
may lead to changes in the understanding of radiation- disorder (ADHD) in their offspring.22 However, chil-
induced thyroid disease and to changes in the clinical dren diagnosed with ADHD do not demonstrate prenatal
management of at least some of these patients, who are thyroid dysfunction, reflected in the newborn serum thy-
known to be at high risk for thyroid tumor develop- roxine levels.23 The most plausible explanation is a de-
ment.” Okerlund20 is suggesting that patients on thyroid creased sensitivity of the nuclear thyroid hormone recep-
hormones and receiving radioiodide or radiation therapy tor to thyroid hormones. We previously reported evi-
should be supplemented with iodine as a preventative dence for improved receptor response to thyroid hor-
measure against the carcinogenic effect of these inter- mones following orthoiodosupplementation.1,4 There-
ventions in iodine depleted thyroid glands. fore, iodine is not only necessary for the synthesis of
thyroid hormones but also for their effect on target cells.
For the US population, Okerlund20 reported a mean This effect is probably due to iodination of the thyroid
value of around 10 mg iodine/thyroid, with a range of 4- hormone receptor.1,4 The essential element iodine,
19 mg. In 56 patients suffering from autoimmune thy- which is the inorganic, non-radioactive forms, deserves
roiditis, but with normal thyroid function, a mean value more attention from researchers and clinicians. It may
of 4.8 mg/thyroid was reported. In 13 patients with be the missing link in patients currently resistant to con-
autoimmune thyroiditis and hypothyroidism, the mean ventional hormonal therapy.
value was 2.3 mg/thyroid. In 12 patients treated with
About the Author
amiodarone, a toxic form of sustained-release iodine,
Jonckheer21 reported a mean ± SD of 30.5±9.2 mg/ Guy E. Abraham, MD, is a former Professor of Obstet-
thyroid. In five patients who experienced thyroid dys- rics, Gynecology, and Endocrinology at the UCLA
function during amiodarone therapy, (three with hypo- (Continued on next page)

THE ORIGINAL INTERNIST Summer 2005 65

School of Medicine. Some 35 years ago, he pioneered 8) Abraham GE. “Serum inorganic iodide levels following inges-
the development of assays to measure minute quantities tion of a tablet form of Lugol solution: Evidence for an entero-
hepatic circulation of iodine.” The Original Internist, 2004; 11
of steroid hormones in biological fluids. He has been (3):29-34.
honored as follows: General Diagnostic Award from the 9) Martindale. The Extra Pharmacopoeia, 28th edition. Reynolds
Canadian Association of Clinical Chemists, 1974; the JEF, editor. The Pharmaceutical Press, 1982; 865.
Medaille d’Honneur from the University of Liege, Bel- 10) Abraham GE, Flechas JD, and Hakala JC. “Optimum levels of
iodine for greatest mental and physical health.” The Original
gium, 1976; the Senior Investigator Award of Phar- Internist, 2002; 9():5-20.
macia, Sweden, 1980. The applications of Dr. Abra- 11) Brownstein D. Iodine: Why You Need It, Why You Can’t Live
ham’s techniques to a variety of female disorders have Without It. Medical Alternative Press, West Bloomfield, MI,
brought a notable improvement to the understanding 2004.
and management of these disorders. Twenty-five years 12) Abraham GE, Flechas JD, and Hakala JC. “Measurement of
urinary iodide levels by ion-selective electrode: Improved sensi-
ago, Dr. Abraham developed nutritional programs for tivity and specificity by chromatography on anion-exchange
women with premenstrual tension syndrome and post- resin.” The Original Internist, 2004; 11(4):19-32.
menopausal osteoporosis. They are now the most com- 13) Abraham GE. “Iodine supplementation markedly increases
monly used dietary programs by American obstetricians urinary excretion of fluoride and bromide.” Townsend Letter,
2003; 238:108-109.
and gynecologists. Dr. Abraham’s current research in- 14) Delange FM. “Iodine deficiency.” In: Werner & Ingbar’s The
terests include the development of assays for the meas- Thyroid. Braverman LE and Utiger RD, editors. Lippincott
urement of iodide and the other halides in biological Williams & Wilkins, 2000; 295-316.
fluids and their applications to the implementation of 15) Galletti PM and Joyet G. “Effect of fluorine on thyroidal iodine
orthoiodosupplementation in medical practice. metabolism in hyperthyroidism.” J Clin Endocr, 1958; 18:1102-
1110.
16) Kirk AB, et al. “Perchlorate and iodide in dairy and breast
REFERENCES milk.” Environ Sci & Technol A, 2005.
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18) Matsuda A and Kosugi S. “A homozygous missense mutation
Internist, 2004; 11(1):17-36.
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2) Kelly FC. “Iodine in medicine and pharmacy since its discovery
defect. J Clin Endo & Metab, 1997; 82:3966-3917.
– 1811-1961.” Proc R Soc Med, 1961; 54:831-836.
19) Brown-Grant K. “Extrathyroidal iodide concentrating mecha-
3) Wolff J and Chaikoff IL. “Plasma inorganic iodide as a homeo-
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174:555-564.
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4) Ab rah a m GE, Flech as JD, and Hakala JC.
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Raton, FL, 1979; 149-160.
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21) Jonckheer MH. “Amiodarone and the thyroid gland. A re-
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(2):29-38.

Table 4
Fluoride and Bromide Levels Measured in 24-hour Urine Collections of 5 Subjects
Following the Iodine/Iodide Loading Test Before and After 1 Month on Iodoral® at 3 Tab/Day

Fluoride (mg/24) Bromide (mg/24h)

After 1 Month After 1 Month
Subject Sex Control Before Iodoral® of Iodoral® Control Before Iodoral® of Iodoral®
1 F 0.40 0.80 0.60 6.8 24.2 18.6
2 F 0.065 1.20 0.80 12.5 36.4 34.0
3 F 0.62 1.80 — 4.8 5.2 —
4 M 0.35 0.62 0.44 6.8 34.8 32.0
5 M 0.05 0.93 0.79 18.4 336.0 288.0
6 M 1.20 1.40 1.20 12.2 24.5 24.0