IODINE AND CANCER

INTRODUCTION

Iodine is an essential trace element. Obviously, the body is capable of making an immense number of chemical compounds using numerous pathways, but it cannot make elements! Trace elements must be derived from food, beverages and from drinking water. The primary sources are soil, lakes or the ocean, and for iodine, the ocean is the largest source. Lands far removed from the oceans typically have low iodine levels, a classical example being the U.S. Midwest which is also called the goiter belt because of the high incidence of this thyroid disorder caused by iodine deficiency. This problem was addressed a long time ago by adding iodine to table salt. It was also added to bread as a dough conditioner but the additive was later changed to a bromine-containing compound which in fact increases the chances of iodine deficiency.

Iodine is necessary for the production of thyroid hormones but is also found in every cell in the body. It is involved in the production of other hormones and enzymes and is involved in numerous biochemical pathways.1 Insufficient iodine intake can cause abnormal neuronal development, mental retardation, congenital abnormalities, spontaneous abortion, miscarriage, congenital hypothyroidism, infertility, goiter, and as well appears to increase the risk of thyroid, breast, prostate, and gastric cancer. For example, after the Chernobyl disaster, the risk of thyroid cancer was inversely associated with urinary iodine excretion levels, suggesting a strong link with iodine status. Also, thyroid uptake of radioactive iodine is enhanced by an iodine deficiency and large doses of potassium iodide are considered the best protection for the thyroid in the event of exposure to radioactive iodine. Some individuals living downwind from nuclear power stations actually keep a bottle of high-dose potassium iodide on hand in case there is an accident. As early as 1976 it was postulated that iodine deficiency was associated with the risk of prostate, endometrial, ovarian and breast cancer. This was based on geographical associations of the prevalence of goiter and the incidence of reproductive cancers.2

According the World Health Organization, nearly 2 billion individuals have insufficient intake of iodine.3 Furthermore, studies based on the National Health and Nutrition Examination Survey I and III which compared the period 1971-1974 with 2000 in the US, found that iodine levels dropped 50%. This drop was seen over all demographic categories including ethnicity, region, economic status, race and population density. Also, the percentage of pregnant women with low iodine levels increased almost 700 %.

In his book Iodine. Why You Need It. Why You Can't Live Without It,1 Dr. David Brownstein describes his own experience with the prevalence of iodine deficiency. Over a number of years he has tested 5000 patients and approximately 96% test low for iodine. Laboratories which conduct iodine testing report similar prevalence of deficiency in over 30,000 individuals. However, this is based on an iodine load test described below, and defining deficient is somewhat arbitrary.

How many readers of this Newsletter have ever had an iodine status test ordered as part of a physical? There is almost no literature on the subject of iodine status testing, and what exists is in a very obscure journal called The Original Internist. Identifying deficiency of course depends on how one defines sufficiency and when sampling world populations one must have a simple test which may not be ideal. This simple test involves determining the iodine level in a casual urine sample. Iodine status is not really on the preventive medicine radar screen. However, there is a good discussion of an interesting approach to a more sophisticated iodine status test in Dr. Brownstein's book.1 This is called the Iodine Loading Test and involves taking 50 mg of iodine/iodate and then collecting a 24-hour urine sample. This sample measures how much of the 50 mg of iodine is eliminated. According to the threshold developed over a number of years, anything less than 90% recovery of the iodine is considered a manifestation of deficiency. This is because according to this view, the iodine body stores should be near saturation for optimum health, and if this is not true, then one excretes less than 90% of the load. Numbers can range all the way to near zero. A low excretion takes on real meaning when it is correlated with clinical symptoms which then show dramatic beneficial changes upon iodine supplementation. As will be discussed later in this review, Brownstsein and colleagues have seen this especially in thyroid diseases, and cancers of the thyroid, breast and ovary. The iodine loading test is reminiscent of the glucose tolerance test where glucose metabolism is assessed by challenging the system with 75 g of glucose and then watching over several hours the changes in blood glucose. In the iodine test, it is also like seeing how full a glass is by not looking but trying to fill it. The overflow provides the answer.

There is considerable evidence that there is a problem worldwide regarding iodine deficiency, but to assess the iodine status involves a test which is not simple, and in fact appears to be available only in four laboratories in the U.S. But kits can be ordered and the samples mailed, and thus anyone wishing to know where they stand can get this test. The two labs with the longest track record appear to be

• FPP Laboratory
  
• Hakala Laboratory

The iodine added to salt can be sodium or potassium iodide or sodium or potassium iodate. The amounts are rather variable and some individuals do not purchase iodized salt or salt naturally containing iodine and thus eliminate what may be their only source of this element. The food sources high in iodine include seafood, seaweed, and kelp. The black nori used to wrap the rice and filling in sushi is also very high is iodine. The current high profile recommendations to reduce salt consumption should also have a deleterious impact on iodine status, although the major salt source is in prepared food, and this may not be fortified.

WHY IS IODINE DEFICIENCY INCREASING?
To understand the forces at work here one must appreciate that iodine is a member of the halide family, familiar to chemistry students as occupying a column on the periodic chart. Other members important in our discussion are fluorine, chlorine and bromine. Of these, bromine compounds play the most important role in inducing iodine deficiency by direct competition. In his book, Brownstein discusses a number of cases where iodine loading dramatically increase bromine excretion and enhanced bromine levels are characteristic of those deficient in iodine.

The seriousness of the problem presented by bromine can be appreciated by the fact that it is widely encountered in the environment. Examples include fire retardants found in numerous consumer products, bromates used as an additive in bread and bun dough, the use of bromine compounds in swimming pools, and their presence in medicines. The increased use of bromine-containing chemicals over the pasts several decades may be the simplest explanation for the decrease in iodine status worldwide.

Intake of perchlorates also decreases iodine status. Perchlorates from industrial, rocket and weapons sources are also a problem in connection with iodine status and there is considerable ground water and river contamination. This in turn results in perchlorate-containing produce, especially from the Southwest US.

Fluorine also interferes with iodine and exposure to fluoride is hard to avoid. It is added to drinking water in many cities and as well it is almost impossible to find fluoride-free toothpaste except in health food stores. All of this is in spite of the absence of convincing evidence that fluoride decreases the risk of dental cavities and in fact, there is considerable evidence falsifying this hypothesis. Avoiding bromine and fluorine and chlorine containing compounds in drinking water can be achieved by using a reverse osmosis system just for drinking and cooking water, a relatively inexpensive approach to pure drinking water which also removes numerous other impurities and toxins. However, in the process, healthy minerals obtained in part from drinking water are lost and must be replaced by supplementation or diet.

Finally, if a hypothyroid condition is treated with a thyroid hormone preparation and there is also an iodine deficiency present, this therapy will exacerbate the iodine deficiency. In other words, the treatment increases the body's need for iodine but there is no additional iodine being supplied.

With this background in mind, we will now discuss the evidence connecting iodine deficiency with breast cancer.

BREAST CANCER

IODINE DEFICIENCY AND BREAST CANCER RISK
There is considerable circumstantial evidence linking iodine deficiency to the prevalence of breast cancer. In addition, there are case histories suggesting that iodine supplementation can slow the progression or even eliminate breast tumors. This evidence is as follows:

• In the developed world Japan has one of the lowest age-adjusted rates of breast cancer mortality with 6.6 per 100,000 as compared to 27.7 and 22.0 for the UK and the US respectively.4 The daily intake of iodine in Japan has been estimated to range from 5 to 13 mg, mostly obtained from seaweed products such as nori, wakame and kombu. Other seafoods are also important sources of iodine in Japan. By comparison, in the UK and US, the average iodine intake is approximately 0.17 and 0.21 mg/day. When Japanese women migrate and adopt the Western lifestyle, the risk of breast cancer increases toward that of women in this new environment. This tends to rule out a genetic factor for the huge disparity in Japanese vs. Western rates of breast cancer mortality.

• During pregnancy and lactation, hormonal stimulation of the mammary gland leads to glandular differentiation and a dramatic enhancement of both iodide absorption and local generation of free iodine. This generation occurs in the same regions of the breast anatomy where the majority of breast cancers arise. It is well known that pregnancy and lactation reduce the risk of breast cancer.5

• Molecular iodine (I2) is effective in diminishing mammary dysplasia and atypia secondary to iodine deficiency.5

• Breast cancer patients are much more likely to exhibit thyroid disease manifest by goiter.6

• Studies with cultured breast cancer cell lines find that an uptake of molecular iodine has an anti-proliferative effect7 and can induce apoptosis (programmed cell death).7,8 Molecular iodine also inhibits the growth of human breast cancer cells.9

• Five case histories presented in Brownstein's book1 illustrate the potential for iodine supplementation to correct iodine deficiency in breast cancer cases and individuals presenting with fibrocystic breast disease. The positive results in the context of these breast diseases will be discussed below.

TOXIC HALOGENS FLUORINE AND BROMINE AND THE BREAST CANCER EPIDEMIC
In his book on iodine, Brownstein asks the question, "Are the toxic halogens fluoride and bromine responsible for the epidemic rise in breast cancer?" This question follows naturally from the information presented above. If one turns to the literature for an answer, it does not appear to be there, which is not surprising. Brownstein describes a study he undertook among his own breast cancer patients. Comparison was with patients who did not have breast cancer. Urinary levels of bromide and fluoride were measured at baseline, one day after taking 50 mg of Iodoral, a commonly used supplement, and 30 days after taking this dose daily. Iodine levels from loading tests were low for all the women tested. As described above, iodine loading displaces bromine and fluorine. What he found was that bromide and fluoride levels were significantly elevated in breast cancer vs. non-breast cancer patients, suggesting that the cancer patients were absorbing and retaining larger amounts of the toxic halides as compared to the controls. This observation clearly deserves to be followed up but even in the absence of a more detailed study, it adds to the importance of achieving and maintaining an iodine sufficient state and this may require ingesting more iodine when the potential for bromide and fluoride intake is high. It also highlights the importance of avoiding these two halogens.

IODINE IN BREAST CANCER THERAPY
There appear to be no organized clinical trials, much less randomized placebo controlled trials. Iodine supplements can not be patented. One of the best preparations was "invented" in 1829 by a French physician named Jean Lugol and is still very popular! Your editor obtains his Lugol's solution from a compounding pharmacy. There is absolutely zero incentive for pharmaceutical companies to conduct studies and in fact cynics wonder if they really want to "cure" cancer. This leaves foundations and government. But iodine deficiency and its role in cancer is totally off the radar screen of mainstream medicine, and thus one is left with little hope of definitive trials and case histories thus are the only source of information regarding efficacy. The safety issue is better researched. Here are five case histories from David Brownstein's book.1

Case History #1. The patient, age 60 was diagnosed with breast cancer in 1989. A holistic doctor put her on 2 mg/day of an iodine supplement. She felt fine for over 10 years, but developed metastatic disease in 2005. She was started on 50 mg/days of a supplement (Iodoral, the tablet form of Lugol's solution). A PET scan 6 weeks later showed her tumors disintegrating. Brownstein commented that he has seen similar results with nodules, cysts and tumors in the thyroid, ovary and uterus. Unfortunately, there was no additional follow-up reported.

Case History #2. The patient, 73 years of age, was diagnosed with breast cancer in 2003. Refused conventional therapy on the grounds that those promoting it could not provide statistics acceptable to her concerning the impact on mortality. She was then treated by Dr. Brownstein. He found her severely iodine deficient. She was treated with 50 mg of Iodoral. Her bromine excretion increased as expected and was still elevated after 30 days but now her iodine excretion was up from a very low amount to 30% of the 50 mg dose. After 3 months on iodine with an additional holistic regimen she felt significantly improved with vastly enhanced energy levels. An ultrasound at 18 months found the malignancy considerably diminished as compared to a baseline scan. After two years on the program, mammography indicated no cancer present which was consistent with an ultrasound done at the same time. This is not an isolated case. Dr. Brownstein states that these results have been repeated over and over in his practice.

Case History #3. This 52-year-old patient was diagnosed with breast cancer two years prior to the writing of this history. She refused chemotherapy and radiation therapy. She had a long history of fibrocystic breast disease which appears to put one at enhanced risk of developing breast cancer. She also had a goiter. Brownstein's tests indicated a poorly functioning immune system and severe iodine deficiency (12% excretion of the load dose whereas the normal is 90%). After 3 months on 50 mg/day of Iodoral her iodine deficiency had resolved and along with this came an improvement in energy and overall feeling of good health. The symptoms of her fibrocystic disease decreased significantly. After 3 years of maintaining iodine sufficiency, she continues to feel well and there have been no signs that the cancer is progressing. In fact, the lesions seen on radiological examination have gotten slightly smaller.

Case History # 4. A 45 year old nurse had suffered from fibrocystic disease for over 15 years. The condition caused her significant pain and made exercising difficult. Frequent drainage of breast cysts was necessary. She was even considering the mastectomy option. She was found to be severely iodine deficient and was treated with 50 mg/day of Iodoral. It took only one month to dramatically reverse her condition, which seemed like a miracle.

Case History #5. This is another case of fibrocystic disease, this time in a 39 year old woman. Again there was a big issue with pain, her iodine loading test revealed a deficiency with only 50% of the load excreted. It took just 2 weeks of Iodoral to significantly eliminate this painful condition and increase her energy and mood levels.

While the two case histories involving fibrocystic disease are not examples of cancer treatment, this condition is regarded as potentially precancerous, and thus these cases are closely related to the main theme of this review.

BIOLOGICAL PLAUSIBILITY OF IODINE DEFICIENCY IN BREAST CARCINOGENESIS
Both the thyroid and the breast are major locations where iodine concentrates. The salivary glands and gastric mucosa also have the ability to concentrate iodine. Thus breast health would be expected to depend on having iodine levels consistent with the demands set by human genetics. As discussed above, there is considerable circumstantial and anecdotal evidence that iodine status is involved in the prevalence of cancer and fibrocystic breast disease and correcting deficiencies can reverse fibrocystic changes and impact breast cancer progression and may even affect regression or a complete cure. Given this, it is surprising that there is so little work reported on potential mechanisms that might account for these observations, observations that go all the way back to before 1990. Today, iodine deficiency seems to be where vitamin D deficiency was in the 1980s. The recommended intake was set to prevent rickets for vitamin D and for Iodine, the focus is still on the minute amounts required to prevent goiter but totally inadequate to provide sufficiency or counteract the onslaught of interfering chemicals. Mainstream medicine does not appear to think iodine deficiency is significant, and there appears little incentive and probably little money for research into the details to the biochemistry associated with the observations and results presented above.

Information concerning potential biochemical mechanisms whereby iodine exerts its influence in breast cancer comes mostly from cell culture studies of breast cancers cells. The general observation is that molecular iodine but not the iodide ion (as from potassium iodide) exhibit potent anti-proliferative effects and impact apoptosis (programmed cell death, a critical aspect of normal cell biology), and that these effects are consistent with animal experiments where mammary cancer is induced chemically. In breast cancer cells, treatment with iodine activates an apoptotic pathway which has been shown to be mitochondrial mediated.10 The search for active derivatives generated by the reaction with iodine has found that a potent compound involved in the inhibition of cancer cell growth is the result of the reaction of iodine with the long-chain omega- 6 fatty acid familiar to readers of this Newsletter, arachidonic acid, which is a major fatty acid in cell walls.8,9,11 It is called 6-iodolactone.11

Animal and cell culture studies do not however, shed much light on how iodine might function to prevent the formation of cancer cells in the first place. It is well known that reproductive history has a consistent effect on increasing or decreasing the risk of developing breast cancer. Early age at menarche, late age at menopause, and not having any pregnancies increase the risk, as does the failure to breastfeed over an extended period. However, as was pointed out some time ago, the majority of women who develop breast cancer do not have any of these risk factors.12 During pregnancy and lactation, hormonal stimulation of the mammary gland leads to glandular differentiation that dramatically enhances both iodide absorption and local generation of free molecular iodine.5 It has been suggested that a high iodine concentration in breast tissue also explains the reduction in breast density often observed following pregnancy and lactation, and that this plays a role in decreasing the risk of developing breast cancer.5

There is also some evidence that iodine can function as an antioxidant and that maintaining a high iodine status as seen in for example Japanese women, affords protection that is in part antioxidant mediated.13

• Lugol's solution, a mixture of 5% iodine and 10% potassium iodide in water. This mixture allows the preparation of a solution with a high concentration of iodine because the potassium iodide and iodine react to form the triiodide ion which provides the high solubility. One drop contains about 5 mg of iodine and 7.5 mg of iodide. This 12.5 mg amount provides what Brownstein terms a physiologic dose. The intake is similar to the average in Japan.
• Iodoral is essentially a tablet formulation of Lugol's solution and is sold in doses of 12.5 and 50 mg per tablet.
• Iosol is also a mixture of iodine and iodide, but ammonium iodide is used instead of potassium iodide. It is sold as a liquid and one drop contains 1.8 mg of iodine total.
• SSKI is simply a saturated solution of potassium iodide, and thus only a source of the iodide ion. Brownstein does not consider this a satisfactory supplement.

The approach to correcting chronic iodine deficiency described above for the treatment of clinical indications such as breast cancer or fibrocystic breast disease involves doses vastly greater than the recommended daily allowance which is about 0.15 mg/day. The conventional reaction to this is to worry about adverse effects, i.e. are high doses safe and what is the evidence. In general terms the high intake in Japan suggests that doses averaging about 13-14 mg/day are completely safe since there is no evidence from Japan that the iodine-rich diet carries enhanced risk for any disorder. Brownstein and his colleagues have been using 50 mg/day over long periods as a therapeutic dose with no problems, and he reports in his book that other physicians who also use this dose level therapeutically have the same observation. Nevertheless, critics are quick to make a list of potential safety issues. They are allergy, autoimmune thyroid diseases, detoxification reactions, iodine-induced hypothyroidism and goiter, iodine-induced hyperthyroidism, iodism (a metallic taste and associated headache) and thyroid cancer. Brownstein finds these to all be very rare. As regards thyroid cancer, if increasing iodine levels increased the risk, then it is hard to explain why declining levels over a number of years have been accompanied by an increase in thyroid cancer. It is only common sense that the use of therapeutic doses should be done under the supervision of someone knowledgeable in the symptoms of these side effects. But this of course presents a serious problem since there are only a very limited number of physicians who are even aware of the material in this review or Brownstein's book. However, if one lived in Japan and ate the traditional diet, would one worry abut the potential intake of 10-15 mg/day of iodine? If not, then perhaps one should not worry about a drop or two a day of Lugol's solution.

There is also the question of how much iodine supplementation to take simply for prevention and promoting overall health. From what has been discussed above, it should be clear that this is not a simple question and is only answered satisfactorily after an iodine loading test and this is not a test that can be routinely ordered to be done at the local clinical laboratory. Also, the amounts needed depend on the bromide-fluoride status of the individual. One can order a test kit, supplement on the basis of the result with Iodoral or Lugol's solution, and then repeat the test, eventually arriving at a dose that maintains one above 95% excretion. In other words, not a simple matter and most easily done with the help of a doctor experienced in this problem.

THYROID CANCER

Thyroid cancer is relatively uncommon, accounting for 0.5 to 1.5% of all cancer worldwide. However, it is the most common endocrine malignancy. There is much less information available from the literature and anecdotal sources concerning the association between iodine status and thyroid cancer. Part of the problem concerns estimating prevalence changes and their correlation with the addition of iodine to salt. Also a major issue is that over the past two to three decades there has been a significant increase in the use of carotid artery ultrasound to screen for and study atherosclerosis. Since the thyroid gland is also imaged during this procedure, thyroid nodules are found that otherwise would have remained unnoticed. This can prompt a biopsy, the discovery of cancer, and thus an increase in prevalence associated with what amounts to unintentional screening. This presents a problem when one attempts to correlate estimated changes in iodine intake and the incidence of thyroid cancer over this time period. Furthermore, the iodine intake in many countries is very low compared to some Asian countries and while salt fortification impacts goiter prevalence, comparing cancer incidence in areas of high goiter incidence with that where the goiter incidence is low still involves comparing populations where the iodine intake can be quite low. Furthermore, there may be a considerable variation in the intake of bromates, perchlorates and fluorides, and as discussed above, iodine intake studies would need to be corrected for this when examining the association between iodine and cancer rates.

The three general types of thyroid cancers are anaplastic, follicular and papillary. The latter is considered much less dangerous. It appears that the overall incidence of all types is not influenced by iodine intake in a population, but iodine intake can shift she distribution in favor of papillary carcinomas. Brownstein points out that thyroid cancer incidence have increased along with iodine deficiency, which is inconsistent with the view of some that increased iodine intake increases the risk. In addition, the incidence of thyroid cancer in Japan14 is much lower than found in the data from the US SEER registries. Thus, while the question of increased risk associated with high intakes of iodine and thyroid cancer has received little study, there is little indication that there is a risk. Also, comparison between areas with adequate or high iodine intakes, iodine deficient regions have a higher proportion of aggressive follicular and anaplastic carcinomas.15

As regards the use of high-dose iodine for the treatment of thyroid cancer, there does not appear to be either studies or anecdotal evidence.

PROSTATE CANCER

Just like breast cancer, prostate cancer prevalence in Japan is much lower than in the US and Japanese men who move to the US have higher incidence than mainland Japanese, the same phenomenon as seen for breast cancer in Japanese women. In fact, Japan has one of the lowest age-adjusted prostate cancer rates in the developed world (13/100,000 vs. 125/100,000 in the US).16 Iodine status as measured by a casual urine sample in Japanese men ranges from 800 to 3400 microg/L whereas for US men a typical value would be 50 microg/L.16 In a Japanese case-control study, a 53% reduction in relative prostate cancer risk was found in men who had a high consumption of seaweed, a significant source of iodine in the Japanese diet.17 Similar results have been reported in other studies, but exhibited only trends rather than a clear-cut benefit.

A recently reported prospective study of iodine status, thyroid function and prostate cancer based on the National Health and Nutrition Examination (NHNES) database found that a history of thyroid disease and a > 10 year period since its diagnosis were significant predictors of prostate cancer. For thyroid disease, the enhanced risk of prostate cancer was 134%.18 There also appears to be a connection between thyroid cancer and prostate cancer. An increase risk of prostate cancer follows the diagnosis of thyroid cancer and conversely, an increase in thyroid cancer follows a diagnosis of prostate cancer.

Thus there is only circumstantial evidence that iodine deficiency is a risk factor for prostate cancer but no studies appear to have been done on the treatment of prostate cancer using therapeutic doses of iodine nor is there anecdotal evidence of therapeutic benefit.

CONCLUSIONS

Mainstream medicine views prevention as involving measuring cholesterol, blood pressure, markers of kidney and liver function, and fasting glucose (which incidentally is not be best way to examine how well glucose metabolism is functioning). Aside from this, it is mostly a wait-for-symptoms game. Screening for such disorders as prostate or breast cancer is plagued by false positives and the resultant over-diagnosis and treatment. It has taken several years, hundreds of papers and the efforts of a handful of experts for us to have reached the point where vitamin D status is on the radar. It is doubtful that recognition of the role of iodine in health will come as quickly. Ask your family physician for an Iodine load test. The reaction should be fascinating.

This review raises the obvious question, is breast cancer in part an iodine deficiency disease? The circumstantial evidence seems quite strong and the hypothesis certainly deserves critical examination. If true, then the indicated therapy is both trivial, safe and inexpensive and of course of no interest to Big Pharma or probably even to conventional oncologists who think in terms of chemotherapy, surgery and radiation, the complete solution. An interesting situation. The same question can be raised for thyroid and prostate cancer, but unfortunately there is much less information available. However, enough is known regarding the connection of iodine with all three of these cancers so that there should be strong motivation for additional experimental and clinical studies.