A43: Antidotes in Depth

Potassium iodide is the antidote to radioactive iodine that may be released into the atmosphere following a nuclear incident. It is approved as a specific blocker of thyroid uptake of radioiodine to reduce the risk of thyroid cancer in susceptible populations. The indications for its use are complex and initiation and maintenance of therapy require great attention to the details of the circumstances of the exposure to limit harm that may result from either undertreatment or overtreatment.

Following the study of thyroid cancers in Pacific Islanders who were subjected to fallout from nuclear testing, scientists concluded in 1957 that potassium iodide (KI) could effectively protect the thyroid from radioactive iodine. The National Council on Radiation Protection and Measurements (NCRP) reported in 1977 that the sudden release of radionuclides, including radioiodine, could affect large numbers of people following a nuclear incident (Fig. A43–1). The following year the US Food and Drug Administration (FDA) requested the production and storage of KI for the purpose of blocking the effects of radioiodine on the thyroid gland when needed.

Chemistry

Iodine is a chemical element, symbol “I,” atomic number 53. Its name derives from the Greek iodes meaning violet, owing to the violet color of elemental iodine vapor. Like other halogens, iodine occurs mainly as a diatomic molecule I₂. Although it is considered a relatively rare element, it is the heaviest essential element used widely in biologic functions. Of 37 iodine isotopes, only ¹²⁷I is stable. The term iodide refers to the ion I^–, which forms inorganic compounds with iodine that is in the oxidation state –1, such as potassium iodide.

Mechanism of Action

Neonates, children, and adolescents are particularly susceptible to the toxic effects of radioactive iodine. During the growth periods for these groups there is increasing growth of the thyroid gland, as well as an increase in thyroglobulin and iodothyronine stores. Thyroid tissue also accumulates a larger percentage of exogenously ingested iodide and more efficiently reuses iodine from degraded hormone. This increased activity during these growth periods explains the greater risk for developing thyroid cancer in children compared to adults following exposure to radioactive iodine. During pregnancy, the maternal thyroid gland is stimulated and takes up more iodine compared to other adults, thus increasing susceptibility in pregnant women to the toxic effects of radioiodine.

Exposure to radioactive iodine may occur via inhalation or via ingestion of contaminated food, as occurred following the Chernobyl incident. Radioiodine may be rapidly absorbed from either the digestive or respiratory tracts. Once incorporated into the thyroid gland, radioiodine exposes thyroid tissue to β and γ emissions, potentially leading to genetic alterations and cancer.³ This is the stochastic effect of radiation (Chap. 134).

Because the chemical properties of radioactive iodine are unchanged from stable iodine, prophylaxis with KI is effective via isotopic dilution. That is, KI competes with radioactive iodine for the active iodine transport system to reduce or dilute the concentration of radioiodine in the serum making the uptake of radioiodine much less likely, essentially blocking it.

Evacuation and Food Interdiction.

KI is not a panacea for radiation exposure. Even if appropriately used during a release of ¹³¹I, KI will not protect against direct radiation exposure or against other radioactive elements that may be included in fallout (ie, cesium and strontium). Depending on radiation levels, communities may be evacuated from areas surrounding a nuclear power plant experiencing a release of radioactive material. Evacuation is most effective if implemented before the passage of a radioactive plume, but this should be guided by dose estimates provided by public health authorities.

The FDA and World Health Organization (WHO) both recommend food interdiction and food control as the principal means to limit public exposure to contamination. Contaminated food that is subsequently canned may ultimately pose no risk to the population if it is stored for sufficient time to allow the radioactive iodine to decay completely. The WHO considers food control to be preferable to iodine prophylaxis and the removal of milk from the diet of some populations to be unfortunate but acceptable.^5,16

Pharmacokinetics

Dietary iodine is well absorbed from the small intestine under normal conditions. It distributes selectively into the thyroid gland, but also to a lesser extent into salivary glands, choroid plexus, and gastric mucosa. Iodine has a volume of distribution of 0.3 L/kg. During pregnancy and lactation, iodine distribution to mammary glands and ovaries increases.

Iodide that is not concentrated in the thyroid is excreted 80% in urine and 20% in feces, although additional losses via sweat can occur and can become an important route of loss in warmer climates. Urine iodine concentrations reflect plasma concentrations and have been used for years as a means to assess dietary iodine intake.

Pharmacodynamics

Iodine, or its ionic form iodide (I^–), is an essential nutrient present in humans in minute total body amounts of 15 to 25 mg. Iodine is required for the synthesis of the thyroid hormones l-triiodothyronine (T₃) and l-thyroxine (T₄), which in turn regulate metabolic processes and determine early growth of most organs, especially the brain. Iodide is actively transported with sodium into thyroid follicular cells, where it is concentrated 20 to 40 fold compared with its serum concentration. It is then transported into the follicular lumen where it iodinates thyroglobulin to form T₃ and T₄ (Chap. 56). Thyroid hormones are metabolized in hepatic and other peripheral (meaning extrathyroid) tissues by sequential deiodination.

Studies have shown over the last 50 years that radioactive iodine uptake can be effectively blocked by KI supplementation.² In nuclear radiology, administration of iodine containing contrast media can deliver up to 45 times the recommended daily intake of free iodine and delay the uptake of therapeutic ¹³¹I for several weeks.^7,15 Following the incident at Chernobyl, the Polish government distributed nearly 18 million doses of KI to the people in its most affected provinces (in addition to food interdiction), while none was distributed to affected areas of Ukraine and Belarus. Studies of these differently treated populations who were exposed to the radioactive plume clearly demonstrated not only a dose-response relationship between radiation dose and the relative risk of thyroid cancer, but also a threefold reduction of this risk via KI supplementation.^3,9 Although some controversy exists regarding increased numbers of detected thyroid cancers possibly due to improved screening, other studies bear out the true increase in these tumors, and also distinguished by genetic analysis radiation-induced cancers from sporadic papillary cancers.^1,10

After the Fukushima incident, the Japanese government gave orders to distribute KI at evacuation sites, but this did not occur. Data on the aftermath of this event are still forthcoming. Interestingly, a shortage in the United States of commercially available KI existed at the same time.¹¹ Chernobyl remains the largest experience of KI distribution following a release of radioactive material from a nuclear incident from which data and recommendations are derived.

Thyroidal Effects

Extensive experience with treating goiter and the use of nutritional supplements in the form of iodized salt has shown that both hyper- and hypothyroidism may result from supplementation with KI.¹³ Specifically, treatment with KI is linked to occasional hyperthyroidism, and iodized salt programs have been associated with subsequent hypothyroidism and thyroid autoimmunity. Both the prevalence of goiter and subclinical hypothyroidism can increase when iodine intake is chronically high. The Wolff-Chaikoff effect, where high concentrations of iodine inhibit the synthesis of thyroid hormones, may be devastating to fetal neurologic development in pregnant women treated with KI, which is why both the FDA and WHO advise against repeat dosing of KI for pregnant women if possible.^5,16

A large study in Poland following the Chernobyl incident investigated the risks and benefits of KI prophylaxis. Of the thousands of men, women, and children who were studied, the vast majority of whom received a single dose of KI, no statistical differences were found between treated and untreated groups when thyroid stimulating hormone (TSH) concentrations were measured among all populations. Additionally, among adults with thyroid disease, no cases of thyrotoxicosis or exacerbation of preexisting thyroid conditions were found. Although pregnant women were not mentioned per se, children born in 1986 and examined in the second and third years of life showed no difference in thyroid status compared with those born after radioiodine was gone from the environment. In newborns, 12 of 3214 treated on the second day of life showed transient decreases in serum free T₄ but had no clinical sequelae.⁸ Another systematic review of studies reporting adverse effects of iodine used for thyroid blocking, which also did not mention pregnant women, concluded that KI supplementation seemed not to induce severe adverse effects, but also that scientifically sound studies of this subject are scarce and provide only weak evidence.¹³

Extrathyroidal Effects

Many extrathyroidal effects of KI are described. Sialadenitis, or iodide mumps, is an inflammation of the salivary glands and appears to be unpredictable. Iododerma is a rare and reversible acneiform eruption related to iodine ingestion that may result from nonspecific immune stimulation.¹¹ Other reactions reported in association with KI use include gastrointestinal disturbances, fever, and shortness of breath.

Although some reports use imprecise definitions when attributing adverse reactions to iodine or iodide-containing medications, “allergy” refers to a specific immune response to target proteins via an immunoglobulin E (IgE) triggered release of cell mediators, such as histamine. There are no studies that demonstrate IgE antibodies to small molecules such as iodine or iodide.

“Allergy” to radiocontrast media is actually an anaphylactoid response to the high osmolarity of these xenobiotics. Anaphylactoid responses manifest by release of similar mediators to anaphylactic response but via non–IgE-mediated pathways. An anaphylactoid response to iodine-containing medications or iodinated contrast materials may be predicted in patients with asthma, allergic rhinitis, and food allergies to chocolate, eggs, and milk. While seafood may contain iodine, allergy to fish or shellfish is due to specific marine proteins and not sensitivity to iodine. Patients manifesting allergic contact dermatitis resulting from iodine containing cleaning preparations such as povidone-iodine do not react to patch testing with KI. Therefore, when physicians consider the safety of KI dosing in the event of radioactive iodine exposure, reactions to radiocontrast media, seafood, and povidone-iodine should not be interpreted as an allergy to KI. Physicians must also consider that there are inactive ingredients or diluents of the KI formulation.

Potassium iodide is listed in pregnancy category D and readily crosses the placenta and distributes into milk. Both the FDA and WHO support the use of KI for pregnant women when instructed to do so by public health authorities.^5,16

After reviewing data from Chernobyl regarding estimated doses and cancer risks in exposed children, the FDA provided recommendations for KI supplementation for various populations, depending on their relative risks (Table A43–1).^5,16

Adults older than 40 years of age face a near-zero risk of developing thyroid cancer from exposure to radioactive iodine. For this group, the complications from iodide supplementation, such as goiter or Graves disease, would likely outweigh any benefit in the setting of relatively mild exposure. However, if public health experts determine that exposure dose may be 5 Gy (500 rad) or greater, which is only likely to occur for those living within a 10 mile radius of a nuclear power plant release, KI is recommended.

Adults 18 to 40 years of age are at risk of developing thyroid cancer that is approximately equal to the risks of side effects of a single dose of iodide supplementation, although it should be understood that both risks are very small. The decision to treat should be based upon the threshold criteria used as well as the risks of iodine supplementation, such as iodine reactions, or a history of past thyroid disease.

Lactating mothers should take KI when instructed to do so by public health authorities. KI is secreted in breast milk and will offer some protection to a neonate, but the risks of treatment are much higher in these patients requiring greater attention to monitoring, as discussed below.

Pregnant women have increased thyroid uptake of iodine, especially in the first trimester, compared with other adults. The developing fetus has increased iodine uptake during the second and third trimesters. Because iodine crosses the placenta, the fetus may potentially be exposed to radioactive iodine, thus supplementation with KI is only recommended at appropriate exposure thresholds.

Children 1 month to 18 years of age are at high risk of thyroid cancer from exposure to radioactive iodine and are at low risk of side effects from supplementation with KI. Therefore, supplementation for children in this age group should begin promptly following official notification of a potential radioactive iodine release.

Neonates are at significantly increased risk from exposure to radioactive iodine because of a marked increase in uptake of iodine resulting from neonatal body cooling in the immediate postdelivery period. At the same time, neonates are susceptible to functional blocking by overloading with stable iodine. Therefore, when supplementation is indicated, KI should promptly be given to neonates with critical attention to dosing. The WHO recommends the KI solution be available for maternity wards in the precise dosing for newborns. Since the most critical time period for thyroid blockage is within the first postpartum week, dosing neonates who are older than one week may be performed at home via dividing, crushing, or suspending tablets in milk, formula, or water.

Timing of Administration

For full blocking effect, KI should be administered shortly before exposure or as soon as possible afterward. Some models describe the blockade of only 50% of iodine uptake when there is a delay of several hours following an exposure.⁶ Depending on the duration and type of risk, administration of KI months after an exposure may also partially reduce thyroid cancer risk.^6,17

Daily Versus Single Dosing

The protective effect of potassium iodide lasts for about 24 hours, so it should be dosed daily for those groups in whom an ongoing risk is perceived. Depending on the dosing estimates for exposure, this group is primarily children aged 1 month to 18 years. Groups in whom a single dose is recommended include pregnant women and neonates, where there is a significant risk of causing harm to the fetus via impaired cognitive development. For lactating women, stable iodine will be delivered to the nursing newborn and may cause functional blocking of iodine uptake by an overload of iodine. Therefore, the FDA recommends that lactating mothers not receive repeated doses except during continuing, severe contamination, which would generally be defined by health officials.

As mentioned previously, Chernobyl is the most significant ­massive release of radioiodine in history and nearly all of our experience and ­recommendations in this type of setting derive from this one event. Although distribution of radioiodine was uneven in Poland, the air concentration of radioiodine had decreased fourfold one week after the first explosion. Therefore, KI prophylaxis was not repeated. It is perhaps based on this experience that it is generally thought that no more than one or two doses of KI would be needed following release of a single radioactive plume, during which other protective measures such as food interdiction or sheltering measures are implemented. While the possibility exists that many repeated releases of radioactive gas might require prolonged prophylaxis, repeat dosing for days to weeks may not be necessary.

Monitoring

Normal thyroid function is critical for proper brain development in a fetus. Just as a fetus and newborn is susceptible to radioiodine uptake, they are also at risk for development of hypothyroidism from repeat dosing of KI. All neonates who are treated with KI in the first weeks of life should be monitored for changes in thyroid stimulating hormone (TSH) and free T₄. Likewise when a lactating mother requires repeat doses of KI, the nursing infant should also be monitored for the development of hypothyroidism.

Several manufacturers formulate potassium iodide and market them as nonprescription, FDA approved products with a shelf life of 7 years. Longevity studies over many years have demonstrated the active ingredients of KI to be very stable. Recognizing that many state and local governments maintain stockpiles of KI for use in the event of a radiation emergency (KI is a part of the US Strategic National Stockpile (SNS), which consists of a large quantities of medications and supplies ready for use in a public health emergency), the FDA has developed guidelines for shelf life extension that manufacturers may use to extend the shelf lives of their products in increments of 2 years.⁴ Tablets are available in both 130 mg and 65 mg doses, as well as an oral solution in a concentration of 65 mg/mL. Iodide containing products not considered useful in radioiodine protection include iodized salt, seaweed, and tincture of iodine.

• KI is a safe and effective means of blocking the uptake of ¹³¹I following a nuclear catastrophe.

• Firm reliance on the evaluation of health officials of the risk of exposure is vital since the overall likelihood of exposure to the critical radiation threshold is very low, except for those living within 10 miles of a nuclear reactor.

• Exposed persons should strictly adhere to dosing guidelines to minimize the potential risks of KI dosing, especially in pregnant women and newborn children.

• “Iodine allergy” is not a contraindication to KI administration in the setting of a confirmed release of radioactive iodine.

• Food interdiction and environmental evacuation or avoidance of the radioactive plume are preferable to KI prophylaxis in the event of a potential exposure and may obviate the need for KI completely.

References