2022 Volume 69 Issue 4 Pages 427-440
The daily consumption of iodine in Japan is higher than in most countries, and there are few reports on iodine metabolism and variance of habitual iodine ingestion in an iodine-sufficient area. To elucidate the patterns of short-term urinary iodine excretion (UIE) and long-term variability of habitual iodine intake, the urinary iodine excretion process after a high dietary iodine load of 3 mg was observed in eight Japanese adults under strict supervision with complete urine collections for three days. In addition, estimated UIE and dietary iodine intake (DII) were assessed in 24 university students using repeated spot urine samples of ten consecutive days and a food frequency questionnaire in each of the four seasons. Approximately 50, 75 and 90% of orally ingested iodine was excreted into the urine at 8, 13 and 22 hours after ingestion, respectively. Almost an equal amount of ingested iodine in meals was cleared within 33.5 h after eating with a maximum excretion rate at 3–4 h. There was a high fluctuation in the UIE and DII in the university students. The intra- and inter-individual crude coefficients of variation were 123 or 294.7% for UIE, and 58.3 or 88.7% for DII, respectively, indicating a higher variance of habitual iodine intake than in other countries. The frequency of occurrence for UIE above 3 mg was every 43 days. Rapid renal clearance of iodine and high variability as well as low frequency of dietary iodine intake might prevent people from being exposed to an excess iodine intake over the long term in Japan.
IODINE is an essential dietary micronutrient, and deficient as well as excessive iodine intakes can induce thyroid dysfunction [1-5]. Except in certain susceptible individuals, i.e., those with underlying thyroid disease or predisposing risk factors, a high iodine intake from food is generally well tolerated in healthy adults without adverse effects; however, their tolerance to iodine varies widely [4, 6]. The tolerable upper intake level (UL) is defined as the highest level of nutrient intake, i.e., likely to pose no risk of adverse health effects for almost everyone in the general population. The ULs for iodine in adults established by the U.S. Institute of Medicine [7] and the European Commission Scientific Committee on Food [8] are 1,100 and 600 μg/day, respectively, while in Japan 3,000 μg/day is recommended as the UL [9]. Although the daily consumption of iodine in Japan is higher than in most countries it is not clear that a higher iodine intake results in a high risk of iodine-induced hypothyroidism or autoimmune thyroid disease [2-4]. In addition, the reasons that Japanese people can tolerate a habitual intake of food with a high iodine content and the underlying mechanism have not yet been elucidated.
When a steady state is present, iodine in urine is regarded as a measure used to estimate bioavailable iodine in the diet. Iodine clearance studies using intravenously or orally ingested radioiodine have been reported; however, information on the short-term change of urinary iodine excretion (UIE) from ingested meals is limited [10-25]. In addition, dietary iodine intake (DII) in individuals is highly variable and the range can vary by more than two orders of magnitude depending on the food choices for that day since iodine tends to be concentrated in certain foods. There are few studies on the urinary excretion and variation of dietary iodine intake in iodine-replete regions. To characterize the iodine metabolism in Japanese, a short-term iodine clearance was assessed in healthy adults after high iodine food ingestion in the first experimental study. In the second observational study we assessed the variability of UIE for 10 consecutive days and DII four times a year at three-month intervals in the same university students.
A randomized, single blind placebo-controlled study was conducted. Eight volunteers, seven females and one male aged 21–66 years, were recruited in Kamakura City. They were all healthy volunteers without a past or present history of thyroidal, renal or metabolic diseases. The mean (SD) values of age, height, body weight, and BMI for all participants were 33.5 (19.6) years, 156.4 (5.4) cm, 51.1 (5.8) kg, and 20.9 (2.1) kg/m2, respectively. As a result of randomly receiving iodine-rich egg powder, the participants were assigned to two groups according to the amount of iodine load, i.e., the high iodine load group (five subjects) and the control group (three subjects).
Experimental protocolAll participants stayed in the same hotel for three consecutive days in March 2010 where the room temperature and humidity were constantly maintained. For three days before the study, they were asked to change neither their dietary habits nor their usual daily activities, and to avoid iodine-rich eggs, seaweeds including Kombu and iodine-based mouthwash. During their three-day hotel stay, they were instructed to maintain their daily activities with short showers only and to avoid perspiration-inducing activities, i.e., intense exercise and bathing. All participants consumed meals with the same menu content and drank the same amount of beverage together at predetermined intervals, and were not allowed to eat any other foods throughout the study period. Meal times were 0830 or 0730 h for breakfast, 1200 h for lunch, and 1900 h for dinner. Participants consumed a total of 3,000 mL of water consisting of commercially available natural water, coffee, black tea or orange juice during the 33.5-h experiment. The amount and frequency of fluids consumed was 400 mL for each of five meals and 200 mL five times between meals. The time of fluid intake in addition to meals was 3, 6, 10, 28.5 and 30 hours after the initial iodine load. Dietary energy intake levels were 1,449 and 1,894 Kcal/day for the first two days, respectively, and 1,181 Kcal for the breakfast and lunch on the third day. The estimated energy requirement for Japanese females of 18–29 y is 1,750 Kcal/day at the lowest physical activity level [26].
The first day of the study was used for transition from the individual diet to the experimental diet, and the three meals contained 106.9 μg of iodine and fluid intake was 1,600 mL in total. On the second day at 0830 h, all the participants had the same breakfast with 49.8 g of an egg powder containing either 2,999.8 or 44.8 μg of iodine. Thereafter, all participants both in the high iodine load group and the control group consumed the same meals containing the same amount of iodine. The loading dose of iodine was adjusted to less than 3 mg/day which was the UL for Japanese adults in 2005 [26]. The daily meals were planned and cooked by the competent dietitians (Y.U. and N.T.) Lunch for all three days and breakfast for the first day were prepared by Y.U., while dinner for all three days and breakfast for all but the first day were provided by the hotel. The menu and iodine contents are in Supplementary Table 1.
Under strict supervision by the investigators the urine samples of all the participants were serially collected for 48 hours at 12.5, 9 and 2 hours before, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 22, 25.5, 27.5, 29.5, 31.5 and 33.5 hours after iodine ingestion. Each urine sample was collected into a separate clean container and after the urine volume was measured a 5–mL aliquot from each void was taken and stored at –30°C to measure iodine and creatinine concentrations. For each timed-spot sample, iodine and creatinine concentrations were measured and the cumulative iodine excretion (μg), the ratio of urinary iodine to ingested iodine (%), and the iodine excretion rate (μg/h) were calculated as follows: Ratio of urinary iodine to ingested iodine (%) = iodine content in urine sample (μg)/cumulative iodine intake (μg) × 100; Iodine excretion rate (μg/h) = iodine content in urine sample at each sampling point (μg)/time since the last urine collection (h).
Preparation of high iodine foodThe iodine-rich food was a chicken egg-based powder with different iodine content. An iodine-rich hen’s egg which contains considerably higher amounts of iodine (400–700 μg/egg) than ordinary eggs was developed in 1976 by giving White Leghorn laying hens feed supplemented with seaweed powder and inorganic iodine [27]. The powdered chicken egg was specifically produced for the study by using either iodine-enriched chicken eggs or commercially available ordinary eggs. The high iodine egg powder and ordinary egg powder contain 6.02 or 0.09 mg of iodine/100 g, respectively. The iodine content was determined using inductive coupled mass spectrometry at the Japan Food Research Laboratories (JFRL), Tokyo, Japan. The freeze-dried egg powder looked the same and was prepared in identical numbered packages by staff not further involved in the study. During the study the randomization code was not available to the participants.
Measurement of iodine content of served mealsThe actual dietary iodine intake from the meals was determined using the duplicate portion sampling method. Duplicate meals were homogenized in a mixer (Classic Blender VSB-2, Saney EL, Kanagawa, Japan), frozen and then analyzed for iodine content by gas chromatography at JFRL.
This study was conducted in accordance with the Declaration of Helsinki. Informed written consent was obtained from each participant. The study protocol was reviewed and approved by the local ethics review board in Mareesia Garden Clinic, Tokyo on February 26, 2010. The clinical trial/study was not registered.
Study 2. Variability of urinary iodine excretion study Subjects and study designA total number of 24 healthy university students without a past and present history of thyroid disease from Kamakura Women’s University, Kamakura City and Kanto Gakuin University, College of Human and Environmental Studies in Yokohama City, Japan were recruited. The study group comprised 10 men and 14 women and their mean (SD) age, height, body weight, and BMI were 20.6 (0.5) years, 162.0 (5.0) cm, 53.5 (10.3) kg, and 20.3 (3.1) kg/m2, respectively.
From October 2012 to July 2013 the same participants provided the spot urine samples collected in the early morning before breakfast at their homes for 10 consecutive days according to a defined schedule of an interval of three months. The participants were asked to change neither their dietary habits nor their usual daily activities. Urine samples kept at 5°C in the participants’ homes were collected and then stored at –30°C until analysis. Average daily iodine intake was estimated repeatedly using a food frequency questionnaire (FFQ) in each urine-sampling period.
Assessment of dietary iodine intake by diet studyHabitual DII was assessed by a semi-quantitative FFQ for iodine developed by the authors [28] and given in μg iodine per day. It contained 50 different iodine-rich food items classified in 10 categories with a specified serving size (Supplementary Table 2). For each food item, participants indicated their average frequency of consumption in the previous month by checking one of 10 frequency categories ranging from “almost never” to “three times/day.” The selected frequency category for each food item was converted to a daily intake. Daily iodine intake from each food was calculated based on frequency of consumption and iodine content of the specific food using the Japanese Food Composition Table 2010 [29] or other database when insufficient information was available.
The coefficient of variation (CV) of estimated UIE and DII was assessed with the crude or log-transformed values. The median (IQR) and inter-individual CV of UIC, estimated UIE and DII were computed using all the urine samples and the estimates by FFQ together. The intra-individual CV of UIE was expressed as the median and the IQR calculated by using the CVs of 40 urine samples from one subject. For DII the median and IQR of intra-individual CV was calculated with the median values of the four estimates by FFQ in one subject.
The research was conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from each of the participants. This study was approved by the ethics committee of Kamakura Women’s University (No. 12002) on October 2, 2012 and registered to UMIN Clinical Trial Registry (UMIN000039145).
Measurement of iodine and creatinine content in urineUrinary iodine (UI) and creatinine concentrations were measured at the iodine laboratory of Hitachi Chemical Co., Ltd., Kawasaki, Japan using the ammonium persulfate digestion with spectrophotometric detection [30] and colorimetric enzymatic assay, respectively. The analytical sensitivity of this assay was 1.39 μg/dL and the intra-assay and inter-assay coefficients of variation were 4.8–5.9% and less than 15%, respectively. To ensure the quality of UI analyses this laboratory has been participating in the “Ensuring the Quality of Urinary Iodine Procedures” program by the Centers for Disease Control and Prevention, U.S.A. [31].
Urinary iodine concentration (UIC) was expressed as a concentration in μg iodine per 1,000 mL of urine (μg/L) or relative to creatinine concentration (UI/Cr), i.e. μg iodine per gram creatinine (μg/gCr). Since the 24-h urinary iodine excretion is regarded as representative of 24-h iodine intake, the estimated 24-h UIE is based on measurement of iodine and creatinine concentrations in spot urine adjusted with anthropometry-based 24-h creatinine reference values for healthy, well-nourished adults as suggested previously [32-34]. The UI/Cr (μg/gCr) values from all the casual urine samples were multiplied by the predicted 24-h creatinine excretion (g/24 h) to give a measure for 24-h UIE (μg/24 h). The equation for predicted creatinine excretion was as follows for Japanese adults. Predicted creatinine excretion (mg/24 hours) = 16.14 × height (cm) + 14.89 × weight (kg) – 2.043 × age (years) – 2,245.45 [35]. BMI was calculated as weight in kilograms divided by height in meters squared. To convert μg iodine/L into μmol iodine/L multiply by 0.0079.
StatisticsThe results were presented as mean, SD, median, interquartile range (IQR) or observed range. Since the UIC, estimated UIE and DII were distributed asymmetrically and skewed, their logarithmically transformed values were used to normalize the distribution. Differences between paired data or groups were examined using one-way ANOVA with Tukey’s multiple comparison test, the Kruskal-Wallis test and Dunn’s multiple comparison test. Differences between two unmatched groups for normally or non-normally distributed data were tested using the unpaired t test and Mann-Whitney test, respectively. Simple linear regression analysis was used to test for correlations between UIE and DII. A p-value less than 0.05 was considered significant. Data processing and statistical analysis were performed using GraphPad Prism 8.0 from GraphPad Software Inc., San Diego, CA, U.S.A.
The characteristics of the participants in the two groups are similar with respect to baseline characteristics and renal function (Table 1). All participants except for one 22-year-old female student in the control group were in good physical status and had no adverse reaction to iodine ingestion at the beginning of the study. She had a loose bowel movement with decreasing urine output suggesting mild dehydration in the latter half of the study period.
| Variable | Iodine load group | Control group | p |
|---|---|---|---|
| Number of subjects | 5 | 3 | — |
| Male/Female | 1/4 | 0/3 | >0.999* |
| Age, yrs. | 27 (11.8) | 49.7 (24.1) | 0.116 |
| Height, cm | 156.8 (6.3) | 155.6 (4.8) | 0.788 |
| Body weight, kg | 53.3 (5.7) | 47.5 (4.8) | 0.192 |
| BMI, kg/m2 | 21.7 (2.2) | 19.6 (1.0) | 0.183 |
| Total iodine intake, μg | 3,204.0 | 249.0 | — |
| Total urine output, mL | 3,131 (483.1) | 2,968 (1,746) | 0.843 |
| Daily urine output, mL/day | 1,634 (252) | 1,548 (911.2) | 0.843 |
| Urine output rate, mL/h | 68.1 (10.5) | 64.5 (37.9) | 0.842 |
| Urinary creatinine excretion, mg/day | 1,242 (354) | 1,592 (952.7) | 0.470 |
Values are mean (SD) except for number of subjects, male/female ratio and total iodine intake.
* Fisher’s exact test
The total amount of ingested iodine during the study period was 3,204 μg in the high iodine load group and 249 μg in the control group, respectively. After a single ingestion of 2,999.8 μg the mean cumulative urinary iodine rapidly increased and exceeded 1,000 μg at 5 hours, 2,000 μg at 11 hours and 3,000 μg at 27.5 hours, then reached 3,187 μg at 33.5 hours. In the control group the mean value of cumulative urinary iodine steadily increased from 6.1 μg to 222.2 μg after 33.5 hours (Fig. 1).
Changes of cumulative urinary iodine excretion in healthy adults after high iodine diet loading.
Values are means and whiskers denote SD, lower arrows indicate the time and dose of iodine in foods, n = 5 in the high iodine load group, n = 3 in the control group. The mean age of subjects was 33.5 years.
The ratio of urinary iodine to ingested iodine in both groups gradually increased to 0.5 at 8 hours, 0.75 at 13 hours, and exceeded 0.9 at 22 hours after iodine ingestion. Except for between 2 and 4 hours and at 29.5 hours there were no statistical differences of the ratio between the two groups throughout the study period by an unpaired t test. The ratios in the control group were significantly higher at 2 hours (p = 0.0406), 3 hours (p = 0.0236) and 4 hours (p = 0.0174) than those in the high iodine load group while at 29.5 hours the opposite relationship was observed (p = 0.016) (Fig. 2).
Changes in the ratio of urinary iodine to ingested iodine from meals in healthy adults after high iodine diet loading.
Urinary iodine excretion ratio is expressed in % of loaded iodine, values are means and whiskers denote SD, upper arrows indicate the time and dose of iodine in foods, n = 5 in the high iodine load group, n = 3 in the control group. The mean age of subjects was 33.5 years. There were significant differences in the ratio between the two groups by an unpaired t test, * p = 0.0124–0.0406, ** p = 0.016.
The mean UIE rate 2 hours before iodine ingestion was 4.9 μg/h in the high iodine load group and 3.9 μg/h in the control group without significant differences between the two groups. One hour after iodine ingestion the mean UIE rate in the high iodine load group steeply increased from 4.9 to 179.3 μg/h and reached the maximum value of 246.8 μg/h at 4 hours, then decreased slowly until 25.5 hours and remained between 23.7 and 33.7 μg/h thereafter. In the control group the mean UIE rate fluctuated slightly between 2.9 and 11.5 μg/h throughout the study period although there were no statistically significant differences (Fig. 3).
Changes in urinary excretion rate of iodine from meals in healthy adults after high iodine diet loading.
Urinary iodine excretion rate is expressed as μg/hr of iodine, values are means and whiskers denote SD, upper arrows indicate the time and dose of iodine in foods, n = 5 in the high iodine load group, n = 3 in the control group. The mean age of subjects was 33.5 years.
After high dietary iodine load (2,999.8 μg) the median UIC of spot urine samples increased rapidly from 169 to 2,260 μg/L at one hour, fluctuated widely and reached the maximum value of 3,890 μg/L at 11 hours (average 30.7 times), then gradually decreased to less than 1,000 μg/L after 22 hours while in the control group the median UIC varied between 47 and 262 μg/L (0.7 and 3.1 times) throughout the study period (Fig. 4A). The median UI/Cr ratio in spot urine samples steeply increased from 1,147 to as high as 5,774 μg/gCr at 4 hours (average 67.9 times) then gradually decreased to 527 μg/gCr at 33.5 hours (average 6.2 times) in the high iodine load group. In the control group the median UI/Cr varied between 84 and 343 (0.95 and 3.65 times) μg/gCr (Fig. 4B).
Changes in urinary iodine concentration and iodine/creatinine ratio in spot urine samples from healthy adults after high iodine diet loading.
Iodine concentration in spot urine samples is expressed in μg/L (Panel A) or as iodine/creatinine ratio in μg/gCr (Panel B), values are medians and whiskers denote range, lower arrows indicate the time and dose of iodine in foods, n = 5 in the high iodine load group, n = 3 in the control group. The mean age of subjects was 33.5 years.
The intra-individual CVs of UIC and UI/Cr for the 24 urine samples from the eight participants were 89.2% and 79.9% in the high iodine load group, and 48.8% or 46.9% in the control group, respectively.
Study 2. Variability study of urinary iodine excretionThe height and body weight of males were higher or heavier than those of females; however, their mean BMI and age were similar (Table 2). The median UIC and estimated UIE for all urine samples from the 24 subjects during one year was 223.0 μg/L and 169.1 μg/day, respectively, and there was no gender difference in median UIC and estimated UIE. The DII ranged from 6.6 to 1,583 μg/day with a median value of 256.7 μg/day. The DII in males was more than twice higher than that in females (Table 3). There was a positive but weak correlation between the crude or log-transformed median values of estimated UIE and DII by FFQ (spearman r = 0.2470, p = 0.0158).
| Variable | Total | Male | Female | p |
|---|---|---|---|---|
| Number of subjects | 24 | 10 | 14 | — |
| Age, yrs. | 20.6 (0.5) | 20.8 (0.4) | 20.5 (0.5) | 0.1158 |
| Height, cm | 161.4 (8.4) | 169.2 (5.6) | 155.9 (4.8) | <0.0001 |
| Body weight, kg | 53.8 (9.1) | 60.6 (4.5) | 48.9 (8.4) | 0.0006 |
| BMI, kg/m2 | 20.5 (2.5) | 21.7 (2.2) | 21.2 (2.0) | 0.2681 |
Values are mean (SD) except for the number of subjects.
| Number of subjects | Number of samples | UIC (μg/L) | Estimated UIE (μg/day) | Days1 | Number of FFQ | DII (μg/day) | |
|---|---|---|---|---|---|---|---|
| Total | 24 | 947 | 223.0 (142.0, 438.0) |
169.1 (104.3, 336.9) |
43 | 96 | 256.7 (122.5, 432.1) |
| Male | 10 | 399 | 208.0 (130.0, 447.0) |
173.8 (109.7, 367.0) |
24.9 | 40 | 373.7* (179.6, 550.8) |
| Female | 14 | 548 | 230.5 (151.3, 415.3) |
161.2 (101.4, 326.7) |
91.3 | 56 | 178.2 (109.6, 338.1) |
Values of UIC, estimated UIE and DII are median (IQR).
UIC, Urinary Iodine Concentration (μg/L); UIE, Urinary Iodine Excretion (μg/day); DII, Dietary Iodine Intake (μg/day).
1 Frequency of the days on which high iodine intake occurred (estimated UIE >3 mg/day)
* Male vs. female, p = 0.0018
The number and ratio of estimated UIE exceeding 3 mg/day were 16 of 399 samples (4.0%) in males, 6 of 548 samples (1.1%) in females and 22 of 947 samples (2.3%) in total subjects. High iodine intake occurred every 43 days in the total subjects and was less frequent in females than in males (Table 3).
The intra-individual CVs of estimated UIE or DII were lower than their inter-individual CVs and there was no difference of inter- or intra-individual CV of estimated UIE or DII between males and females (Table 4).
| Intra-individual CV (%) | Inter-individual CV (%) | ||||
|---|---|---|---|---|---|
| Crude | Log-transformed | Crude | Log-transformed | ||
| Estimated UIE | Total | 123.0 (92.5, 180.4) | 17.3 (14.9, 18.3) | 294.7 | 19.5 |
| Male | 168.3 (92.9, 192.4) | 17.7 (15.8, 19.0) | 301.4 | 20.6 | |
| Female | 117.6 (85.1, 147.4) | 16.5 (14.8, 18.3) | 248.6 | 18.5 | |
| DII | Total | 58.3 (40.1, 70.4) | 12.2 (6.7, 15.7) | 88.7 | 18.0 |
| Male | 59.5 (43.4, 103.1) | 11.4 (6.3, 17.5) | 77.9 | 17.1 | |
| Female | 53.2 (38.4, 69.7) | 12.4 (7.0, 14.7) | 89.4 | 17.4 | |
Values of intra-individual CV are the median (IQR) of 24 subjects.
UIE, Urinary iodine excretion (μg/day); DII, Dietary iodine intake (μg/day)
There was no difference of inter- or intra-individual CV of estimated UIE or DII between males and females.
The median values of UIC, estimated UIE, DII as well as inter-individual CV of estimated UIE were higher in autumn and winter than those in spring and summer (data not shown).
From earlier iodine balance studies, it is obvious that ingested radioiodine [36] or stable iodide in foods [10, 11] are nearly completely absorbed in the stomach and duodenum, and rapidly distributed in the extracellular spaces. Under the condition of adequate iodine supply, about 10% of absorbed iodine is taken up by the thyroid gland and approximately 90% of dietary iodine is rapidly excreted into urine [37]. Another 1–2% of absorbed iodine is excreted in feces [1]. The kidney is the main pathway for iodine elimination. Plasma iodide is largely or completely filtered at the glomerulus and some of the filtered I- is mainly reabsorbed passively [38] and in part through pendrin-mediated transport of iodine [39] from the tubular urine [40]. Since the iodine excreted in urine is the sum of ingested iodide which is not taken up by the thyroid and the extrathyroidal iodide derived from the peripheral catabolism of thyroid hormones or iodothyronines by deiodination, the ideal method to measure iodine bioavailability would be to use radioiodine and to quantify urinary and fecal excretion as well as thyroid uptake. In most literature on iodine metabolism using stable iodine the amount of ingested iodine divided by the amount of iodine excreted in the urine is regarded as the urinary excretion rate, because it is impossible to measure the amount of extrathyroidal iodide.
In our first study, a short-term clearance experiment was conducted under strict control for food and water intake with complete urine collection. When a large amount of iodine (3 mg) was loaded the excretion rate markedly increased and peaked at 3–4 h; however, the time for complete clearance was delayed by 10 hours or more than in the subjects who received 44.8 μg of iodine as the first iodine loading. Based on the change in the ratio of urinary iodine to ingested iodine, it can be considered that approximately 50, 75 and 90% of orally ingested iodine was excreted into the urine at 8, 13 and 22 hours after ingestion, respectively. Almost 100% of iodine in meals was cleared within 33.5 hours after eating.
Two peaks in the ratio appeared in the control group at 4 and 27.5 hours after iodine ingestion; however, statistically significant change was not confirmed by ordinary one-way ANOVA with multiple comparisons probably because of the small sample size. It was noteworthy that there was no difference in the ratio of urinary iodine to ingested iodine between the high iodine load group (3 mg of iodine) and the control group (44.8 μg of iodine) except for at the beginning of the iodine load. Although the exact reason for the higher ratio in the control group between 2 and 4 hours after iodine loading was not clear, it might be related to a change in the iodine excretion rate due to the loaded amount of iodine. This may be because as well as in the high iodine load group, a transient increased excretion rate of iodine was observed in the control group which was from 6.1 to 10.0 μg/h (Fig. 3). The other possibility is the effect of intermittent water loading on urinary iodine excretion. Although all participants in the control and high iodine loading groups received the exact same pattern of water loading, it has been reported that a high-water intake even within the physiological range could lead to an additional renal iodine loss in healthy adults and adolescents [39].
Our results suggest that the renal stable iodine clearance was comparable to or more rapid than the results of previous clearance studies using radioiodine administered orally [41-44] or intravenously [43, 45, 46]. The renal clearance rate of radioiodine given intravenously was 70.3% after 24 hours in Japanese subjects [46] and faster than in the New York subjects (53.7%) [45], while the rates of radioiodine given orally were 72 or 88% in Japan [44], and 53 to 81% [41] or 60% [42] in the U.S. within 24 hours after ingestion also suggesting a faster clearance rate of iodine in Japanese. Other studies on short-term excretion process within 24 or 48 hours after a single ingestion of iodine from seaweed or potassium iodide (KI) in adults has been reported in Japan [13], the U.S. [14], the UK [15], France, Belgium [12] and Denmark [16]. In eight Japanese male adults residing in Nagasaki where the mean UIC was 406 μg/dL, around 15% or 30% of ingested seaweed iodine (16.7 mg) or KI (76 mg), respectively, were recovered in urine at 6 hours after iodine ingestion which was consistent with our results [13]. In 25 Caucasian American females a capsule of seaweed containing 475 μg of iodine was consumed daily for seven weeks and the bioavailability of seaweed was 59.8% in the first 48 hours [14]. In Glasgow, UK, a dose of 712 μg of iodine from encapsulated edible seaweed or KI supplement was ingested in 24 healthy females with insufficient iodine intake (median UIC: 78 μg/L). The clearance ratios were 10.5% at 2 hours and 24.6% at 5 hours after receiving KI while those of the seaweed supplement were 0% at 2 hours and 21.1% at 5 hours. Cumulated iodine output over a 24-h period following the ingestion of iodine was 59.1% or 33.6% of the KI supplement or the seaweed supplement group with the peak iodine excretion at 0–2 or 2–5 hours, respectively [15]. The iodide bioavailability of two different types of seaweed (2 mg), KI (2.5 mg) and monoiodotyrosine (1.7 mg) was compared in nine males from Marseille and Brussels, and better bioavailability of iodine in KI than in monoiodotyrosine or seaweeds was observed within 24 hours [12]. In a recent study from Denmark, UI/Cr spot urine samples were measured in 9 euthyroid adults at 6, 12 and 24 hours after eating a meal of sushi with seaweed salad. The UI/Cr value peaked in the 6-h spot urine sample (up to 385%) and returned to preloading levels after 24 hours [16]. Twenty-four Chinese women with a mean age of 22 years provided 24-h urine samples once a week along with duplicated diet samples in 2014 over 4 weeks. The mean iodine excretion ratio calculated by dividing 24-h UIE by dietary iodine intake was 0.55 [17]. These data suggest slower dietary iodine excretion than in Japanese as well as slower gastrointestinal absorption and renal excretion of seaweed iodine in food than KI irrespective of study population or seaweed species. The slower urinary excretion rate of ingested iodine reported in countries other than Japan might be attributed to several factors including absorption from the gut, thyroidal iodine uptake depending on the individual and populational iodine intake level and renal function for iodine excretion. Further research is necessary.
In the first study after ingesting the meals containing even a small amount of iodine, the urinary iodine level expressed as UIC or UI/Cr increased rapidly up to 30.7 or 6.2 times and fluctuated widely at least for one day suggesting that UIC and UI/Cr in single spot samples are inadequate for assessing iodine nutritional status at the individual level. However, to assess a population’s iodine status the median UIC in spot urine samples correlates well with that from 24-h collection samples since the variations in urinary iodine excretion among individuals even out in a large number of samples [2, 3].
In the second study, the crude estimated UIE and DII from foods fluctuated highly with an intra- and inter-individual CV of 123.0 or 294.7% for estimated UIE, and 58.3 or 88.7% for DII, respectively. Several studies on the variance of UIE have been reported in Japan [18], Europe [19-21], South America [22] and China [17]. In 14 young Japanese female adults with the mean age of 25 y residing in Tokyo, spot urine samples were collected five times at three-week intervals from 2009 to 2010. The mean intra- and inter- individual CVs of UIC were 67 and 182%, respectively [18]. The CV of UIE in our study was much higher than this report. In countries other than Japan the intra-individual CVs of UIE ranged from 21 to 48.1% and the inter-individual CVs were 24.0 to 62% respectively, indicating lower CV values than those in Japan. Using a dietary record (DR) three studies on variance of iodine intake from foods were conducted in Japanese adults in 1996–1997 [23, 24], and in 2002–2003 [25]. The median DII for all of the observed days ranged from 107 to 413 μg/day (median 251 μg/day) in three DR studies and was consistent with our result (256.7 μg/day) by FFQ. The intra-individual CV exceeded 100% and was far higher than that in our study (58.3%) [23-25]. In the present study, the intra-individual CV was lower than the inter-individual CV consistent with previous reports [18-22]; however, in two studies from China and Japan the intra-individual CV was higher than the inter-individual CV, i.e., 48.1% vs. 24.0% and 404.2% vs. 48.2%, respectively [17, 23], and these conflicting results are still under debate.
Iodine intake exceeding 3 mg/d was observed in approximately 38% of healthy adults around 50 years in one study [25] and the frequency of occurrence for daily iodine intake above 3 mg was every 8.5 days in another study [23]. In our study the rate and frequency of UIE exceeding 3 mg/day were only 2.2% and once every 43 days suggesting a smaller variation of iodine intake in our study subjects. The reasons for the discrepancy of CV values in UIE or DII among studies could be explained by the differences in diet study methods, gender and age of the participants or iodine status in the study area.
High iodine intake observed between autumn and winter in our study may be attributed to the dietary habit that in cold seasons most people consume iodine-rich “nabemono,” a Japanese stew prepared with Kombu soup stock, more frequently than in other seasons. The major food groups contributing to total iodine intake in Japan are seaweed, i.e., kombu (Laminariaceae), hijiki (Hizikia fusiforme), wakame (Undaria pinnatifida) and nori (Pyropia) followed by milk, milk products, fish, and shellfish (codfish, bonito, tuna, giant pacific oyster, and eel) and are quite different from other countries. In U.S. adults, consumption of dairy products, eggs, and breads was an important contributor to adequate iodine intake based on a nationally-representative dataset in 2007–2012 [47]. In Europe the main iodine sources of healthy German women in their 30s were milk and dairy products (37%), meat and meat products (21%) and bread and cereal products (19% of the iodine intake) [11]. In Japan, without seaweeds the mean iodine intake from fish and dairy products decreased to less than 100 μg/d which is comparable to the value in some European countries suggesting that people who do not frequently consume a Japanese-type diet including seaweed are at a similar risk of iodine deficiency as people in other countries [25].
Most healthy people in Japan are very tolerant of excess iodine intake from food without any thyroid dysfunction. Several factors may contribute to tolerance to dietary iodine intake in a systematic manner, such as underlying iodine nutritional status, dietary habits, genetic factors, ethnicity, and bioavailability of iodine including iodine absorption, utilization, and secretion. In addition, high quantities of iodine intake from food are intermittent rather than continuous [23, 25]. In Japan exposure to high iodine-containing foods usually begins in utero and via breast milk. Early exposure to high iodine might be important in the habituation to high ambient levels of dietary iodine although there is no evidence until now. The safety and tolerance to high iodine intake from seaweed in people who have not been exposed to it from infancy might be different than it is in Japan.
The strength of our study includes the strictly controlled diet experiment by keeping the iodine intake constant, and the complete urine collections. In the second study longitudinal spot urine samples were collected for 10 consecutive days in each of the four seasons of one year since the UIC from 10 spot samples can be used to assess individual iodine status [21]. The limitations are the small sample size and lack of thyroid function test. In addition, we have not measured the iodine content in consumed fluid i.e., coffee, tea, orange juice and a commercially available natural water, in which iodine content was reported to be under the detection limit (13.9 μg/L) by APDM method [48]. However, we measured the same products by using ICP-MS whose detection limit was 3 μg/L and their iodine concentration was under this limit [unpublished data]. Therefore, the iodine content that the participants took from beverage was less than 6 μg/day that might be neglectable amount.
In conclusion this study showed the short-term renal clearance process of dietary iodine and the long-term variation of habitual iodine intake in Japanese living in an iodine-sufficient area. From our results it is speculated that the low frequency of high iodine intake from the diet and rapid renal clearance of ingested iodine prevent the population from being exposed to high iodine intake over the long term and might also be possible factors for the tolerance of dietary iodine intake although our findings may not necessarily apply to other populations.
The authors thank all students in Kamakura Women’s University, Kamakura City and Kanto Gakuin University, College of Human and Environmental Studies who participated in the study. We are grateful for the assistance of Ms. Sheryn Mason in the preparation of the manuscript.
The authors’ responsibilities were as follows—Y.F., N.T., Y.S. and M.I.: designed the research; Y.F., N.T., Y.U. and M.M.: conducted the research; J.Y.: provided essential materials; Y.F., N.T. and Y.U.: analyzed and interpreted the data; Y.F.: wrote the manuscript; Y.F.: was the principal investigator and had primary responsibility for final content; and all authors: read and approved the final manuscript.
No competing financial interests exist.
| Day 1 (Transitional period) | Day 2 (Iodine loading period) | Day 3 (cont’d) | |||||
|---|---|---|---|---|---|---|---|
| Both groups | High iodine loading group | Control group | Both groups | ||||
| Foodstuff | Weight, g | Foodstuff | Weight, g | Foodstuff | Weight, g | ||
| Breakfast | Bread | 60 | Iodine-enriched egg powder | Ordinary egg powder | 49.8 | Bread | 55 |
| Butter | 10 | Bread | 55 | Potato salad | 37 | ||
| Boiled egg | 50 | Potato salad | 37 | Salad | 22 | ||
| Banana | 100 | Salad | 22 | Salad dressing | 5 | ||
| Coffee | 200 | Salad dressing | 5 | Loin ham | 10 | ||
| Sausage | 43 | Salami | 7 | ||||
| Satsuma orange | 46 | Scrambled eggs | 112 | ||||
| Orange juice | 200 | Ketchup | 5 | ||||
| Coffee | 200 | Satsuma orange | 15 | ||||
| Natural Water | 200 | Orange juice | 200 | ||||
| Coffee | 200 | ||||||
| Natural Water | 200 | ||||||
| Iodine content | 12.6 μg | 2,999.8 μg | 44.8 μg | 17.4 μg | |||
| Lunch | Rice ball of Umeboshi without seaweed | 101 | Same menu as the first day | Same menu as the first day | |||
| Inarizushi | 170 | ||||||
| Black tea | 200 | ||||||
| Natural Water | 200 | ||||||
| Iodine content | 93.4 μg | 93.4 μg | 93.4 μg | 93.4 μg | |||
| Dinner | Bread | 55 | Same menu as the first day | ||||
| Sautéed pork fillet | 100 | ||||||
| Vegetable garnishes: | |||||||
| Turnip | 10 | ||||||
| Spinach | 13 | ||||||
| Potato | 32 | ||||||
| Black tea | 200 | ||||||
| Natural Water | 200 | ||||||
| Gravy | 14 | ||||||
| Fresh Shiitake mushroom | 12 | ||||||
| Broccoli | 9 | ||||||
| Baby corn | 8 | ||||||
| Carrot | 8 | ||||||
| Iodine content | not detectable | not detectable | |||||
| Daily iodine intake | 106.0 μg/day | 3,093.2 μg/day | 138.2 μg/day | 110.8 μg/day | |||
| Foods of food groups | Food items | Reference portion size | Iodine content (μg)/Portion size | Frequency of consuming foods | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Never eats | Within a month | Within a week | Within a day | |||||||||||
| 1d | 2d | 3d | 1 d | 2–3 d | 4–5 d | once | twice | 3 times | ||||||
| Algae | Kombu | 1. Tsukudani1 | 10 g | 1,100 | ||||||||||
| 2. Kobumaki2 | 30 g | 3,240 | ||||||||||||
| 3. Tororo Kombu (tangle flakes) | 3 g | 6,848.6 | ||||||||||||
| 4. Soup with Kombu extract | 200 mL | 252 | ||||||||||||
| Wakame | 5. Wakame Salad or Vinegarded Wakame | 20 g | 1,143.4 | |||||||||||
| 6. Miso or clear soup | 10 g | 778.8 | ||||||||||||
| 7. Fruit-bearing leaves (Mekabu) | 40 g | 156 | ||||||||||||
| Nori | 8. Purple laver, Seasoned and toasted | 2 g | 121.9 | |||||||||||
| 9. Purple laver, Toasted | 1.5 g | 31.5 | ||||||||||||
| 10. Hitoegusa Tsukudani3 | 10 g | 18.1 | ||||||||||||
| Agar jelly | 11. Mitsumame4 | 30 g | 6.3 | |||||||||||
| 12. Tokoroten5 | 50 g | 120 | ||||||||||||
| Other brown algae | 13. Hijiki | 20 g | 9,400 | |||||||||||
| 14. Mozuku | 40 g | 56 | ||||||||||||
| Fishes & Shell fishes | 15. Horse mackerrels | 65 g | 13.7 | |||||||||||
| 16. Sardines | 50 g | 16.5 | ||||||||||||
| 17. Eel | 80 g | 61.6 | ||||||||||||
| 18. Skipjack | 80 g | 20 | ||||||||||||
| 19. Salmons | 80 g | 4 | ||||||||||||
| 20. Mackerels | 80 g | 16.8 | ||||||||||||
| 21. Pacific saury | 75 g | 16.1 | ||||||||||||
| 22. Shishamo | 30 g | 16.7 | ||||||||||||
| 23. Sea breams | 80 g | 6.4 | ||||||||||||
| 24. Cod fishes | 100 g | 260 | ||||||||||||
| 25. Walleye pollack (Tarako) | 30 g | 39 | ||||||||||||
| 26. Yellowtail | 100 g | 24 | ||||||||||||
| 27. Tunas | 80 g | 9.6 | ||||||||||||
| 28. Oysters | 15 g | 9.8 | ||||||||||||
| Soup | 29. Miso-soup | 150 mL | 94.5 (53.2)* | |||||||||||
| 30. Clear soup | 150 mL | 94.5 (103.9)* | ||||||||||||
| Noodle | 31. Noodles in hot broth (Kakeudon6, Kakesoba7) | 250 mL | 157.5 (258.3)* | |||||||||||
| 32. Dipping noodles (Tsukemen8) | 100 mL | 63 (143.5)* | ||||||||||||
| One-pot dish (Nabemono) | 33. Oden9 | 200 mL | 126 (109.3)* | |||||||||||
| 34. One-pot dish (Yosenabe10, Sukiyaki, etc.) | 250 mL | 157.5 (268.8)* | ||||||||||||
| Prepared foods | 35. Instant one-pot dish | one meal | 216.1 | |||||||||||
| 36. Instant clear soup | 51.4 | |||||||||||||
| 37. Instant soup | 51.4 | |||||||||||||
| 38. Instant miso-soup | 43.7 | |||||||||||||
| 39. Instant noodle | 7.8 | |||||||||||||
| 40. Chazuke11 | 23.2 | |||||||||||||
| 41. Furikake12 | 23.2 | |||||||||||||
| Seasonings & Spices | 42. Vinegar with Kombu extract | 5 mL | 22.5 | |||||||||||
| 43. Soy sauce with Kombu extract | 5 mL | 100 | ||||||||||||
| 44. Salt with Kombu powder or extract | 6 g | 270.6 | ||||||||||||
| Eggs | 45. Hen’s egg | 50 g | 24 | |||||||||||
| 46. Japanese quail’s egg | 10 g | 14 | ||||||||||||
| 47. Iodine-riched egg13 | 50 g | 650 | ||||||||||||
| Confectioneries | 48. Potato chips | 30 g | 78 | |||||||||||
| 49. Rice cracker (Shio-senbei) | 15 g | 16.5 | ||||||||||||
| Tea | 50. Kobu-cha (Kombu powder for drink) | 2 g | 576.3 | |||||||||||
* One portion using homemade soup stock (ready-made soup stock)
1. Kombu boiled in soy sauce, 2. a roll of tang containing dried fish in it cooked with sugar and soy souce, 3. Nori simmered in soy sauce and sugar, 4. a mixture of gelatine cubes, boiled beans and fruit topped with molasses, 5. a jelly-like food made from red seaweed (tengusa), 6. Udon noodles in broth, 7. Buckwheat noodles in soup, 8. Cold nooldes accompanied by soup for dipping, 9. a dish containing all kinds of ingredients cooked in a special broth of soy sauce, sugar, sake, etc., 10. a mixed stew of chicken, seafood and vegetables cooked at the table, 11. a quick dish of boiled rice with tea poured on it, 12. a tastily seasoned dried food for sprinkling on rice, 13. Eggs produced by hens raised on feed containing seaweed
