Iodine

Carcinogenicity

Description of key information

Animal data:

An carcinogenicity study was conducted, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. In the former, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the two-stage carcinogenicity study, thyroidal weights and the incidence of thyroid tumors derived from the follicular epithelium were significantly increased in the DHPN+KI as compared with the DHPN alone group. In conclusion, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid.In the salivary gland, KI was suggested to have carcinogenic potential via an epigenetic mechanism, only active at a high dose. Further,the results suggest that excess KI has a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats. The risk for humans suffering from thyroid tumors because of KI consumption must be very low, from the present findings, even with long-term exposure.

A summary of the animal data in the WHO CICADs review noted that a lifetime exposure to approximately 50 mg of potassium iodide per kilogram body weight per day induced a statistically borderline increase of salivary gland tumours in rats. In two two-stage studies, iodide had a promoting effect on thyroid tumours after initiation by a nitrosamine.

In the recnt WHO evaluation of Iodine in drinking water (2020), 2 carcinognicity studies in rats are described. Male Wistar rats were fed diets that were iodine deficient (0.5 mg/kg), adequate (12 mg/kg) or rich (200 mg/kg) for up to 10 months (estimated as 0.05, 1.2 or 20 mg/kg bw/day). From month 2, rats were also administered weekly injections of the carcinogen N-nitrosobis(2-hydroxypropyl)amine. In the iodine-adequate and iodine-rich groups, papillary carcinomas were reported in 33% and 29% of the animals, respectively. In the iodine-deficient group, all animals developed papillary and follicular carcinomas. The effects were suggested to b related to the goitrogenic and/or goitre-promoting effect of TSH (Yamashita et al., 1990).

In another rat study, rats were given potassium iodide in their drinking-water for 2 years, with intakes estimated as 0, 0.6, 5.3 or 53 mg/kg bw/day. Metaplasia, as a result of lobular impairment, of the thyroid was reported, suggested that the metaplasia lesions may develop into carcinoma via a non-genotoxic, proliferation-dependent mechanism (EVM, 2003).

Human data:

The carcinogenicity of iodine has been extensively assessed in peer reviewed reports such as the ATSDR toxicological profile for iodine (2004) and the recent World Health Organisation CICADs review of iodine and inorganic iodides (2009). The ATSDR report summarises that the relationship between iodide intake and thyroid cancer has been examined in a number of large-scale epidemiology studies. The results of these studies suggest that an increase in iodide intake could be a risk factor for thyroid cancer in specific populations, especially those populations that are iodine-deficient, endemic goitre regions. However, not all studies have determined that there is an increased risk of cancer. Therefore, the ATSDR have concluded that the relationship between iodine intake and thyroid cancer remains unclear. The ATSDR notes a recurrent observation of an apparent shift towards a higher occurence of papilary cancer after an increase in iodine intake in otherwise iodine-deficient populations. Two studies observed a significant excess of thyroid gland cancer in populations from endemic goitre regions where the diets were supplemented to approximate iodine intakes of 3.5 μg/kg/day. Results from more recent epidemiology studies are equivocal in terms of incrased Iodine intake and development of thyoid cancer, Huang et al., (2020) found an increased risk of developing papillary thyroid carcinoma (PTC) from excessive chronic iodine exposure while Cao et al., 2017 did not find a correlation between iodin intake and an increased risk of thyroid cancer.

In a large review study by Zimmermann and Galetti (2015) of available animal and human data, the evidence linking iodine intake and TC from animal studies, ecological studies of iodine intake and differentiated and undifferentiated TC, iodine intake and mortality from TC and occult TC at autopsy, as well as the case–control and cohort studies of TC and intake of seafood and milk products, was evaluated. A new meta-analysis of pooled measures of effect from case–control studies of total iodine intake and TC was performed. Finally, the post-Chernobyl studies linking iodine status and risk of TC after radiation exposure was performed. The available evidence suggests iodine deficiency is a risk factor for TC, particularly for follicular TC and possibly, for anaplastic TC.

The ATSDR has concluded that the relationship between iodine intake and thyroid cancer remains unclear in humans. The same conclusion was derived by WHO (2020) in their latest evaluation of Iodine in drinking water.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

amount of animals used is lower than recommended.

GLP compliance:

not specified

Specific details on test material used for the study:

- Purity: more than 99%
- Source: Nacalai Tesque (Kyoto, Japan).

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male

Details on test animals or test system and environmental conditions:

An excess of 200 male and 200 female 5-wk old F344/ DuCrj rats were purchased from Charles River Japan (Atsugi, Japan) as specific pathogen free (SPF) animals. They were housed two or three to a polycarbonate cage with wood chips (Softchip, Sankyo Laboratory Service, Tokyo, Japan) for bedding, in an air-conditioned animal room (room temperature, 24±1℃; relative humidity, 55±5%; ventilation, 18 times/hr; 12-hr light/dark cycle). Cages were changed twice a week. Only animals showing no abnormalities during a 1-wk acclimatization period were used in the study. Distilled water alone or containing KI and CRF-1 diet (Oriental Yeast, Tokyo, Japan) were available ad lib. throughout.

Route of administration:

oral: drinking water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

104 weeks

Dose / conc.:

1 000 ppm (nominal)

Remarks:

1000 ppm was set as the highest dose, exceeding the 260 ppm which has been reported to induce colloid goiters.

Dose / conc.:

100 ppm (nominal)

Dose / conc.:

10 ppm (nominal)

No. of animals per sex per dose:

Both sexes were divided into four groups, each consisting of 60, 40, 40 and 60 rats after the acclimatization, and given KI in the drinking water at concentrations of 0, 10, 100 and 1000 ppm for 2 yr, respectively.

Control animals:

yes, concurrent no treatment

Details on study design:

During the treatment period, general condition was checked daily, and water consumption was recorded every 2 wk up to 12 wk, and every 4 wk thereafter. Body weights were recorded at the same times.
White blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), hematocrit (Ht) and platelet count (PLT) were recorded with the aid of an automated hematology analyzer (Sysmex M-2000, Toa Medical Electronics Co., Ltd, Hyogo, Japan).

Sacrifice and pathology:

In the 0 and 1000 ppm groups, five rats each were necropsied 3, 6, 12 and 18 months after the initiation of the treatment. All survivors were fasted overnight prior to necropsy, which was performed after exsanguination from the aorta under ether anesthesia. Livers, kidneys, lungs, hearts, spleens, adrenals, brains, pituitaries and thyroids were fixed in 10% neutral buffered formalin, for the interim necropsy. For animals treated for 2 yr, in addition to the organs described above, testes, noses, tongues, tracheas, salivary glands, esophagus, stomachs, small and large intestines, pancreas, urinary bladders, prostates, seminal vesicles, ovaries, uteri, vaginae, mammary glands, lymph nodes, sternums, femurs, spinal cords, eye balls, skin and skeletal muscles were fixed in the same manner. Grossly visible lesions were also separately fixed. Histopathological examination was performed on hematoxylin-eosin (HE)-stained specimens processed routinely. Animals that died or were killed in a moribund condition were also necropsied and examined histopathologically.

Statistics:

Body weight, water consumption, organ weight and hematology data were analyzed for homogeneity of variance using Bartlett's test. When they proved to be homogeneous, one-way analysis of variance was applied. If significant heterogeneity of variance (P≤0.01) was apparent, the equivalent non-parametric statistical method of Kruskal-Wallis was employed. Where significant differences between the groups were detected, a multiple comparison test (Dunnett's test or Scheffe's method) was used. Final survival rates and the incidences of tumors were compared with the Fisher's exact probability test.

Mortality:

mortality observed, treatment-related

Description (incidence):

Survival rates of male rats were decreased in the 100 and 1000 ppm groups as compared to the control from around 80 wk after the initiation of the treatment. The rates for females of any treated groups were similar to that of the controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights in the 1000 ppm groups of both sexes were depressed in the latter half of the treatment period

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Water consumption in all treated groups was similar to the control level,

Haematological findings:

no effects observed

Description (incidence and severity):

Hematological examination did not reveal any effects of the treatments.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Increased in the 10, 100 and 1000 ppm groups of both sexes. This lesion was composed of increased colloid in the lumen and flattened epithelia due to the compression. Thyroid proliferative lesions derived from follicular epithelia were not increased by KI-treatment, although examples were observed in each group.
No KI-related induction of any lesions was apparent in the other organs or tissues. Lesions with incidences more than 25% in one or more groups were, foci of cellular alteration in the liver and hyperplasias of the pituitary in both sexes, C-cell hyperplasias of the thyroid, medullary hyperplasias and pheochromocytomas of the adrenals, and inter- stitial cell tumors of the testis in males, and cystic endometrial hyperplasias and endometrial stromal polyps of the uterus in females. However, these are all known to spontaneously occur and neither increase in their incidence nor special types of lesions were observed in the treated groups.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the salivary gland, focal acinar atrophy, ductular proliferation and squamous metaplasias were frequently observed, and SCCs were noted in four males and three females of the 1000 ppm group. Lobular atrophies were well-circumscribed from the surrounding tissue and triangular in shape, suggesting focal lesions related to single ducts, and accompanied by ductular proliferation in most cases. Squamous metaplasias were observed in the epithelium of proliferating ductules, and the morphological continuum to squamous cell carcinomas were observed in these metaplasias.

Relevance of carcinogenic effects / potential:

Both males and females showing follicular dilatation in the thyroid were increased in the 10, 100 and 1000 ppm group in the present long-term study. This change is not neoplastic, resembling the morphological alteration reported to be observed in humans under conditions of chronic exposure to excess iodine. The no-effect-level for these lesions can be concluded to be less than 10 ppm, since they were observed even at this low dose. However, neither focal hyperplasias, adenomas nor carcinomas derived from the follicular epithelium were increased, despite the fact that KI was administered for 2 yr. It was therefore concluded that long-term treatment of KI per se does not result in thyroid tumor induction in rats. In contrast, SCCs were observed in the submandibular gland in the 1000 ppm groups of both sexes, along with focal acinar atrophy and/or ductular proliferation, frequently accompanied by squamous metaplasia. Based on the fact that the cell proliferation of these proliferating ductules was higher in cases with metaplasia, and the evidence of a morphological continuum from metaplasias to SCCs, a histogenetic relationship is suspected.

Dose descriptor:

NOEL

Effect level:

< 10 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Lowest effective dose / conc.:

10 ppm

System:

endocrine system

Organ:

thyroid gland

With regard to animals necropsied 3, 6, 12 and 18 months after the initiation of the treatment, the numbers with follicular dilatation in the thyroid were apparently increased in the 1000 ppm group as compared to the controls from 3 months. No treatment-related effects were evident in other organs.

Conclusions:

An carcinogenicity study was conducted, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. Excess KI was shown to have a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats.

Executive summary:

An carcinogenicity study was conducted, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. In the former, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the two-stage carcinogenicity study, thyroidal weights and the incidence of thyroid tumors derived from the follicular epithelium were significantly increased in the DHPN+KI as compared with the DHPN alone group.

In conclusion, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the salivary gland, KI was suggested to have carcinogenic potential via an epigenetic mechanism, only active at a high dose. Further, the results suggest that excess KI has a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats. The risk for humans suffering from thyroid tumors because of KI consumption must be very low, from the present findings, even with long-term exposure.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The impact of iodized salt prophylaxis on thyroid cancer (TC) have been analyzed by comparing data from the early 1960s with those corresponding to the period 1986 to 1995, when iodine supply was normalized.

GLP compliance:

not specified

Species:

other: human

Route of administration:

not specified

Statistics:

Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to check for significant differences between groups. No adjustments for multiple comparisons were made, because the increase of the type-2 error caused by such an adjustment has to be considered as more serious than the loss of control over the significance level of the universal null hypothesis that all statements bearing the label "statistically significant" are simultaneously true. The simultaneous impact of several prognostic variables (TNM stages, histology, age, sex) on survival was investigated using Cox regression.

- Incidence of thyroid cancer in Tyrol:

The total incidence rates for TC have shown a constant rise during past decades. This is demonstrated by the mean crude incidence rates of 3.07 for the period 1960 to 1970, and of 3.98 from 1971 to 1980. The current incidence figures are almost twice as high as those observed previously.

- Age:

Patients with "curable" tumor stages (group A), were significantly younger than patients with advanced tumor stages in group B (T4 or distant metastases or mediastinal lymph nodes). This difference could be shown for both papillary- and follicular- type TC. Patients with papillary TC were younger at the time of diagnosis than patients with follicular carcinoma (p < 0.01) or anaplastic cancer.

- Sex:

The overall female-to-male (f/m) ratio was 2.9/1. No significant difference in the female-to male-ratios was found between group A and B, nor between papillary and follicular TC, nor when comparing age group younger than 55 years with age group older than 55 years. The f/m ratio for anaplastic carcinoma was 1.2/1.

- Distribution of histology and TNM stages:

Papillary carcinoma was the predominant tumor type (54.4%), followed by follicular carcinoma. Anaplastic carcinoma was seen in 4.5%, and medullary TC in 2% of patients. A shift to a higher proportion of well-differentiated tumor types during the last decades was observed. A marked shift towards less advanced tumor stages could be seen: 72.2% belonged to the "curable" group A (T 1-3, N 0-1a, M0); 27.7% had either tumor stage T4; or N1b, or distant metastases (group B). Distant metastases were present in 17.9% of all patients and in 14.1% already at diagnosis. The proportion of cases presenting metastases according to the histological classification was 7.5% for papillary TC; 22.6% for follicular TC; 33% for medullary TC: and 75% for anaplastic TC.

- Death due to TC during follow-up:

Forty-nine of 439 patients died during the evaluation period. In 33 cases, death could be attributed to TC, ie, in 7.5% of all cases. In the remaining 16 cases, the cause of death was either cardiovascular disease or an additional tumor. In 5 cases information concerning the cause of death was not available. Mortality according to the histological type was 2% for papillary TC; 6.1% for follicular TC; 33.3% for medullary, TC; and 65% for anaplastic TC. Most patients who died, showed either follicular or anaplastic TC (69%) and a predominance of advanced tumor stages. None of the deceased patients was younger than 50 years and no patient with an original stage T1 died.

- Kaplan-Meier survival analysis:

Patients in group A showed a significantly better survival than patients in group B within differentiated TC (p < 0.001). The survival rate of patients with papillary carcinoma was better than patients with follicular TC, in case that no adjustment was made for tumor stage (p = 0.025). However, if the comparison of survival in patients with papillary and follicular TC was made within the respective, stage-adjusted subgroups (group A and B), survival did not differ significantly. Survival for patients with an age of 55 years or less was significantly better than for older patients (p<0.001); this could be shown for both papillary (p = 0.002) and follicular TC (p = 0.025), confirming the results of the Cox Regression.

- Simultaneous impact of variables on prognosis by multivariate Cox regression analysis:

Considering the prognostic impact of age, sex, histological type (papillary and follicular), and tumor stage (group A and B), only the parameters age (p = 0.005) and stage (p < 0.001) remained statistically significant. Sex and histological type no longer showed a significant impact on survival within differentiated TC.

Conclusions:

Together with normalization of iodine supply in an endemic goiter region the epidemiological profile of TC has changed. Even though the incidence of TC has risen, prognosis has significantly improved due to a shift towards differentiated forms of TC that are diagnosed at earlier stages.

Executive summary:

The impact of iodized salt prophylaxis on thyroid cancer (TC) have been analyzed by comparing data from the early 1960s with those corresponding to the period 1986 to 1995, when iodine supply was normalized. The study included 439 patients from Tyrol and Southern Tyrol.

The incidence of TC in Tyrol has risen during the past decades from 3.07 between in 1957 and 1970 to 7.8 between 1990 and 1994 (CR/100000/year). A rise in the percentage of differentiated adenocarcinomas (56% to 91.5%) with a predominance of papillary TC (54.4%) along with a decrease of anaplastic TC were observed. In addition to these histological features, a shift to less advanced TNM stages, eg, T1-3, N0-1a, M0, was obvious, increasing from 29% to 72.2%, whereas advanced tumors, ie, T4 or N1b or M1, decreased from 71% to 28%. These changes have significantly improved prognosis. The current 5-year survival rate is 90.7% as compared with a rate of 73% in the 1960s; the values for 7-year survival are 89% and 48%, respectively. The marked effects of age, tumor stages, and histology on prognosis were confirmed with the Kaplan-Meier method.

In conclusion, together with normalization of iodine supply in an endemic goiter region the epidemiological profile of TC has changed. Even though the incidence of TC has risen, prognosis has significantly improved due to a shift towards differentiated forms of TC that are diagnosed at earlier stages.

Reference 3

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Thyroid cancer and thyroiditis after iodine prophylaxis over a 31-year period was investigated.

GLP compliance:

not specified

Species:

other: human

- Thyroid cancer:

One hundred and forty-four thyroid malignancies from 110 females and 34 males living in the province of Salta were analysed in the 31-year period. The average number of cases seen was 3.9 per year during the first period and 5.3 in the second period. The incidences of thyroid cancer were 1.33/1E+5/year in the capital, 0.73 in ValIe de Lerma, and 0.60 in the other more remote regions for the period 1980-1988, for which data on the exact geographical area of origin of the patients were available. The crude incidence rate for the province of Salta in the first period was 0.78/1E+5/year and 0.84 in the second, when figures are adjusted for the population in 1960 and 1980, respectively. It can be seen that papillary carcinomas form the largest group of tumours in both periods, with nearly twice as many in the second period as the first, while the numbers of follicular carcinoma and medullary carcinoma remained about the same. The ratio of papillary to follicular carcinoma rose from 1.7 : 1 in the first period to 3.1 : 1 in the second. All three thyroid lymphomas were of the non-Hodgkin’s type, and all occurred in the second period in females aged over 50. Severe lymphoid thyroiditis was present in the two cases with assessable background thyroid tissue.

 

- Thyroiditis

The frequency of lymphoid infiltrate in females in the whole series with an adequate amount of background thyroid available rose from 1 out of 12 (8%) in those operated on before 1963 to 6 out of 21 (28%) operated within 10 years post-prophylaxis and 12 out of 51 (23%) in those operated on more than 10 years after prophylaxis was introduced. Overall, 18 out of 72 (25%) patients had thyroiditis in the post-iodination period. After iodized salt prophylaxis, thyroiditis was more frequent in patients with papillary carcinoma in general (31 %), and clinically significant papillary carcinomas in particular (35%), than in those with non-papillary tumours (6%) (x2, P < 0.05 and P < 0.025 respectively). In the post-prophylaxis period, lymphoid infiltrates occurred in 1/9 (11%) cases aged under 20, in 8/28 (28%) aged 20-39, and in 9/35 (26%) aged 40 or over.

Conclusions:

A high dietary intake of iodine may be associated with a high frequency of papillary carcinoma and thyroiditis, and that thyroiditis is more commonly associated with papillary carcinoma than with other thyroid tumours. The occurrence of non-Hodgkin's lymphomas only in the postprophylaxis period may be linked to an increase in thyroiditis.

Executive summary:

Thyroid cancer and thyroiditis after iodine prophylaxis over a 31-year period was investigated.

For the analysis of thyroid cancer the material was divided in two periods. The first 15 years (59 cases), including 5 years before prophylaxis, was compared with the second 16 years (85 cases), a period well after iodine supplementation of salt. Histological diagnosis of the tumours was based on the WHO system. Moderate to severe thyroiditis in the non-tumoral surrounding thyroid from female patients was recorded. For this, the material was analysed in the two periods in relation to the introduction of iodine prophylaxis in 1963, taking account of the age of the patients.

Papillary carcinomas formed the largest group of tumours in both periods, with nearly twice as many in the second period as the first, while the numbers of follicular and medullary carcinomas remained about the same. The ratio of papillary to follicular carcinoma rose from 1.7 : 1 in the first period to 3.1 : 1 in the second. All three thyroid lymphomas were of the non-Hodgkin's type, and all occurred in the second period in females aged over 50. A severe lymphoid thyroiditis was present in the two cases with assessable background thyroid tissue. The frequency of lymphoid infiltrate in females rose from 8% (1/12) before 1963 to 25% (18/72) after prophylaxis in the whole series. After salt prophylaxis, thyroiditis was more frequent in patients with papillary carcinoma in general (31 %), and clinically significant papillary carcinomas in particular (35%), than in those with non-papillary tumours (6%) (x2, P<0.05 and P<0.025, respectively).

It indicates that a high dietary intake of iodine may be associated with a high frequency of papillary carcinoma and thyroiditis, and that thyroiditis is more commonly associated with papillary carcinoma than with other thyroid tumours. The occurrence of non-Hodgkin's lymphomas only in the postprophylaxis period may be linked to an increase in thyroiditis.

Reference 4

Endpoint:

carcinogenicity: oral

Type of information:

other: Epidemiological study

Adequacy of study:

supporting study

Principles of method if other than guideline:

An epidemiological study elucidating the association between excessive chronic iodine exposure and the risk of developing papillary thyroid carcinoma (PTC).

GLP compliance:

no

For the assessment of excessive chronic iodine exposure, among patients with PTC who exhibited high UICs, 81.4% were from historically non‑iodine deficient regions (Table III). Among those residing in historically iodine‑excessive regions, 66.7% exhibited a high UIC, whereas only 7.4% had low UIC values. An association between high UIC and historically iodine‑excessive regions was also noted. Thus, in the present study, high UIC was found to independently reflect excessive chronic iodine exposure in patients with PTC.

The results revealed that almost half of the patients with PTC (44.3%) also exhibited a high UIC (≥300 µg/l). Multivariate analysis revealed that the adjusted odds ratio for high UIC was 3.987 (95% CI: 1.355‑11.736) and the adjusted area under the receiver operating characteristic curve was 0.776 (95% CI: 0.687‑0.864), which was associated with PTC risk in patients with thyroid nodules. Integrated ecological assessment of chronic iodine exposures demonstrated that >80% (81.4%) of the patients with PTC who also exhibited a high UIC were from historically non‑iodine‑deficient regions, and 66.7% of patients with PTC who resided in historically iodine‑excessive regions were characterized by high UICs. Importantly, a high UIC was significantly associated with capsular invasion and extra‑thyroid metastasis (P<0.05).

 

In conclusion, excessive chronic iodine exposure is significantly associated with the risk of PTC, which contributes to increased capsular invasion and extrathyroid metastases.

Conclusions:

An Chinse epidemiological study was performed to elucidate the association between excessive chronic iodine exposure and the risk of developing papillary thyroid carcinoma (PTC) using demographic information and pathological characteristics of patients with thyroid nodules. A fasting urine specimen was collected, and creatinine and urinary iodine concentration (UIC) were determined. The results of the present study suggested that almost half of the patients with PTC (44.3%) exhibited a high UIC (≥300 µg/l), and that the proportion of patients with PTC with a high UIC was significantly higher compared with that observed in those without PTC (44.3 vs. 22.2%, respectively). Collectively, the results of the present study indicated that excessive chronic iodine exposure may promote capsular invasion and extra thyroid metastasis and may be significantly associated with the risk of PTC.

Executive summary:

The aim of the present epidemiological study was to elucidate the association between excessive chronic iodine exposure and the risk of developing papillary thyroid carcinoma (PTC). The demographic information and pathological characteristics of patients with thyroid nodules were retrieved from medical records at The Second Hospital of Shandong University (China). A fasting urine specimen was collected, and creatinine and urinary iodine concentration (UIC) were determined. The water iodine data from the domicile districts of these patients were collated from published reports. UIC was innovatively combined with water iodine values to determine the intrinsic association between iodine exposure and the clinical characteristics of PTC. Ecological integrated assessment was performed to determine whether there is an association of excessive chronic iodine exposure with capsular invasion and extrathyroid metastases.

The results of the present study suggested that almost half of the patients with PTC (44.3%) exhibited a high UIC (≥300 µg/l), and that the proportion of patients with PTC with a high UIC was significantly higher compared with that observed in those without PTC (44.3 vs. 22.2%, respectively). Collectively, the results of the present study indicated that excessive chronic iodine exposure may promote capsular invasion and extra thyroid metastasis and may be significantly associated with the risk of PTC.

Reference 5

Endpoint:

carcinogenicity: oral

Type of information:

other: Epidemiological study

Adequacy of study:

supporting study

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

A Chinese study investigating the relationship between iodine intake and thyroid cancer (TC) perfomed using meta-analysis.

GLP compliance:

no

All of the included studies were case–control studies, which retrospectively assessed iodine exposure using questionnaires. Of a total of 3566 papers identified from the initial searches, 23 studies were identified to be potentially eligible for inclusion after reviewing titles and abstracts. Of these 23 full-text papers, 13 studies were deemed to be suitable. Five studies were excluded from the 13 full-text papers because they were pooled analyses. Thus, there were 8 studies included in the metaanalysis evaluating the estimate the possible relationship between iodine intake and TC risk from iodine exposure from consumption of shellefish and saltwater fish in different location with high consumption of fish (China, US, Sweden, Norway, South Pacific, Kuwait).

The effect of iodine consumption on the risk of TC was assessed using the pooled odds ratio (OR) and 95% confidence interval (CI). The meta-analysis included 8 case–control studies (n=4974; 2213 cases; 2761 controls). More than adequate or excess iodine intake (>300mg/d) decreased the risk of TC (OR 0.74, 95% CI 0.60, 0.92). High consumption of saltwater fish or shellfish decreased the risk of TC (OR 0.72, 95% CI 0.55, 0.95; OR 0.70, 95% CI 0.52, 0.96; respectively). A higher intake of dietary iodine was as a protective factor for TC.

Conclusions:

A Chinese study investigating the relationship between iodine intake and thyorid cancr (TC) was perfomed using meta-analysis. 8 studies wre included in the metaanalysis evaluating the estimate the possible relationship between iodine intake and TC risk from iodine exposure from consumption of shellefish and saltwater fish in different location with high consumption of fish (China, US, Sweden, Norway, South Pacific, Kuwait). This present meta-analysis demonstrated that a higher iodine intake (≥300mg/d) and high consumption of saltwater fish and shellfish were protective factors for TC. All of the patients in the included studies were identified by histopathological diagnosis. The data included in this present study were included after a comprehensive search of the published literature, but the analysis remained limited because there were only 3 studies that calculated the specific amount of iodine intake.

Executive summary:

The relationship between iodine intake and thyroide cancer (TC) risk is controversy and a meta-analysis of all available epidemiological studies was performd to provide a comprehensive estimate of the possible relationship between iodine intake from seafood and TC risk.

All of the included studies in the evaluation were case–control studies, which retrospectively assessed iodine exposure using questionnaires. Of a total of 3566 papers identified from the initial searches, 23 studies were identified to be potentially eligible for inclusion after reviewing titles and abstracts. Of these 23 full-text papers, 13 studies were deemed to be suitable. Five studies were excluded from the 13 full-text papers because they were pooled analyses. Thus, there were 8 studies included in the metaanalysis evaluating the estimate the possible relationship between iodine intake and TC risk from iodine exposure from consumption of shellefish and saltwater fish in different location with high consumption of fish (China, US, Sweden, Norway, South Pacific, Kuwait).

The effect of iodine consumption on the risk of TC was assessed using the pooled odds ratio (OR) and 95% confidence interval (CI). The meta-analysis included 8 case–control studies (n=4974; 2213 cases; 2761 controls). More than adequate or excess iodine intake (>300mg/d) decreased the risk of TC (OR 0.74, 95% CI 0.60, 0.92). High consumption of saltwater fish or shellfish decreased the risk of TC (OR 0.72, 95% CI 0.55, 0.95; OR 0.70, 95% CI 0.52, 0.96; respectively). A higher intake of dietary iodine was as a protective factor for TC.

This present meta-analysis demonstrated that a higher iodine intake (≥300mg/d) and high consumption of saltwater fish and shellfish were protective factors for TC. All of the patients in the included studies were identified by histopathological diagnosis. The data included in this present study were included after a comprehensive search of the published literature, but the analysis remained limited because there were only 3 studies that calculated the specific amount of iodine intake.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Excessive chronic iodine exposure has been associated with metaplasia of the thyroid and possible development into carcinoma, considered to occur via a non-genotoxic mechanism.

Further, some increase in squamous cell carcinomas in the salivary gland following chronic oral exposure to iodine also considered to occur via a non-genotoxic mechanism, were seen. This could though be related to the fact that iodine is a local irritant and be mediated by sustained irritation through chronic exposure followed by reparative cell proliferation resulting in possible metaplasia in the salivary gland which concentrate iodine/iodide. Other observatiosn relates to development of papillary thyroid carcinoma (PTC) from excessive chronic iodine exposure but the overall evidence from animal and human data are not conclusive towards a classification.

Thus, Iodine is not classifiable as a human carcinogen, according to the International Agency for Research on Cancer and classified iodine as A4 – not classifiable as a human carcinogen, according to the American Conference of Governmental Industrial Hygienists.

The ATSDR has concluded that the relationship between iodine intake and thyroid cancer remains unclear in humans. The same conclusion was derived in the recent evaluation from WHO (2020), stating that the evidence from human studies is equivocal in relation to thyroid cancer.

Overall, the available information is inconclusive and is therefore not sufficient to support a hazard classification for this endpoint.

Additional information

It is generally accepted that humans and rats differ in their sensitivity to thyroid imbalance, which precludes the use of animal data (WHO, 2020). The available human data evaluating the relationship between iodine intake and thyroid cancer remains unclear and concluded to be quivocal as concluded by ATSDR (2004) and WHO (2020).

Specifically WHO (2020) concluded that:

- "Evidence from human studies is equivocal; in iodine-deficient populations, increased iodide intake has been reported as a risk factor for thyroid cancer (Harach & Williams, 1995; Bacher-Stier et al., 1997; Franceschi, 1998; Franceschi & Dal Maso, 1999). However, more recent studies have produced contrary findings (Zimmermann & Galetti, 2015; Cao et al., 2017)."

Further, the evaluation of iodine by EVM is in acordance to the evlaution by ATSDR (2004) and WHO (2020) stating that:

- "No data have been identified on the carcinogenicity of iodine. Both iodine deficiency and excess can promote tumour formation in animals pre-exposed to known carcinogens. Metaplasia of the thyroid was reported in rats given potassium iodide in drinking water for two years. This was thought to occur via a non-genotoxic proliferation dependent mechanism. Human epidemiological studies have shown variations in the incidence of thyroid cancer, depending on the levels of iodine available in water supplies in these areas. The type of cancer appears to differ depending on whether iodine levels are deficient or excess. Changes to the pattern of thyroid tumours have been noted after prophylaxis. The mutagenicity data for iodine are generally negative."

Key references:

- Agency for Toxic Substances and Disease Registry (ATSDR). 2004. Toxicological profile for iodine.

- World Health Organization (WHO). 2009. Iodine and inorganic iodides. In: Concise International Chemical Assessment Document 72.

- WHO, 2020: Iodin in drinking water, Background document for development of WHO guidelines for drinking-water quality.

- EVM (Expert group on Vitamins and minerals), 2003. Iodine: Safe upper levels for vitamins and minerals.