Iodine

Immunotoxicity

Description of key information

There is a large amount of information that investigates the effect of excess iodide on the thyroid and the link between excessive iodide exposure and the development of autoimmune thyroid disease in susceptible individuals. Autoimmune thyroid disease can result in hypothyroidism or hyperthyroidism (associated with Graves’ disease).These effects have been assessed in the Agency for Toxic Substance and Disease Registry review of iodine (ATSDR, 2004).

Autoimmune thyroiditis is an inflammation of the thyroid gland that can lead to effects such as follicular degeneration, follicular hyperplasia, fibrosis of the gland, and hypothyroidism. The features of autoimmune thyroiditis are IgG auto antibodies to thyroglobulin and the presence of thyroid peroxidase. In the autoimmune response, human lymphocytes recognise and proliferate as a response to iodinated human thyroglobulin but not iodine free thyroglobulin. In general, in autoimmune prone individuals, excess iodine accelerates autoimmune thyroiditis whereas in instances of iodine deficiency, this attenuates thyroiditis. The ATSDR notes that the evidence for inducing autoimmune thyroiditis in humans is incomplete. Autoimmunity, characterised by IgG autoantibodies to thyroglobulin and thyroid peroxidase, has been observed in some studies in individuals whose iodide intakes were <500 μg/day (Hall et al. 1966; Kahaly et al. 1997, 1998; Koutras et al. 1996 reviewed in ATSDR, 2004), and not in other studies in which intakes were similar or higher (Boyages et al. 1989; Li et al. 1987 reviewed in ATSDR, 2004).

The variable dose response relationship suggests that other factors other than iodide intake are responsible for the development of thyroid autoimmunity. In animal studies, iodine in general does not induce autoimmune thyroiditis in outbred strains of rats. However, doses of 70–95 mg I/kg/day (in drinking water) for 8–12 weeks may increase the incidence of autoimmune thyroiditis in inbred strains of rats that develop spontaneous thyroid autoimmunity. The ATSDR also reports that oral exposure to iodide can produce allergic reactions in sensitive individuals. Types of reactions noted include urticaria (hives), acneiform skin lesions (ioderma) and fevers. More serious cases recorded involve angioedema (localised oedema), vasculitis, peritonitis and pneumonitis, and complement activation. Humoral and cell-mediated immune responses are thought to contribute to these reactions. The ATSDR states generally that reactions have occurred relating to repeated oral doses of iodide ranging between 300 – 1600 mg I/day (5–23 mg/kg/day). However, in many of these cases other factors such as pre-existing disease and related drug therapy may have contributed to the reaction of iodine. Therefore, any dose response relationship for ioderma remains uncertain.

In conclusion, the review by the ATSDR has identified from epidemiological and clinical case literature that thyroid autoimmunity and allergic reactions are potential immunological effects regarding exposure to excess iodine. Thyroid autoimmunity is an extremely important mechanism of thyroid gland disease, though the ATSDR notes that the mechanisms by which iodine may induce thyroid autoimmunity are not completely understood. The production of antibodies to highly iodinated thyroglobulin has been suggested as a potential contributor. A specific immunotoxicity study for this endpoint is not considered to be necessary as there is sufficient information as described above and in more detail by the ATSDR (2004), to confirm that the thyroid gland is the primary target organ for iodine exposure, and that the thyroid autoimmunity reaction also relates to effects on this target organ.

This conclusion has also been derived by WHO (2020), in their latest background guideline document for Iodine in drinking water, in which it is concluded that immunological effect following chronic oral exposure to excess iodine in humans have been reported as thyroid gland autoimmunity or immune reactions such as ioderma. As iodine is classified for specific target organ toxicity (STOT) (repeated exposure) Category 1 with the thyroid as the primary target organ, a suitable classification has been assigned which considers the above information. Further specific immunotoxicity data would not alter the STOT Category 1 classification or the proposed risk mitigation measures.

- ATSDR, 2004: Toxicological Profile for Iodine. U.S. Department of Health and Human Services.

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

Additional information

There is a large amount of information that investigates the effect of excess iodide on the thyroid and the link between excessive iodide exposure and the development of autoimmune thyroid disease in susceptible individuals. Autoimmune thyroid disease can result in hypothyroidism or hyperthyroidism (associated with Graves’ disease).These effects have been assessed in the Agency for Toxic Substance and Disease Registry review of iodine (ATSDR, 2004) as well as WHO (2020), in their latest background guideline document for Iodine in drinking water. In this, it was concluded that immunological effect following chronic oral exposure to excess iodine in humans have been reported as thyroid gland autoimmunity or immune reactions such as ioderma.

Reference:

- ATSDR, 2004: Toxicological Profile for Iodine. U.S. Department of Health and Human Services.

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

Justification for classification or non-classification

As iodine is classified for specific target organ toxicity (STOT) (repeated exposure) Category 1 with the thyroid as the primary target organ, a suitable classification has been assigned which considers the above information. Further specific immunotoxicity data would not alter the STOT Category 1 classification or the proposed risk mitigation measures.