Iodine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: assessment

Justification for type of information:

A toxicokinetic and dermal absorption study is not required for iodine as there is an extensive amount of publications on the toxicokinetics and dermal absorption of this substance. These publications have been comprehensively reviewed by the Agency for Toxic Substance and Disease Registry review of iodine (ATSDR, 2004) and also by the World Health Organisation (WHO, 2009) This information is summarised further below and is considered to meet the obligations set out in the REACH regulations under Annex I, Section 1.0.2 (that the human health hazard assessment shall consider the toxicokinetic profile (i.e. absorption, metabolism, distribution and elimination) and Annex VIII, Section 8.8.1 (Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information). As this information has come from recognised reliable sources, the primary information sources cited have not been revisited as suggested in the Guidance for the implementation of REACH – Guidance on information requirements and chemical safety assessment: Chapter R3: Information gathering.

Results and discussion

Any other information on results incl. tables

Absorption:

 

Iodine (I₂) is considered to be readily absorbed through the lungs and the gastrointestinal tract, based on available reports. Radioiodine (as I₂vapour) was inhaled in a human volunteer study, where virtually all of the inhaled iodine was removed from the respiratory tract with a half-time of approximately 10 minutes. (Black & Hounam, 1968; Morgan et al., 1968 – reported in ATSDR, 2004) Much of the clearance of iodine from the respiratory tract was transferred to the gastrointestinal tract which suggested that the initial deposition was primarily in the conducting airways and moved by mucociliary clearance. The rapid absorption of iodine vapour is supported by animal studies in mice, rats, dogs, and sheep (Willard & Bair, 1961; Bair et al., 1963 – reported in ATSDR, 2004).

 

Iodine that is ingested orally in the form of water soluble salts (such as potassium or sodium iodide) typically results in 100% absorption from the gastro-intestinal tract. In seven euthyroid adults who ingested a single tracer dose of¹³¹I, <1% of the administered radiolabel was found in the faeces, suggesting nearly complete absorption of the ingested radioiodine (Fisher et al., 1965 – reported in ATSDR, 2004). In the same study, 20 other euthyroid adults that received daily oral doses of potassium iodide for 13 weeks had daily iodine urinary excretion levels of approximately 80–90% of the estimated daily intake. This also suggests near complete absorption (Fisher et al., 1965 – reported in ATSDR, 2004). In a separate acute ingestion study in 9 healthy adults, the urinary and thyroid radioiodine accounted for 97% (± 5, SD) of a single ingested dose of radioiodine. In the same study, two subjects ingested the tracer dose in conjunction with a dose of 5 or 15 mg stable iodide (presumed to be potassium or sodium iodide). The recoveries of radioiodine in the thyroid and the urine were 96% and 98% respectively. (Ramsden et al., 1967 – reported in ATSDR, 2004). In more recent study, a faecal excretion range of 1-2% was reported. (Larsen et al., 1998; Hays, 2001 – reported in ATSDR, 2004). The overall gastrointestinal absorption in different subpopulations (children, adolescents and adults) appears to be similar. This is based on measurements of 24 hour thyroid uptakes of radioiodine administered orally. (Oliner et al., 1957; Van Dilla & Fulwyler, 1963; Cuddihy, 1966 – reported in ATSDR, 2004). However, the uptake from oral administration to newborns has been shown to be lower than that for older infants and adults, where the estimated uptake ranges from 2% to 20% other than the most soluble forms. (Ogborn et al., 1960; Morrison et al., 1963; ICRP, 1996 – reported in WHO, 2009).

 

Iodine in food appears to be nearly completely absorbed. In a dietary balance study, 12 healthy adult women were given daily intakes of 170–180 μg for two 7-day periods. The results showed that 96–98% of the daily intake was excreted in the urine, which indicated near-total absorption of the administered dose (Jahreis et al., 2001 - reported in ATSDR, 2004). Iodine that is incorporated into bovine milk appears to be nearly completely absorbed when ingested (Comar et al., 1963; Cuddihy, 1966 - reported in ATSDR, 2004)

 

The dermal absorption of iodine was investigated in humans that received topical applications of¹³¹I as potassium iodide or molecular iodine (Harrison, 1963 – reported by ATSDR, 2004). In one part of this study, topical applications of tracer concentrations of an aqueous solution containing K¹³¹I were administered to a 12.5 cm²area of one forearm on each individual. The absorption was estimated to be approximately 0.1% when using 3 day cumulative urine radioactivity as a measure. In a separate part of the same study, two women received similar topical applications of aqueous tracer¹³¹I₂along with 0.1 mg of¹²⁷I₂carrier. Dermal absorption was estimated to be 0.06-0.09% of the applied dose. Also, in the same study, a 12.5 cm²area of the skin was exposed to iodine vapour for 30 minutes or 2 hours. The dermal absorption was found to vary depending on the amount of¹²⁷I₂carrier in the vapour. At the lowest carrier amount (0.8 mg applied to skin) the absorption of¹³¹I was 1.2% of the activity that was on the skin at the end of the 2 hour exposure. This absorption value was supported in another study (Gorodinskiy et al., 1979 - reported by ATSDR, 2004). In this study the whole body skin of seven human male volunteers was exposed for 4 hours to a low concentration (~4 Bq/l) of¹³¹I gas with protection against inhalation. The accumulation of¹³¹I in the thyroid was used as the measure of dermal uptake. The results were compared with those from a previous inhalation study, and it was determined that, for comparable air concentrations, that dermal absorption was 1-2% of the inhalation uptake.

 

On the basis of the above information reported from the ATSDR (and also cited by the WHO and USEPA), the dermal absorption of iodine is assumed to be 1%.

 

 

Distribution:

 

Irrespective of the route of exposure to inorganic iodine, the distribution of absorbed iodine is similar,. This conclusion is supported by a study in which human subjects were orally exposed to tracer levels of radio-labelled iodine as sodium iodide. The results determined that approximately 20–30% iodine was distributed to the thyroid, and 30–60% was excreted in the urine after approximately 10 hours. Essentially the same results were observed after the ingestion of a tracer dose of Na¹³²I (Morgan et al. 1967a, 1967b – reported in ATSDR, 2004). Similar results were found in human volunteers that inhaled tracer levels of radioiodine as I₂(Black & Hounam, 1968 – reported in ATSDR, 2004). Also, similar results were found in studies in monkeys ingesting iodide and monkeys that inhaled particulate aerosols of sodium iodide (Thieblemont et al., 1965; Perrault et al.,1967 – reported in ATSDR, 2004)

 

A number of chemicals and agents are associated with reducing dietary iodine absorption and incorporation. This includes thiocyanates, isothiocyanates, nitrates, fluorides, calcium, magnesium, smoking and iron in food and water (Ubom, 1991 - reported in WHO, 2009). Large amounts of absorbed iodine from sources such as radiological contrast media, from iodide liberated from erythrosine, from the antiarrhythmic drug amiodarone, from water purification tablets, from skin and dental disinfectants also reduce iodine uptake, resulting in the production of iodine deficiency symptoms (European Commission, 2002 - reported in WHO, 2009).

 

The human body contains approximately 10–15 mg of iodine. As a proportion of this amount, approximately 70–90% is in the thyroid gland, which accumulates iodine in producing thyroid hormones for export to the blood and other tissues (Cavalieri 1997; Hays 2001; Stather and Greenhalgh 1983 - reported in ATSDR, 2004). Under normal circumstances, the concentration of iodine in serum is approximately 50–100 μg/L. Approximately 5% of the iodine is in inorganic form, with the remaining 95% consisting of the various organic forms of iodine, primarily as protein complexes of the thyroid hormones T4 (tetraiodothyronine) and T3 (triiodothyronine). (Fisher et al. 1965; Nagataki et al. 1967; Sternthal et al. 1980; Wagner et al. 1961 - reported in ATSDR, 2004). The tissue distribution of iodide and organic iodine are very different and are interrelated by metabolic pathways that lead to the iodination and deiodination of proteins and thyroid hormones in the body. Iodine is predominantly confined to the extracellular fluid. However, tissues that have specialised transport mechanisms for accumulating iodide are exceptions. These tissues include the thyroid, choroid plexus, mammary glands, salivary glands, gastric mucosa, placenta, and sweat glands (Brown-

Grant 1961 - reported in ATSDR, 2004).

 

 

The concentrations of iodide in serum, which is indicative of extracellular fluid concentrations, normally range from 5 to 15 μg/L. This indicates a total extracellular iodide content of the human body of approximately 85–170 μg, assuming an extracellular fluid volume of approximately 17 L (Cavalieri 1997; Saller et al. 1998 - reported in ATSDR, 2004). The concentration of iodide in the thyroid are usually 20-50 times that of serum (0.2–0.4 mg/dL, 15–30 nM). However concentrations greater than 100 times that of blood occur when the gland is stimulated by thyrotrophin (a TSH) and concentrations in excess of 400 times blood have been observed (Wolff 1964 - reported in ATSDR, 2004).

 

 

The iodide is actively transported into the thyroid follicle by the Sodium Iodine Symporter (NIS) and is then oxidised to molecular iodine. Following that, iodine is bound to the amino acid tyrosine in thyroglobulin in the colloid to produce the thyroid hormones T3 and T4 and their various intermediates and degradation products. The uptake of iodide into the thyroid depends upon the intake of iodide into the body, with the percentage of thyroid intake increasing with decreasing levels of iodide intake (Delange & Ermans, 1996 - reported in ATSDR, 2004). The thyroid hormones are lipophilic and can pass through the placental barrier. Therefore maternal exposure to iodine would typically result in exposure of the foetus to thyroid hormones (ICRP, 2002 – reported in ATSDR, 2004). The accumulation of iodide in the foetal thyroid starts at about 70 – 80 days of gestation and precedes the development of thyroid follicles (Evans et al., 1967; Book & Goldman, 1975 - reported in ATSDR, 2004). The uptake of iodide by the foetus increases with the development of the foetal thyroid, and reaches its peak at approximately 6 months of gestation (Aboul-Khair et al., 1966; Evans et al., 1967 - reported in ATSDR, 2004).

 

 

The uptake of iodide by the thyroid gland is 3-4 times greater during the first 10 days of postnatal life than in adults. However, this falls to adult levels after about 10–14 days of age (Van Middlesworth, 1954; Ogborn et al., 1960; Fisher et al., 1962; Kearns & Philipsborn, 1962; Morrison et al., 1963 - reported in ATSDR, 2004).  

 

 

Metabolism:

 

The metabolism of absorbed iodine is expected to be similar, irrespective of the route of exposure to inorganic iodine. Molecular iodine (and ingested sodium iodide and inhaled methyl iodide) all appear to undergo rapid conversion to iodide (Morgan & Morgan, 1967; Morgan et al., 1967a,b, 1968; Black & Hounam, 1968 - reported in ATSDR, 2004). For by-products of metabolic reactions in the gastrointestinal tract it has been suggested that these may differ for iodine and iodide, and could be responsible for differences in some reported effects (Sherer et al., 1991 - reported in WHO, 2009).  

 

Iodine in the thyroid gland is incorporated into the protein, thyroglobulin. Iodine forms covalent complexes with tyrosine residues. The iodination of thyroglobulin is catalysed by the enzyme thyroid peroxidise. Iodination occurs at the follicular cell-lumen interface and the processes involved are the oxidation of iodide to form a reactive intermediate, the formation of monoiodotyrosine and diiodotyrosine residues in thyroglobulin, and the coupling of the iodinated tyrosine residues to form T4 (coupling of two diiodotyrosine residues) or T3 (coupling of a monoiodotyrosine and diiodotyrosine residue) in thyroglobulin. In the thyroid, the T4/T3 ratio is approximately 15:1; however, the relative amounts of T4 and T3 produced can depend on the availability of iodide, as low levels of iodide result in a lower T4/T3 synthesis ratio (Taurog 1996 - reported in ATSDR, 2004). The lipophilic T3 and T4 enters the blood via diffusion through the plasma membrane. More than 99% of both T3 and T4 combine with blood transport proteins, predominantly thyroxine binding globulin. The process is regulated by the pituitary hormone, thyroid stimulating hormone (TSH). TSH is released in response to thyrotropin releasing hormone from the hypothalamus as a response to low blood thyroid hormone level or lowered metabolic rate or body temperature (Guyton & Hall, 1996 - reported in WHO, 2009).

 

The main metabolic pathways for iodine outside the thyroid gland involve the catabolism of T3 and T4 and include:

 

- Deiodination reactions;

- Ether bond cleavage of thyronine;

- Oxidative deamination and decarboxylation of the side-chain of thyronine; and

- Conjugation of the phenolic hydroxyl group on thyronine with glucuronic acid and sulphate.

 

The monodeiodination of T4 to T3 is the major source of production of peripheral T3. T3 has a greater potency as a hormone than T₄, and, together with the production of 3,3′,5-triiodo-L-thyronine, account for about 80% of total T₄turnover in humans. (Engler & Burger, 1984; Visser, 1990 - reported in ATSDR, 2004). Iodothyroine deiodinases also catalyse the inactivation of T4 and T3 (Darras et al., 1999; Peeters et al., 2001 - reported in ATSDR, 2004). Deiodination is catalysed by selenium-dependent deiodinase enzymes.

 

The alanine side chain of the iodothyronines can undergo oxidative deamination and decarboxylation which represents approximately 2% and 14% of total T3 and T4 turnover, respectively. (Braverman et al., 1970; Gavin et al., 1980; Pittman et al., 1980; Visser, 1990 reported in ATSDR, 2004). The enzymes that catalyse these reactions have not been well characterised.

 

In the liver and probably in other tissues, the sulphate conjugation of the phenolic group of iodothyronines occurs. In the human liver, this reaction is catalysed by the enzyme phenolic arylsulphotransferase (Young, 1990 - reported in ATSDR, 2004). Iodothyronines that have one iodine moiety on the phenolic ring preferentially undergo sulphation (Sekura et al., 1981; Visser, 1994 - reported in ATSDR, 2004), with the sulphated products then undergoing deiodination.

 

Also in the liver, the glucuronide conjugation of the phenolic hydroxyl group of the iodothyronines occurs. This reaction may also occur in other tissues. The identity of the glucuronyltransferase enzymes that catalyse this conjugation reaction have not yet been determined, but such has been shown to occur in rats for microsomal bilirubin,p-nitrophenol, and androsterone uridine diphosphate–glucuronyltransferases (Visser et al., 1993 - reported in ATSDR, 2004). 

 

Ether bond cleavage of iodotyrosines represents a minor pathway of metabolism. This mechanism explains the observation of diiodotyrosine in the serum of some patients who received high dosages of T₄or who had severe bacterial infections (Meinhold et al., 1981, 1987, 1991 - reported in ATSDR, 2004).

 

Excretion

 

The main route of excretion for iodine is via the urine in the iodide form. With respect to the elimination of absorbed iodine, urinary excretion accounts for >97% and faeces accounts for another 1-2%. (Larsen et al., 1998; Hays, 2001 - reported in ATSDR, 2004). However, not all iodide that is filtered by the kidney remains in the urine. During steady-state conditions of radioiodine concentration, the renal plasma clearance was about 30% of the glomerular filtration rate. This suggests tubular reabsorption of the element. (Vadstrup, 1993 – reported in ATSDR, 2004). In other studies investigating the renal clearance in dogs, further evidence for tubular reabsorption of iodide was demonstrated. (Walser & Rahill, 1965; Beyer et al., 1981 - reported in ATSDR, 2004). The exact mechanism for reabsorption has not been clearly established.

 

Glucuronide and sulphate conjugates of T3, T4 and their metabolites are secreted into the bile. The total biliary secretion of T4 and metabolites was approximately 10-15% of the daily metabolic clearance of T4 (Myant, 1956; Langer et al., 1988 - reported in ATSDR, 2004).

In rats, about 30% of T4 clearance has been attributed for by the biliary secretion of the glucuronide conjugate and 5% as the sulphate conjugate. Once the conjugates are secreted, extensive hydrolysis occurs, with the reabsorption of iodothyronine in the small intestine. (Visser, 1990 - reported in ATSDR, 2004)

 

Other routes of excretion for absorbed iodine can be through breast milk, saliva, sweat, tears and exhaled air. (Cavalieri, 1997 - reported in ATSDR, 2004). In an adult patient that received an oral tracer of radioiodine (¹²³I), approximately 0.01% of the dose was recovered in the tears over a 4 hour period, with peak activity 1 hour after dosing (Bakheet et al., 1998 - reported in ATSDR, 2004). The radioactivity was still present in the tears, 24 hours post-exposure. The secretion of iodine in human saliva has also been recorded (Brown-Grant, 1961; Wolff, 1983; Mandel & Mandel, 2003 - reported in ATSDR, 2004). However, the contribution of secretion in human saliva is probably minimal. Under conditions of strenuous physical activity, appreciable amounts of iodide can excreted in the sweat. (Mao et al., 2001 - reported in ATSDR, 2004).

 

The elimination of iodide in breast milk is well documented. (Hedrick et al., 1986; Spencer et al., 1986; Dydek & Blue, 1988; Lawes, 1992; Robinson et al., 1994; Rubow et al., 1994; Morita et al., 1998 – reported n ATSDR, 2004). A transfer coefficient of 0.12 day per litre of

milk has been estimated for¹³¹I from intake to breast milk (ratio of steady-state¹³¹I concentration in breast milk to¹³¹I intake rate) (Simon et al., 2002 - reported in ATSDR, 2004). The proportion of absorbed iodide that is excreted in breast milk is a function of both thyroid status and iodine intake, with a larger fraction of the absorbed dose excreted in breast milk in the hypothyroid state. In a case of a hyperthyroid woman who received an oral tracer dose of Na¹²³I during lactation, approximately 2.5% of the dose was excreted over a 5.5 day period (Morita et al., 1998 – reported in ATSDR, 2004). In another case involving a hyperthyroid patient, approximately 2.6% of an oral dose was excreted in breast milk (Hedrick et al., 1986 – reported in ATSDR, 2004) . In contrast to the previous cases, a hypothyroid patient administered Na¹²³I orally excreted 25% of the radioiodine in her breast milk in 41 hours (Robinson et al., 1994 – reported in ATSDR, 2004).

 

The whole body elimination half-time of absorbed iodine has been estimated to be approximately 31 days in healthy adult males, However, considerable inter-individual variability is documented. (Van Dilla & Fulwyler, 1963; Hays, 2001 – reported in ATSDR, 2004).

 

 

Overall conclusions on toxicokinetics

 

Molecular iodine and also inorganic compounds of iodine are readily absorbed via the oral and inhalation routes of exposure. In human studies, dermal absorption is not considered to be a significant route of exposure, and represents 1% of the applied dose. Iodine is excreted via urine, faeces, sweat and breast milk.

 

References:

 

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

 

 

ECHA, 2008 (a) - Guidance on information requirements and chemical safety assessment: Chapter R3: Information gathering

 

ECHA, 2008 (b) - Guidance on information requirements and chemical safety assessment: Chapter R7c: Endpoint specific guidance

 

USEPA, 2006: Iodine and Iodophor Complexes, Revised Toxicology Chapter in Support of Issuance of the Reregistration Eligibility Document (RED) Document

 

WHO Concise International Chemical Assessment Document (CICADS) 72 - Iodine and Inorganic Iodides: Human Health Aspects (2009).