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Carcinogenicity

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Description of key information

7.7 Carcinogenicity: 
KS - rat (2 year inhal). TMN-518. KL.1, NOAEL: Non-neoplastic 5 ppm; Neoplastic 20 ppm (NOAEC 5 or 20 ppm (mg/m3 from ppm = ppm x mwt(141.935)/24.45 = 29 or 116 mg/m3 respectively);
KS - mouse (18 month diet). TMN-585. KL.1, NOAEL: Non-neoplastic 600 ppm (84 or 100 mg/kg/day for males and females respectively); Neoplastic 200 ppm (males - 28 mg/kg/day) and 600 ppm (females - 100 mg/kg/day)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
28 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
116 mg/m³

Justification for classification or non-classification

There is a convincing weight of evidence to conclude that iodomethane should not be classified for carcinogenicity.

Additional information

The 2 year inhalatory rat carcinogenicity study confirmed non-neoplastic and neoplastic NOAEC of 5 and 20 ppm respectively (alternatively, 29 and 116 mg/m3). The neoplastic NOAEL was based on increased thyroid follicular tumours (adenoma and combined adenoma/carcinoma) in males (only) at the maximum dose tested (60 ppm). These thyroid changes were accompanied by increased gland weights and markedly elevated serum TSH levels throughout the study, which were thought to have played a prominent role in the development of thyroid follicular cell tumours.

 

The non-neoplastic findings included squamous metaplasia of the salivary glands, follicular hyperplasia, follicular cystic hyperplasia, cytoplasmic vaculoation of follicular cells and changes in the olfactory epithelium (degenerative changes and/or regenerative cyst-like formation).

 

The 18 month dietary mouse carcinogenicity study confirmed a non-neoplastic NOAEL of 600 ppm (84 or 100 mg/kg/day for males and females, respectively). The neoplastic NOAEL was established at 200 ppm (28 mg/kg/day) for males and 600 ppm (100 mg/kg/day) for females. As with the rat study, the mouse neoplastic NOAEL was based on thyroid follicular tumours, with again increased TSH levels accompanying these tumours.

 

The non-neoplastic findings included local irritant effects in the upper gastrointestinal tract (due to the irritant nature of the test material rather than a true systemic effect) and adaptive changes resulting from elevated TSH levels.

 

Data from the chronic rat study demonstrate that iodomethane has a specific effect on the thyroid gland, increasing thyroid size through stimulation of cellular hyperplasia. Collectively the mechanistic data suggests that iodomethane metabolised to iodide exerts actions centrally on the thyroid gland (mechanism of action discussed below).

 

The proposed non genotoxic mode of action (MOA) of thyroid follicular tumours in rodents chronically exposed to iodomethane was systematically evaluated using the IPCS Framework for Analysing the Relevance of a Cancer Mode of Action to Humans (IPCS, 2007). The results of this evaluation are as follows.

 

A 2-year inhalation carcinogenicity study in rats revealed a significant increase in thyroid follicular adenomas in male rats at the highest dose of 60 ppm. There was a marginal increase in females. There was no effect at 20 ppm. The incidence of thyroid follicular adenomas and carcinomas combined was slightly increased in male mice in an 18-month dietary carcinogenicity study at the highest dose of 600 ppm. The MTD was exceeded in both studies based on the degree of bodyweight and bodyweight gain reduction relative to controls.

 

The proposed MOA for iodomethane induced thyroid follicular tumours in rodents involves the perturbation of homeostasis of the hypothalamic-pituitary-thyroid axis caused by excess circulating iodide derived from the metabolism of iodomethane. Excess iodide acts centrally on the thyroid by inhibiting production and release of T4. Reduced circulating levels of T4 and T3 cause a compensatory increase in circulating TSH from the pituitary resulting in sustained stimulation of the thyroid to produce thyroid hormone. This leads to enlargement of the thyroid and proliferation of thyroid follicular cells (hyperplasia). Thyroid hyperplasia can eventually progress to neoplasia,

 

The key events for the proposed MOA were established in a 2-day investigative study in male rats supported by pituitary and thyroid hormone measurements and pathology investigations in the 2-year study:

- There was a marked dose dependent and exposure time related increase in serum iodide levels among rats exposed to 25 or 100 ppm iodomethane in the 2-day study which was reversible upon cessation of exposure

- Excess iodide is known to act centrally on the thyroid to inhibit the production and release of T4

- Dose related decreases in both serum T4 and T3 and marked dose related increases in serum TSH were observed after 18 hours following the second exposure to 25 or 100 ppm in the 2-day study. A similar pattern of thyroid and pituitary hormone changes was observed after 26 weeks in the 2-year study at 60 ppm. Thereafter, the magnitude of the changes was notably reduced indicating that compensatory mechanisms were operating

- Thyroid growth was evident in male rats at 60 ppm in the chronic study characterised by significantly increased thyroid weights after 52 weeks of exposure and increases in follicular cell hyperplasia. This correlated with an early onset of thyroid follicular adenomas after 52 weeks in male rats

- There is a good dose correlation for the key events in the proposed MOA and the occurrence of thyroid tumours.

- There is a logical temporal response for the key events in the proposed MOA in which the key events characterising altered thyroid function precede thyroid tumour formation

- There are many studies in rodents demonstrating the relationship between sustained perturbation of the hypothalamic-pituitary-thyroid axis, prolonged stimulation of the thyroid gland by TSH, and the progression of thyroid follicular cells to hyperplasia and eventually neoplasia

- Iodinated compounds are known to perturb thyroid hormone homeostasis in rodents and cause increases in circulating TSH. Oral administration of iodinated glycerol for 2 years produced thyroid tumours in male rats

Evaluation of other potential modes of action concluded that:

- Iodomethane is unlikely to be genotoxic in the whole animal and as such a genotoxic MOA is unlikely to be a plausible MOA for the target organ specificity of thyroid follicular cell tumours in the long term rodent bioassays

- T4 metabolism is not the primary site of iodomethane action on the pituitary-thyroid axis. The potential contribution from possible perturbation of 5’-deiodinase activity on peripheral metabolism of T4 via excess iodide could not be excluded.

Assessment of the human relevance of the MOA identified for the thyroid tumours in the rat showed that:

- Thyroid cancer in humans is rare

- Increased iodide intake may be risk factor for thyroid cancer but overall humans appear to have a low susceptibility to thyroid cancer and the risks arising from disturbances to thyroid hormone homeostasis are low

- There are no fundamental qualitative differences in key events between rodents and humans and the MOA cannot be reasonably excluded on this basis

- There are several species differences in thyroid physiology and biochemistry between rodents and humans. The weight of evidence suggests that rodents are quantitatively much more sensitive than humans to thyroid-pituitary disruption and hormonal imbalances leading to thyroid growth and tumour formation

- Humans would be less sensitive to the effects of excess iodide on thyroid function and thyroid tumour development. Thyroid tumours in male rats were only induced at a dose level which resulted in general toxicity and which exceeded an MTD. Thus it is extremely unlikely that exposure of humans to iodomethane would lead to sustained elevation of TSH since exposures would have to exceed tolerable levels of toxicity.

 

In conclusion, there are no plausible scenarios whereby iodomethane exposure would lead to sustained elevation of TSH in humans and potential thyroid tumour formation. There is a convincing weight of evidence to conclude that iodomethane should not be classified for carcinogenicity.

References:

International Programme on Chemical Safety (IPCS) (2007). Harmonization Project Document No. 4. Part 1: IPCS framework for analysing the relevance of a cancer mode of action for humans and case-studies, Part 2: IPCS framework for analysing the relevance of a non-cancer mode of action for humans. World Health Organisation, Geneva.


Carcinogenicity: via oral route (target organ): glandular: thyroids

Carcinogenicity: via inhalation route (target organ): glandular: thyroids

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