Registration Dossier

Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study design is considered appropriate to assess the effects of goitre attributed to excessive iodine intake. A number of potential confounding factors have been addressed, as discussed below. The measurements and parameters used to estimate effects on the thyroid are considered to be appropriate, and the grading of goitre is based on modified WHO criteria, and is considered to be reliable. The use of this data (Boyages et al., 1989; Li et al, 1987) is considered to be acceptable as both the ATSDR and WHO have used this study as the basis for setting a mimimum risk level (ATSDR) and a Tolerable Daily Intake (WHO) of 0.01 mg/kg bw/day which are values for acceptable chronic oral exposure to iodine. These terms are analogous to a DNEL (Derived No Effect Level). As authoritative reviews of iodine have used this data is derive acceptable iodine intake concentrations, this data is considered to be reliable and valid.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1989
Report Date:
1989
Reference Type:
publication
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
no guideline available
Deviations:
not applicable
Principles of method if other than guideline:
The thyroid status in two groups of children (aged 7-15 years) was compared. The children resided in two areas of China where drinking water iodide concentrations were either 462.5 μg/L (n=120) or 54 μg/L (N=51).
GLP compliance:
no
Remarks:
Not applicable

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
The details on the test material are not completely clear in the publications, but based on the ATSDR and WHO reviews of these publications, iodine in the drinking water is in the iodide form (sodium iodide and potassium iodide). The data from this study is appropriate for read across when noting that the ATSDR review states that the gastrointestinal absorption of iodine is considered to be approximately 100% following an ingested dose of water soluble salts such as potassium or sodium iodide. Iodine is also metabolised to iodide in humans.

Method

Type of population:
other: Children
Ethical approval:
not specified
Details on study design:
The thyroid status in two groups of children (aged 7-15 years) was compared. The children resided in two villages in central China. Gaojiabu village is 600 km from the coast in Shanxi province where the drinking water is obtained from shallow wells (iodine concentration 462.5 μg/L: high iodine group). The local primary school has 316 pupils, 120 children aged 7-15 were examined. The control group (low iodine group) was 51 schoolchildren, also aged 7-15 from Huanglou village. The drinking water was obtained from a deep well where the iodine concentration was 54 μg/L. The parameters recorded included height, sitting height, and weight. The clinical thyroid status was determined, and the goitre size was scored based on a modified WHO criteria:

Grade 0 = No goitre
Grade 1 = Palpable goitre (1a, just palpable and soft; 1b palpable and firm)
Grade 2 = Visible goitre while the neck is in the neutral position
Grade 3 = Very large goitre

The thyroid was analysed using ultrasonography in 10 Gaojiabu children with grade 2 goitres and 11 age and sex matched controls. Furthermore, thyroid 131I uptake was measured in 8 of the 10 children from Gaojiabu, where the study authors were particularly investigating whether signs of cretinism had occurred. The cognitive functions was assessed using the Hiskey-Nebraska test of learning by Australian and Chinese psychologists. According to the study authors, this scale has been verified for use in China.

Urine samples were collected from 93 children from Gaojiabu and 12 children from Huanglou. The urine and creatinine concentrations were measured with a Technicon autoanalyzer II. Blood samples were taken from 30 children from Gaojiabu and from 28 children in Huanglou. Parameters such as serum total triiodothyronine (T3), thyroxine (T4) and free thyroxine (FT4) concentrations were measured using commercial radioimmunoassay (RIA) kits (obtained from Baxter Travenol Diagnostics, Cambridge, MA) and serum thyroid-stimulating hormone (TSH) concentrations were assayed by a sensitive immunoradiometric assay (Sucrosep TSH IRMA; Boots Celltech Diagnostics UK). Following collection, all of the urine and serum samples were frozen until they were tested.




Exposure assessment:
measured
Details on exposure:
As discussed above, exposure to iodine was through iodide present in drinking water. The amount of iodine ingested was indirectly determined by recording the urinary iodine/creatinine concentrations. These values were used in the ATSDR (2004) and WHO (2009) publications to estimate iodine ingestion through the drinking water.
Statistical methods:
The statistical evaluation was by paired sample analysis and Students t test before and after log transformation. The results are given as a mean and Standard Deviation (SD).

Results and discussion

Results:
The results table from Boyages et al 1989 (Table 1 below) summarises the data from Lt et al., 1987 and is given in the "Any other information on results..." section below.

All of the subjects were euthyroid from both villages and displayed no abnormal neurological signs. The mean height, sitting height/height ratio and bodyweight were similar in the two populations (p >0.05). The cognitive function was not determined to be significantly different between the villages (Gaojiabu, mean IQ 84 [SD 16]; Huanglou, 85 [17]; p > 0.05)

In the high iodine group there was a 65% prevalence of goitre compared with 15% in the low iodine group. Also, the high iodine group contained 15% of subjects that had a grade 2 goitre, compared with 0% having a grade 2 goitre in the low iodine group. As stated above, although the subjects were all euthyroid with normal values for serum thyroid hormones and TSH concentrations, TSH concentrations were significantly higher (33%) in the high iodine group.

In the ATSDR (2004) and WHO (2009) reviews, the data on urinary iodine/creatinine concentrations was used to estimate iodine ingestion. This allowed for the determination of iodine exposure concentrations . The ATSDR noted that urinary iodine was 1,236 μg I/g creatinine in the
high iodine group and 428 μg I/g creatinine in the low iodine group.

The assumptions made were:

- Children have an assumed body weight of 40 kg;
- The lean body mass is 85% of body weight; and
- The above urinary iodine/creatinine ratios are approximately equivalent to iodine excretion rates, or steady state ingestion rates of 1,150 (29 μg/kg/day).

This gave a calculated intake of 1150 μg/day (29 μg/kg/day) in the high iodide group and 400 μg/day (10 μg/kg/day) in the low iodide group. For further background on the extrapolation to calculate the daily iodine intake, refer to Appendix A of the ATSDR review of iodine 2004.







Confounding factors:
Consideration has been given to controlling a number of factors in this study to ensure that iodine exposure is the main factor resulting in thyroid effects. The subjects in the low iodine and high iodine groups are of the same age range (7-15) and there was no significant differences in the height, sitting height/weight and weight of the children. It is also assumed that the children are of a similar ethnic background. Age and sex was also matched between the high dose and low dose groups when assessing grade 2 goitres. No consideration has been given to the possible impact of differences in diet between the two villages. However, the effects of excessive iodine ingestion on the thyroid are well characterised and it is clear that the high concentration of iodine in drinking water is causing these effects, particularly as the high dose iodine group was from a village in China where goitre was endemic. Consideration of diet is therefore not considered to significantly effect the findings of this study.
Strengths and weaknesses:
The study design is considered appropriate to assess the effects of goitre attributed to excessive iodine intake. A number of key potential confounding factors have been addressed, as discussed above. According to Boyages, 1989, sporadic iodide goitre is rare. Therefore the effects noted in the high iodide group can be attributed to excessive iodine exposure. The measurements and parameters used to estimate effects on the thyroid are considerd to be appropriate, and the grading of goitre is based on modified WHO criteria, and is considered to be acceptable. The use of this data (Boyages et al., 1989; Li et al, 1987) is considered to be reliable as both the ATSDR and WHO have used this study as the basis for setting a mimimum risk level (ATSDR) and a Tolerable Daily Intake (WHO) of 0.01 mg/kg bw/day which are values for acceptable chronic oral exposure to iodine. These terms are analogous to a DNEL (Derived No Effect Level). As authoritative reviews of iodine have used this data to derive acceptable iodine intake concentrations, these publications are considered to be reliable and valid.


Any other information on results incl. tables

Table 1 Epidemiological and biochemical features of the iodine excess and iodine sufficient villages

 

 

Iodine excess (Gaojiabu)

Iodine sufficient (Huanglo)

Clinical thyroid status

Euthyroid

Euthyroid

Goitre prevalence

65%

15%

Goitre-Grade 2

15%

0%

Iodine/drinking water

463 µg/l

54 µg/l

Urinary iodine/creatinine

1236.5 ± 1.5 µg/g

428.4 ± 3.4 µg/g

Free thyroxine (FT4)

(NR 11.1 – 25.0)

19.1 ± 3.4 pmol/l

16.2 ± 3.0 pmol/l*

Total triiodothyronine (T3)

(NR 1.2 – 2.8)

1.6 ± 0.3 nmol/l

1.9 ± 0.2 nmol/l #

Thyrotropin (TSH)

(NR 0.1 – 6.0)

5.2 ± 2.1 mIU/l

 

3.9 ± 1.0 mIU/l ^

 

Results are mean ± SD

*P< 0.05; #P<0.001; ^P>0.05

 

Applicant's summary and conclusion

Conclusions:
In the high iodine group there was a 65% prevalence of goitre compared with 15% in the low iodine group. Also, the high iodine group contained 15% of subjects that had a grade 2 goitre, compared with 0% having a grade 2 goitre in the low iodine group. As stated above, although the subjects were all euthyroid with normal values for serum thyroid hormones and TSH concentrations, TSH concentrations were significantly higher (33%) in the high iodine group.

Using the calculations stated in ATSDR, 2004, the urinary iodine/creatinine ratios were used to determine a calculated iodide intake of 29 μg/kg/day in the high iodide group and 10 μg/kg/day in the low iodide group.

10 μg/kg/day is considered to be a No-Observed Effect Level in children based on the thyroid effects (subclinical hypothyroidism with thyroid
gland enlargement) noted in the high iodine group.


Executive summary:

In this study, the thyroid status in two groups of children (aged 7-15 years) was compared. The children resided in two areas of China where drinking water iodide concentrations were either 462.5 μg/L (n=120) or 54 μg/L (N=51) (Boyages et al. 1989; Li et al. 1987).

In the high iodine group there was a 65% prevalence of goitre compared with 15% in the low iodine group. Also, the high iodine group contained 15% of subjects that had a grade 2 goitre, compared with 0% having a grade 2 goitre in the low iodine group. Although the subjects were all euthyroid with normal values for serum thyroid hormones and TSH concentrations, TSH concentrations were significantly higher (33%) in the high iodine group.

Using the calculations stated in ATSDR, 2004, the urinary iodine/creatinine ratios were used to determine a calculated iodide intake of 29 μg/kg/day in the high iodide group and 10 μg/kg/day in the low iodide group. 10 μg/kg/day is considered to be a No-Observed Effect Level in children based on the thyroid effects (subclinical hypothyroidism with thyroid gland enlargement) noted in the high iodine group.

The study design is considered appropriate to assess the effects of goitre attributed to excessive iodine intake. A number of potential confounding factors have been addressed. The measurements and parameters used to estimate effects on the thyroid are considered to be appropriate, and the grading of goitre is based on modified WHO criteria, and is considered to be reliable. The use of this data (Boyages et al., 1989; Li et al, 1987) is considered to be acceptable as both the ATSDR and WHO have used this study as the basis for setting a mimimum risk level (ATSDR) and a Tolerable Daily Intake (WHO) of 0.01 mg/kg bw/day which are values for acceptable oral chronic exposure to iodine. As authoritative reviews of iodine have used this data is derive acceptable iodine intake concentrations, this data is considered to be reliable and valid.