Imidazolidine-2-thione

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Correlation between blood ethylenethiourea and thyroid gland disorders among banana plantation workers in the Philippines.

Author:

Panganiban L, Cortes-Maramba N, Dioquino C, Lurenda Suplido M, Ho H, Francisco-Rivera A, and Manglicmot-Yabes A.

Year:

2004

Bibliographic source:

Environmental Health Perspectives, vol 112, number 1, 42-45

Materials and methods

Study type:

case control study (prospective)

Endpoint addressed:

carcinogenicity

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The aim was to correlate ETU levels with the incidence of thyroid gland disorders among banana plantation workers exposed to EBDC.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Imidazolidine-2-thione

EC Number:

202-506-9

EC Name:

Imidazolidine-2-thione

Cas Number:

96-45-7

Molecular formula:

C3H6N2S

IUPAC Name:

imidazolidine-2-thione

Details on test material:

Other name : Ethylenethiourea (ETU)

Method

Type of population:

occupational

Details on study design:

The authors randomly selected 88 workers, 21-53 years of age, with a 3-year history of direct or indirect exposure to EBDCs from four plantations using large amounts of dithiocarbamates for the past 20 years. The 57 directly exposed workers included mixers, assistant mixers, sprayers, flagmen, and clean-up laborers. The 31 indirectly exposed workers consisted of supervisors, maintenance crew, and research aides. The last exposure of these workers occurred between 1 and 9 days before the study was conducted. The authors randomly selected 43 control workers had no exposure to EBDCs and resied at least 50 km away from the banana plantations.
This cross-sectional study was conducted on 11–13 October 1999 among the EBDC-exposed workers and 7–8 December 2000 for organic-farm workers. The arthors collected a demographic profile, nutritional history, work background, and exposure data using face-to-face interviews. Physical examination centered on the thyroid gland. Thyroid-stimulating hormone (TSH) and free thyronine (T4) determinations were performed using immunoradiometric assay and radioimmunoassay methods, respectively, by the Medical Research Laboratory of the Philippine General Hospital. Free T4 was determined only among subjects with elevated TSH levels. The Bureau of Research and Laboratory of the Department of Health analyzed iodine in urine using an acid-digestion method and urinary creatinine using Jaffe’s reaction. The urine, blood, and environmental samples were analyzed for the presence of ETU by the Toxicology Laboratory of the Department of Pharmacology (University of the Philippines College of Medicine) using HPLC with an ultraviolet detector. Thyroid gland ultrasound was performed by a trained radiologist at the Tagum Regional Hospital. A fine needle aspiration biopsy was performed on subjects who had palpable nodules.
Environmental samples were collected from air through 4–8 hr continuous monitoring using 0.37-mm polyvinyl chloride filters and an air sampling device. Soil samples were collected from the top down to 0.5 m from the surface. All biologic and environmental samples were stored on dry ice and sent to the respective laboratories 24–48 hr after collection. Good laboratory practice and quality control measures were observed during the conduct of the tests.

Exposure assessment:

not specified

Details on exposure:

EBDCs were applied through aerial and backpack spraying on a weekly and daily basis, respectively. Other fungicides were used at the same time or interchangeably with EBDCs. The primary routes of exposure to farmers were inhalation and skin contact.

Statistical methods:

Descriptive statistics, Student t-test, analysis of variance, Fisher’s exact test, Pearson’s correlation analysis, and regression analysis were performed using the Statistical Package for Social Sciences (SPSS) for Windows, version 10 (SPSS, Chicago, IL, USA).

Results and discussion

Results:

The authors found enlarged thyroid glands in 17 workers from the EBDC-using plantations and only 2 among the organic-farm workers. There was no significant difference in the neck diameter of the two groups (p = 0.07) after controlling for variables such as age, sex, height, and weight. The authors found no significant difference in the physical diagnosis of goiter in the two groups for both female (p = 0.16) and male (p = 0.79) workers.
TSH levels were higher among both types of exposed workers compared with those of organic-farm workers (p = 0.34) (Table 1). Compared with control values, TSH values were elevated in three exposed workers (5.1, 5.8, and 6.2 mIU/L), although their free T4 levels were within normal limits (12.9–15.5 pMol/L). After controlling for age, we found no statistically significant difference in the TSH levels between the exposed and control groups (p = 0.24).
The mean level of urinary iodine among the exposed group was not significantly different from that of the control group after correcting for dietary differences (p = 0.45).
Nine of the exposed workers and three organic-farm workers had abnormal thyroid ultrasound results. Of the exposed workers, five showed normal-sized thyroid glands with solitary nodules. Among the control group, two had diffuse thyroid parenchymal disease and one with a small solitary nodule (Table 2). Results of the Fisher’s exact test on the pro-portion of exposed and control farmers with abnormal thyroid ultrasound findings showed no significant difference (p = 1.000). Age and dietary preferences had insignificant influence on the development of goiter among the study groups at p = 0.421 and p = 0.559, respectively.

When corrected for age and diet, blood ETU levels remained significantly different among the three groups (p < 0.001). Urinary ETU levels also remained insignificant after correction for age and diet (p = 0.67). Blood ETU correlated poorly with urinary ETU levels (p = 0.156, r2 = 0.024). ETU was detected in both soil and air samples from all plantations (Table 1). The Student t-test showed significant differences in the ETU levels of air and soil from the two areas (p s 0.001 and p = 0.003, respectively). Temperature and humidity levels in both study and control areas were not statistically different (p = 0.09 and p = 0.13, respectively).
ETU in blood and urine was poorly correlated with environmental ETU levels. The same is true with urinary iodine and TSH levels. Furthermore, urinary and blood ETU levels were not correlated with TSH and time of spraying. Neither was there a relationship between TSH and spraying time. However, there was a strong correlation between the size of solitary nodules and blood ETU levels (p = 0.001) (Table 3).

Confounding factors:

The number, age, and sex of the persons examined in directly exposed, indirectly exposed, and control groups are summarized in Table 1. Despite attempts to select participants within the same age range, the exposed male workers were significantly older than their control counterparts. In general, there appeared to be a higher intake of seaweed, other seafood, and cassava among the exposed group, while the diet of the control group consisted mainly of vegetables. There was no significant difference between the two groups in the intake of fish.
Comparison of the exposed and control groups using Fisher’s exact test showed no significant differences regarding history of known thyroid gland disorders and diabetes mellitus in first degree relatives (p = 0.227 and p = 1.0, respectively).

Strengths and weaknesses:

no data

Any other information on results incl. tables

Table 1 : Demographic profile and laboratory examinations for exposed and control workers.

Parameters	Directly exposed (n = 57)	Indirectly exposed (n=31)	Control (n=43)	p-Value
Age
Mean +/- SE	35.5+/-0.88	37.8+/-1.31	33.5+/-1.27	0.05^a
Range	21-50	22-53	20-50
Sex
Male	57	20	34
Female	0	11	9
Blood ETU
Mean +/- SE, ppb	4.45+/-0.55	2.55+/-0.60	0.30+/-0.04	<0.001^a
GM (SE), ppb	2.55 (0.32)	0.98 (0.42)	0 (0.36)	<0.001^a
Urinary ETU
Mean +/- SE, ppb	378.34+/-50.11	267.16+/-69.9	26.31+/-6.39	0.10^a
GM (SE), ppb	94.73 (0.32)	134.21(0.49)	14.09 (0.62)	0.10^a
TSH^b(mean +/- SE, mlU/L) Adjusted for age	1.79+/-0.13	1.77+/-0.21	1.52+/-0.12	0.34^a 0.24^c
Urinary iodine/g creatinine, Adjusted for dietary preferences	155.2+/-12.25	188.08+/-23.09	110.67+/-4.95	<0.001^e 0.45^c
Air ETU^d(ng/m3)	8.8		16.17	<0.001^e
Soil ETU^f(ng/g)	51.36		10.62	0.003^e
GM = geometric mean. ^aAnalysis variance ^bNormal value = 0.3-0.5mlU/L ^cLinear regression ^dUS EPA Yean 2000 remediation goal for ambient air = 61 ng/m3 (US EPA 2000) ^eIndependent Student t-test ^fUS EPA Year 2000 remediation goal for industrial soil = 22 000 ng/g (US EPA 2000).

Table 2 : Laboratory results of workers with abnormal ultrasound findings.

Subject no.	Sex/age (years)	Ultrasoundfindings	TSH (mIU/L)	Iodine (µg/gcreatinine)	Blood ETU (ppb)	Urinary ETU (ppb)
Directly exposed workers
1	M/21	Contracted thyroid lobe (4.4x1.40x1.3 cm)	1.80	213.94	6.73	270.42
2	M/36	Contracted thyroid lobe (5.05x0.95x1.45 cm)	1.20	209.00	2.21	117.82
3	M/21	Diffuse thyroid enlargement with solitary nodule (1.25x0.9x0.95 cm)	0.40	25.75	2.34	600.56
Indirectly exposed workers
4	M/36	Solitary thyroid nodule (1.2x0.6x0.8 cm)	1.70	99.47	2.95	435.14
5	F/41	Multinodular goiter (1.9x1.4x1.0 cm, 4.5x4.2x3.7 cm, 1.2x2.1x0.6 cm)	0.8	No specimen	2.88	No specimen
6	F/39	Solitary thyroid nodule (2.5x2.0x1.6 cm)	2.40	No specimen	10.25	No specimen
7	M/40	Solitary thyroid nodule (1.15x1.05x0.75 cm)	1.20	26.98	< 0.1	17.08
8	F/41	Solitary thyroid nodule (0.9x0.65x0.60 cm)	0.70	92.03	1.17	91.26
9	M/45	Solitary thyroid nodule (1.10x0.85x0.45 cm)	1.0	170.0	1.17	35.75
Unexposed workers
1	M/39	Diffuse thyroid parenchymal disease (Rt, 5.25 cm, Lt, 5.40 cm)	1.20	81.83	0.43	< 0.1
2	F/32	Small solid solitary nodule (0.8x0.4x0.7 cm)	2.10	98.11	< 0.1	24.76
3	F/46	Diffuse thyroid parenchymal disease (Rt, 7.10 cm, Lt, 6.45 cm)	0.90	116.83	< 0.1	65.84

Table 3 : Correlation studies between urinary and blood ETU levels and environmental ETU levels, thyroid function, nodule size, and exposure history.

Parameter	r2	p-Value
Blood ETU and air ETU	0.241	0.026
Blood ETU and soil ETU	0.244	0.024
Urinary ETU and air ETU	0.051	0.655
Urinary ETU and soil ETU	0.057	0.620
Urinary iodine and TSH	0.245	0.008
Blood ETU and TSH	0.000	0.999
Urinary ETU and TSH	0.102	0.334
Nodule size and blood ETU	0.956	0.001
Nodule size and urinary ETU	0.594	0.213
Nodule size and urinary iodine	0.759	0.080
Nodule size and TSH	0.575	0.177
Spraying time and blood ETU	0.107	0.438
Spraying time and urinary ETU	0.083	0.541
Spraying time and TSH	0.075	0.585

Applicant's summary and conclusion

Conclusions:

The present study among Banana plantation workers showed differences in TSH levels among the three study groups; TSH was significantly higher in the study group compared to the control group. It is difficult to ascertain the real prevalence of thyroid gland disorders and actual finding of clinical hypothyroidism among the workers.

Executive summary:

Ethylenebisdithiocarbamates (EBDCs) are metabolized into ethylenethiourea (ETU), a possible human carcinogen and an antithyroid compound. In this study the aim was to correlate ETU levels with the incidence of thyroid gland disorders among banana plantation workers exposed to EBDC.The authors randomly selected 57 directly exposed workers and 31 indirectly exposed workers from four banana plantations and 43 workers from an organic farm; all subjects underwent complete medical examinations and laboratory tests. Results showed a higher mean thyroid-stimulating hormone measurement among exposed workers compared with the control group, although the levels were well within normal range. Nine of the exposed farmers had abnormal thyroid ultrasound findings, consisting mostly of solitary nodules, compared with three among the control group. Analysis of variance showed significantly different blood ETU levels among the directly exposed, indirectly exposed,and control groups (p< 0.001), but ETU levels in urine were not significantly different (p= 0.10).Environmental ETU levels were below the U.S. Environmental Protection Agency remediation levels. Among farmers with solitary thyroid nodules, there are found a very good direct correlation between the size of the nodule and blood ETU level. This study showed that blood ETU is a more reliable biomarker for EBDC exposure than urinary ETU; therefore, the determination of blood ETU should be part of medical surveillance efforts among workers exposed to EBDC to detect occurrences of thyroid gland disorders.