Ziel
Exposure of the thyroid to radioactive iodine represents a potential hazard of ionizing radiation and may lead to thyroid cancer or thyroid dysfunction. The project aims to define the risks of low doses to the thyroid, the biological effects of radioiodine and the potentials risks of preventive administration of stable iodine. To this end:
a human thyroid cell line will be developed to study the radiobiology of human thyroid cells;
the relative carcinogenic risks of radioiodine and external radiation will be compared and set in relation to thyroid morphology;
uptake of stable iodine will be studied in several regions of the Community to obtain information on relative risks of stable iodine applications after an accident liberating radioiodine.
Research has been carried out into the development of a model of human thyroid cell line. Until now the study of the radiobiology of the human thyroid has had to rely on unsatisfactory models. The need for differentiated cell lines has therefore been recognized as a major aim radiobiological research. Relatively well differentiated human keratinocyte cell lines have been obtained using the immortalizing genes of human papilloma viruses (HPV), therefore the feasibility of applying this methodology to human thyroid cells has been studied.
Human thyroid cells were transfected with a deoxyribonucleic acid (DNA) fragment containing the full immortalizing genes E6-E7 under the control of the powerful long terminal repeat (LTR) promotor. Cells that showed epitheloid morphology and secreted thyroglobulin stimulated by thyrotropin were retained as a cell line for further studies.
A model of transgenic mice has been developed for thyroid tumorigenesis.
The thyroglobulin promoter upstream of chloramphenicol acteyl transferase complementary deoxyribonucleic acid (cDNA) was injected into mouse oocytes and was shown to be able to target the expression of the gene specifically in the thyroid of injected mice and of their offspring. In the transgenic mice and their progeny Large T (LT) expression in the thyroid was confirmed. These mice developed progressive goiters immediately after birth. The follicular tumours associated with the goiter concentrated radioiodide but the oxidation of this iodide was greatly decreased. These animals represent faithful experimental models of the human thyroid tumours progression.
Further research involved the control of thyroid cell proliferation. The stimulatory effects of thyroid stimulating hormone (TSH), cyclic adenosine monophosphate (AMP) enhancers, epidermal growth factor, and phorbol esters on thyroid cell proliferation in dog cells were confirmed. On the other hand. However TSH and cyclic AMP enhancers induced both proliferation a nd differentiation in the same cells at the same time and showed that epithelial cells cyclic AMP activated the 2 supposedly opposite processes.
In human thyroid cells in culture, it has shown that transforming growth factor (TGF) inhibits proliferation but also differentiation expression. Thus TGF beta could in the human thyroid be the negative factor controlling growth.
Iodidine deficiency data, demonstrate a wide range of dietary iodine supply in Europe with large areas of 2 wild to severe iodine deficiency. As effects of radioiodine contamination are directly proportional to the relative thyroid uptake it can be shown that general iodine prophylaxis in Europe would, besides its clinical benegicial effects, prevent more than 2/3 of the eventual population radiation burden from nuclear accidents, or otherwise.
A study has been carried out to determine the transformation rate in the thyroid and to develop a formal approach to the question of the appropriateness of absorbed dose as an index for risk in the thyroid.
The estimate of fetal brain dose from maternally ingested iodine-131 in the fetal thyroid has been extended form 8 to 16 weeks to the entire gestational period.
It is inferred that at no stage in gestation does the range of iodine-131 electrons exceed the minimum brain thyroid distance. The data for fetal anatomical distances was modelledby linear regression. The data for absorbed fractions have been obtained by modelling the data of Berger (1968) using the 'pcnonlin package'.
The average brain dose estimate is entirely due to gamma emissions from the fetal thyroid and ranges form 0 to 60 uGy/MBq maternally ingested iodine-131. It is comparable to the permanently present dose from maternal organs. The dose peaks in the weeks 18 to 24. A maximum local dose has also been calculated using modelled minimum thyroid brain distances and the biokinetic data for each stage of gestation. The dose varies from 0 to 800 uGy/MBq maternally ingested iodine-131. This dose is intended to represent the upper limit of the dose to any part of the brain during the entire gestational period.
An examination of the appropriateness of thyroid absorbed dose as a concept to use with risk estimates has been undertaken. In broadest terms the limitations of the use of organ absorbed dose were found to be:
inappropriate biokinetic and anatomical parameters;
breakdown of conventional dose estimation at a cellular level and for small organs;
exclusion of detriment to other organs from radiation emanating from that organ which receives highest dose;
incompatibility with a truly stochastic model of radiocarcinogenesis.
The incompatibility with a stochastic model of radiocarcinogenesis arises from the exclusion of number of cells exposed as a parameter contributing to risk in conve ntional risk estimation. To enable the inclusion of number of cells exposed it is suggested that this has to be related to a more accessible parameter such as mass.
Methods of measuring cells/g were examined. Section studies could provide accurate information on absolute figures of number of cell/g of tissues and cell yield from digestion was a relative reflection of cell number/g. Modelling using spherical follicles was found to give a poor reflection of morphologic composition of the glands.
Data on number of cells in 1 g of human thyroid tissue is not widely available. However a figure of 3EB for epethilial cells/g was calculated from section data by Coclet et al (1989) for Belgian euthyroid human tissue. This is similar to data for other species. Examination of the literature found that animal studies suggest that upon thyroid stimulating hormone (TSH) stimulation, the number of cells/g remains approximately constant but that it may rise on involution. Cell yield from digestion experiments trebled for colloid goitre tissue also suggesting a different number of cells/g for certain thyroid tissue types.
Urinary iodine excretion has been studied and used as an index of dietary iodine intake in populations residing on either side of the Irish Sea. Seasonal variations in urinary iodine excretion were examined and related to dietary milk iodine content. Using ultrasound scanning the thyroid volume and the frequency of thyroid nodules in the study populations were monitored and recommendations were made on iodine dosage and the frequency of administration required to maintain optimal levels.
Urinary iodine excretion was measured in random urine samples obtained from subjects residing in the Dublin area. A disturbing finding for which no immediate explanation was forthcoming, was that mean urinary iodine values calculated for various centres showed wide variations (72 to 204 ug/g). It was however noted that urine samples had been obtained at different times of the year.
As milk has been reported to form an important source of dietary iodine intake, it was decided to look for possible seasonal variations in dietary milk iodine content in Ireland. It was found that the iodine content of milk was at its highest during the winter months (February to April) when cattle were housed and receiving food supplements. Iodine values declined during the summer months when the cattle were once again put out to pasture.
Variations in urinary iodine excretion paralleled those observed in milk iodine content being highest in winter showing a maximum of 222 ug/Kg in February and lowest in Summer (44 ug/kg in July).
Preliminary studies on urinary iodine excretion in pregnant mothers show an increase in excretion over the 3 trimesters of pregnancy. As this was a cross-sectional study and therefore subject to increased error, a prospective study following the same patients through their pregnancies is now underway.
As no data exists on thyroid volume in the Irish population a study using an ultrasound scanner fitted with a 7.5 m/hz linear transducer was undertaken.
The mean thy roid volume for 158 females was 12.2 +/- 7.7 ml and for 153 males 15.6 +/- 5.0 ml. These values were significantly different but the difference could be accounted for on the basis of greater male body weight. The % of enlarged thyroid glands in females was 7.6% and in males 2.6%. However thyroid enlargement was encountered more frequently in older subjects.
In order to establish optimum conditions for iodine prophylaxis, measured doses of iodine containing preparations were given to healthy volunteers. Preliminary findings on iodine kinetics were obtained using sequential urine and serum iodine measurements.
University of Brussels (J.E. Dumont)
The project aims at developing tools for investigating the problems of the action of low radiation doses to the thyroid. To this end, attempts will be made to develop and characterize a human thyroid cell line. Various approaches will be tried, such as transformation by transfection of genes of human papilloma virus, serial cultures of human tumour cells, XAray and chemical transformation. The cell line obtained, and similar cell lines that may be developed in other laboratories, will be characterized with respect to the differentiation characteristics (particularly iodine metabolism), growth characteristics and growth factor requirements.
The transformation of the cell line by oncogenes (such as SV40) will be assessed on the basis of formation of foci, subculturing, characterization of the transformed cell to evaluate the possibility of using the cell line for XAray transformation studies. The investigation will concentrate on developing and quantifying parameters for malignant transformation of such cells. The paramaters will be compared to those of normal human thyroid cells in primary culture. This system will later be used to determine the risks of radiationAinduced cell transformation and for investigating the role of oncogenes and protooncogenes in this process. The laboratory has already considerable experience in culturing and studying human thyroid cells obtained from biopsy material.
Federated Dublin Voluntary Hospitals (J. Malone)
This part of the Irradiation and Thyroid Disease contract is concerned with a critical examination of two assumptions that underlie all the dose and level of exposure limits for thyroid irradiation; intervention levels; and countermeasures used by governments and international organizations. Firstly, much of thyroid irradiation is due to 131I and no firm basis in the scientific literature exists for the values of its biological effectiveness (for cell transformation) with respect to high dose X-rays or gamma rays. In fact any value from 0 to 1 can be justified based on at least one reference from a well established group. Values for 131I biological effectiveness in cell survival studies are now much better established. Experimental methods based on cell culture techniques will be evaluated and established where worthwhile, to help clarify this area of uncertainty.
Secondly, there are serious reasons to doubt the validity of using absorbed dose only as a predictor of detriment in a gland whose mass may vary from 10 g to 100 g in adults. The case for this statement is clearly made in the State of the Art Review with the original proposal. It is proposed to examine both the validity of the case and the most acceptable alternatives to absorbed dose.
University College, Dublin (P. Smyth)
The dietary iodine intake of populations of both adults and school children residing in different parts of Ireland and in Wales is currently under evaluation. Dietary iodine is being assessed by measuring its excretion in random urine samples. As milk intake has been reported to form the major source of dietary iodine in Northern European Countries, the contribution of seasonal variations in milk iodine content to the daily dietary supply is also being evaluated. A relationship between seasonal variations in urinary iodine excretion and dietary milk iodine content is beginning to emerge. In view of the relative importance of milk in the diet of the young; particular attention is being paid to such studies in school children.
The kinetics of oral iodine administration are being studied by giving known doses to adult volunteers and doing sequential urine and serum iodine estimations. The relative importance of iodine dosage and duration of therapy in achieving a desired plateau of circulating iodine is being investigated.
Finally, high resolution ultrasound scanning is being applied to the accurate measurement of thyroid volume and the frequency of occurrence of thyroid nodules in the study population. Findings are being compared with published results from other European countries.
Wissenschaftliches Gebiet (EuroSciVoc)
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht. Siehe: Das European Science Vocabulary.
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht. Siehe: Das European Science Vocabulary.
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Finanzierungsregelung (oder „Art der Maßnahme“) innerhalb eines Programms mit gemeinsamen Merkmalen. Sieht folgendes vor: den Umfang der finanzierten Maßnahmen, den Erstattungssatz, spezifische Bewertungskriterien für die Finanzierung und die Verwendung vereinfachter Kostenformen wie Pauschalbeträge.
Koordinator
BRUXELLES
Belgien
Die Gesamtkosten, die dieser Organisation durch die Beteiligung am Projekt entstanden sind, einschließlich der direkten und indirekten Kosten. Dieser Betrag ist Teil des Gesamtbudgets des Projekts.