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ASSESSMENT OF INTERNAL DOSE FROM RADIONUCLIDES USING STABLE ISOTOPE TRACER TECHNIQUES IN MAN

Objective

The limits for the intake of radionuclides as recommended by the International Commission on Radiological Protection (IRCP) are calculated on the basis of the metabolic data and dosimetric models given in ICRP Publication 30. Much of the information on the behaviour of the radionuclides in the body is derived from animal studies and broad assumptions are made where information is lacking. There are, however, no generally accepted criteria for extrapolating animal data to man. Furthermore, IRCP Publication 30 refers exclusively to occupationally exposed adult persons. IRCP does not recommend the use of these data and models for calculating doses for members of the public. There is therefore a continuing and accepted need for more realistic human metabolic data, especially with respect to the variability of dose values for nonstandard, nonoccupational conditions (variability with valency state and chemical form of the radionuclides, food constituents, age dependency).

The common way by which metabolic data in humans are obtained is either from measurements after accidental exposure or from experimental studies where radioactive nuclides are used as tracers. Human studies with radioactive tracers, however, while very valuable, are becoming increasingly restricted to perform especially when healthy persons or even children are involved. A promising possibility of undertaking metabolic studies in man seems to be use of isotopically enriched stable elements as tracers.

This project aims to obtain biokinetic data in humans by a novel stable isotope approach and to assess radiation doses for several relevant radionuclides for which the current state of knowledge is poor. The elements identified are Sr, Ce, Ba, Ru, Te, Zr, Pu and higher actinides. Whereas Sr, Ce, Ba, Te and Zr can be studied by substituting the radioactive nuclides by stable isotopes of the same element as tracers, for Pu and the higher actinides stable analogues will be used as surrogates. Promising candidates are Eu, Gd, and Yb as analogues for Am and Cm respectively, whereas Hf may be considered a Pu analogue.
Analytical methods for the measurement of tellurium concentrations in biological materials have been developed. Graphite furnace atomic absorption spectrometry (GFAAs) achieved detection limits of 10 ug/kg of wet weight for plant material (cress) and 0.2 ug/kg for body fluids.

After an initial test of the biokinetics of tellurium in mammals, performed in swine, a series of studies was carried out on male human volunteers, to investigate intestinal absorption and excretion of tellurium in man. The tellurium was administered in several chemical forms: tellurate, tellurite, metallic tellurium (powder of grain size 1 um), and in cress cultivated on a medium containing tellurium.

No toxic symptoms were observed for oral administration of 15 to 55 ug of tellurium. Fractional intestinal uptake values were derived from the cumulative excretion curves. For tellurate the mean fractional absorption was 28%, with a standard deviation of 11%. For metallic tellurium, the absorbed fraction was 16%, plus or minus 3%. Absorption of tellurium from organic matter was delayed compared to absorption of tellurium salt, but the fractional intestinal absorption was similar (26% plus or minus 10%). However, adding a dressing to the cress decrease absorption to 10%. Excretion of tellurite was slower than that of tellurate, which perhaps explains the higher toxicity of the tetravalent tellurium compounds.

Analytical techniques for isotopic tracer studies using tellurium have not yet been developed. Preliminary investigations with man spectrometric methods were discouraging.

Methods for determiningstrontium concentrations in biological samples using EFAAS were successfully developed, for use in the measurement of intestinal strontium from food.

Construction of an irradiation chamber for the activation of isotopes producing short lived radionuclides has been completed. The computer controlled driving system permits up to 40 samples to be mounted in the chamber, each with different specifically programmed irradiation times. It is also possible to move samples from the irradiation room without the need for direct intervention.

Optimization of the proton activation methodology for the specific determination of stable tellurium isotopes in plasma samples has been performed. Tellurium-124 and tellurium-126 proved to be the most suitable isotopes for use as tracers. They produce radioactive nuclei with sufficiently long half lives (4.18 and 13.02 days respectively) to allow an off line detection and a significant reduction of the background due to the matrix. The yields of the induced reactions were measured to identify the best incident proton energy (11.2 MeV). At this energy there was not cross interference in the production of the 2 radionuclides.

The linear relationship between the intensities of the specific gamma rays and the amounts of tellurium-124 and tellurium-126 present in the samples was tested. The measured tellurium-124 and tellurium-126 content values in samples doped with different but known amounts of the isotopes showed good correspondence with the added values, indicating that the procedure is not affected by hidden systematic errors, and that there is no volatilization of radioactive products from the sample.

Plasma samples enriched with known amounts of the isotopes were analysed to determine the detection limits of proton nuclear activation analysis. These proved to be 4 ng/ml for tellurium-124 and 8 ng/ml for tellurium-126. This technique was used to determine the percentage intestinal tellurium absorption of a rabbit (5.0%, plus or minus 0.8%).

A series of studies has been carried out to assess uptake and excretion of stable isotopes analogous to radionuclides. The human intake, uptake and excretion of the rare earth elements have been measured using inductively coupled plasma mass spectrometry (ICP-MS). Procedures have been developed to separate and concentrate the rare earth elements from matrices such as faecal ash and urine, using selected radio tracers to estimate yield.

Three conclusions were drawn. Firstly, the close similarity in the form of the abundance curve and the intake and excretion curves for each element showed that human uptake and excretion mechanisms were insensitive to the slight chemical differences across the rare earth group, and therefore perhaps also insensitive to the small differences between the rare earths and the actinides, their intended analogues. Secondly, absolute faecal excretion levels were very similar to the levels found in the standard diet samples. Thirdly, urinary excretion was about 10% of the intake and faecal excretion levels, indicating a greater uptake of rare earths than hitherto supposed.

The validity of the use of europium and gadolinium as surrogates for americium and curium was assessed. Chromatographic studies using gel chromatography on Sephacryl, DEAE-Sepharose and Blue Sepharose established that both europium-152 and gadolinium-153 were bound to serum transferrin following labelling of serum either in vivo, by intravenous injection of the radionuclides as citrate complexes inter rats, or in vitro, by the addition of the radionuclides, as the nitrilotriactetic acid complexes, to rat serum. Separation of the protein on the ion exchange medium DEAE-Sepharose suggested that the europium transferrin and gadolinium transferrin complexes tended to dissociate on the gel, but affinity chromatography on Blue Sepharose CL-6B established that about 20% of the total serum radioactivity was associated with transferrin.

Spectroscopic studies using ultraviolet difference spectroscopy indicated that for both metals a maximum of 2 atoms of metal could be bound to each transferrin molecule. Saturation of transferrin labelled with europium-152 or gadolinium-153 with inactive iron resulted in the release of the bound lanthanide. These results suggest that iron binding sites on the transferrin molecule are involved in the binding of these lanthanide metals. Preliminary studies using spectroscopy combined with computer speciation modelling suggest that the conditional stability constants for the formation of the europium and gadolimium complexes are low, probably 10 or more orders of magnitude less than for iron or plutonium complexes.
The goals of this project require the collaboration of several laboratories by contributing their special expertise and experience in the different aspects involved.

The contribution from GSF Frankfurt is to provide metabolic data for certain radionuclides by stable isotope tracer investigation in man. A major part of this work is to evaluate the variability of uptake and metabolism for nonstandard conditions.

As shown in the general description of the project, the main task of the University of Milano will be quantitative measurement of trace stable isotopes (Ce, Ru, Zr, Te) in biological tissues and the subsequent application to biokinetic studies.

In the Harwell Laboratory, many studies have been carried out in which radiotracers have been used to assess human uptake of stable species such as lead, cadmium and arsenic, and radioactive species such as radium and plutonium.

Recently, a new mass spectrometric technique became available which enabled stable isotope techniques to be used with human subjects, with a potentially rapid measurement time compared with traditional thermal ionization mass spectrometric procedures.

Work carried out thus far in this laboratory using ICPAMS, and funded by the UK Department of Health, has concentrated on strontium as an analogue for Sr90.

In the current research programme, these studies with strontium will be extended to children, and the equivalency assessed of extrinsic and intrinsic labelling. The contribution of Kernforschungszentrum Karlsruhe is concerned with the biochemical validation of selected lanthanide or other elements as surrogates for the actinides plutonium, americium and curium which could be used for metabolic studies in human subjects.

The tasks and contributions of GSF Neuherberg to the project are the following:
review of the available database for the elements relevant for the project;
planning of the experimental design within the limits of the measuring techniques, thus especially defining the kind of samples selected, the necessary frequencies of sampling after administration and the temporal pattern of sampling in order to prepare an optimal evaluation;
evaluation of the measured data, aiming to develop or to improve biokinetic models suitable for dosimetric purposes;
calculation of dose conversion factors for the relevant radionuclides for members of the general public taking into account the important dependencies on age and on chemical characteristics as far as investigated experimentally.

Coordinator

GSF-Forschungszentrum für Umwelt und Gesundheit GmbH
Address
Ingolstädter Landstraße 1
85764 Neuherberg
Germany

Participants (3)

Forschungszentrum Karlsruhe Technik und Umwelt GmbH
Germany
Address

76021 Karlsruhe
THE UNIVERSITY OF MILANO
Italy
Address
Via Celoria 16
20133 Milano
United Kingdom Atomic Energy Authority
United Kingdom
Address
353,Harwell
OX11 0RA Didcot - Oxfordshire