Targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) employing an enzymatic assay for γ-hydroxybutyric acid (GHB) in biofluids.

HYPOTHESIS: An enzymatic assay for quantification of γ-hydroxybutyric acid (GHB) in biofluids can be employed for targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) in selected populations. RATIONALE: We used a two-tiered study approach, in which the first study (proof of concept) examined 7 urine samples derived from patients with SSADHD and 5 controls, and the second study (feasibility study) examined a broader sample population of patients and controls, including plasma. OBJECTIVE: Split samples of urine and plasma (anonymized) were evaluated by enzymatic assay, gas chromatography alone (proof of concept) and gas chromatography-mass spectrometry, and the results compared. METHOD: Multiple detection methods have been developed to detect GHB. We evaluated an enzymatic assay which employs recombinant GHB dehydrogenase coupled to NADH production, the latter quantified on a Cobas Integra 400 Plus. Results: In our proof of concept study, we analyzed 12 urine samples (5 controls, 7 SSADHD), and in the feasibility study we evaluated 33 urine samples (23 controls, 10 SSADHD) and 31 plasma samples (14 controls, 17 SSADHD). The enzymatic assay carried out on a routine clinical chemistry analyzer was robust, revealing excellent agreement with instrumental methods in urine (GC-FID: r = 0.997, p ≤ 0.001; GC-MS: r = 0.99, p ≤ 0.001); however, the assay slightly over-estimated GHB levels in plasma, especially those in which GHB levels were low. Conversely, correlations for the enzymatic assay with comparator methods for higher plasma GHB levels were excellent (GC-MS; r = 0.993, p ≤ 0.001). CONCLUSION: We have evaluated the capacity of this enzymatic assay to identify patients with SSADHD via quantitation of GHB. The data suggests that the enzymatic assay may be a suitable screening method to detect SSADHD in selected populations using urine. In addition, the assay can be used in basic research the elucidate the mechanism of the underlying disease or monitor GHB- levels for the evaluation of drug candidates. SYNOPSIS: An enzymatic assay for GHB in biofluids was evaluated as a screening method for SSADHD and found to be reliable in urine, but in need of refinement for application to plasma.

Performance of a PADC personal neutron dosemeter at simulated and real workplace fields of the nuclear industry.

In the framework of the EVIDOS (Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields) project, funded by the EC, measurements with PADC personal neutron dosemeters were carried out at several workplace fields of the nuclear industry and at simulated workplace fields. The measured personal neutron dose equivalents of the PADC personal neutron dosemeter are compared with values that were assessed within the EVIDOS project by other partners. The detection limits for different spectra types are given. In cases were the neutron dose was too low to be measured by the PADC personal neutron dosemeter, the response is estimated by convoluting the responses to monoenergetic neutrons with the dose energy distribution measured within EVIDOS. The advantages and limitations of the PADC personal neutron dosemeter are discussed.

Twenty-year follow-up of a Pu/Am inhalation case.

In 1983 a technician inhaled a mixture of Pu/Am aerosols in an accidental situation in the hotlab of Paul Scherrer Institute (PSI). This case is of interest for long-term follow-up since the technician was relatively young (26 y) at the time of intake, no chelating agent was used to alter retention and excretion and the inhaled activity was rather high (approximately 20 kBq of alpha emitters). The results obtained from periodic lung counts, urinary and faecal excretions as well as from some bone and liver measurements up to the year 2003 are presented. The measurements were mainly made at PSI but also at FZK Karlsruhe, Germany, and PNNL Hanford, USA. The evaluation and dose estimation of this case was done by several institutions, such as FZK, PNNL and NRPB in addition to PSI. Elements of the case were used in international biokinetic model validation programs by EURADOS/EULEP and IAEA and the 241Am data are given as example in Annex E of the ICRP 'Guide for the Practical Application of the ICRP Human Respiratory Tract Model'. An overview is given on the various results obtained by the different institutions using their models and methods for interpretation of the measured data. While estimation of intake varies by more than an order of magnitude, final estimation of effective committed dose varies only in the range of 0.5-1.5 Sv.

Integration of external and internal dosimetry in Switzerland.

Individual monitoring regulations in Switzerland are based on the ICRP60 recommendations. The annual limit of 20 mSv for the effective dose applies to the sum of external and internal radiation. External radiation is monitored monthly or quarterly with TLD, DIS or CR-39 dosemeters by 10 approved external dosimetry services and reported as Hp(10) and Hp(0.07). Internal monitoring is done in two steps. At the workplace, simple screening measurements are done frequently in order to recognise a possible incorporation. If a nuclide dependent activity threshold is exceeded then one of the seven approved dosimetry services for internal radiation does an incorporation measurement to assess the committed effective dose E50. The dosimetry services report all the measured or assessed dose values to the employer and to the National Dose Registry. The employer records the annually accumulated dose values into the individual dose certificate of the occupationally exposed person, both the external dose Hp(10) and the internal dose E50 as well as the total effective dose E=Hp(10)+E50. Based on the national dose registry an annual report on the dosimetry in Switzerland is published which contains the statistics for the total effective dose, as well as separate statistics for external and internal exposure.

State-of-the-art dosimetric methods for internal and external exposures: conclusions of a EURADOS action.

In radiation protection dosimetry the quantity of interest is the effective dose (E); the dose limit to an adult worker applies to the sum of the relevant doses from external exposures and the relevant committed effective doses from intakes of radionuclides, during the same period of time. A EURADOS study was carried out to investigate how the results from personal dosemeters for external radiation, from workplace monitoring and from monitoring of internal exposures can be combined into a consistent system of individual monitoring. The integration of dosimetric methods and data for external and internal radiation require the complete characterisation of the occupational exposure present at the workplace, and the availability of adequate equipment and tools for the assessment of effective dose. To evaluate the capability of services to accomplish this approach, a European Dosimetry Network has been established among 28 European countries through the respective contact-persons and their dosimetric facilities which collaborated with EURADOS providing relevant data about performance and legal aspects. The information collected was presented as a monograph in Radiation Protection Dosimetry in 2004. The more relevant conclusions of this study are presented here.

Progress report of the CR-39 neutron personal monitoring service at PSI.

At the Paul Scherrer Institute a personal neutron dosimetry system based on chemically etched CR-39 detectors and automatic track counting is in routine use since the beginning of 1998. The quality of the CR-39 detectors has always been a crucial aspect to maintain a trustable personal neutron dosimetry system. This paper summarises the 7 y experience in routine use. The effect of detector material defects which could lead to false positive neutron doses is described. The potentiality of improving the background statistics by extending the pre-etch time is investigated and involves as a drawback a quite lower sensitivity to thermal neutrons. Furthermore, the impact of small changes in the production process of the detectors on the response to fast and thermal neutrons is shown. For the personal dosimetry at CERN, a new dosimetry concept was launched by combining a CR-39 neutron dosemeter with a Direct-Ion Storage (DIS) dosemeter for photon and beta radiation. The usage period of the CR-39 dosemeters is prolonged now from 3 months up to 12 months. In this context, the long-term behaviour over 1 y of the background track density and the response to Am-Be are described.

Performance of a personal neutron dosemeter based on direct ion storage at workplace fields in the nuclear industry.

In the framework of the EVIDOS project, funded by the EC, measurements were carried out using dosemeters, based on ionisation chambers with direct ion storage (DIS-N), at several workplace fields, namely, at a fuel processing plant, a boiling and a pressurised water reactor, and near transport and storage casks. The measurements and results obtained with the DIS-N in these workplaces, which are representative for the nuclear industry, are described in this study. Different dosemeter configurations of converter and shielding materials were considered. The results are compared with values for personal dose equivalent which were assessed within the EVIDOS project by other partners. The advantages and limitations of the DIS-N dosemeter are discussed.

Individual monitoring for internal exposures in Europe: conclusions of an EURADOS action.

Once the EC Directive 96/29 has been implemented into national regulation across Europe, the coordination of dosimetry laboratories for the monitoring of occupational exposures becomes the principal aim to achieve. Within this framework the European Radiation Dosimetry Group, EURADOS, carried out an Action on 'Harmonisation of Individual Monitoring' (2000-2004) to promote coordination in the field of individual monitoring of occupational exposures throughout Europe. With reference to internal exposures, the main aims were the completion of a catalogue of internal dosimetry services and an inventory of methods and techniques used for individual monitoring at European internal dosimetry facilities. At the end of this EURADOS Action, a report was published in Radiation Protection Dosimetry in 2004. The information collected related to various topics: the equipments used for the measurement of internal exposures, calibration and sensitivity data, the methods applied for the assessment of internal doses, Quality Control procedures, Quality Assurance Programmes in the facilities and legal requirements. The information to be presented here will give a general overview of the actual status of individual monitoring for internal exposures in Europe.

Aspects of harmonisation of individual monitoring for external radiation in Europe: conclusions of a EURADOS action.

Following the publication of the EU Council Directive 96/29, EURADOS coordinated two working groups (WGs) for promoting the process of harmonisation on individual monitoring of occupationally exposed persons in Europe. An overview of the major findings of the second WG is presented. Information on the technical and quality standards and on the accreditation and approval procedures has been compiled. The catalogue of dosimetric services has been updated and extended. An overview of national regulations and standards for protection from radon and other natural sources in workplaces has been made, attempting to combine the results from individual monitoring for external, internal and workplace monitoring. A first status description of the active personal dosemeters, including legislative and technical information, and their implementation has been made. The importance of practical factors on the uncertainty in the dose measurement has been estimated. Even if a big progress has been made towards harmonisation, there is still work to be done.

Thermoluminescent detectors applied in individual monitoring of radiation workers in Europe--a review based on the EURADOS questionnaire.

Among the activities of EURADOS Working Group 2 formed by experts from several European countries is the harmonisation of individual monitoring as part of radiation protection of occupationally exposed persons. Here, we provide information about thermoluminescent detectors (TLDs) applied by the European dosimetric services and the dosimetric characteristics of dosemeters in which these detectors are applied. Among 91 services from 29 countries which responded to the EURADOS questionnaire, 61 apply dosemeters with TLDs for the determination of personal dose equivalent H(p)(10) for photons and beta radiation, and 16 services use TLDs for neutron albedo dosemeters. Those most frequently used are standard lithium fluoride TLDs (mainly TLD-100, TLD-700, Polish MTS-N and MTS-7, Russian DTG-4), high-sensitive lithium fluoride (GR-200, MCP-N) and lithium borate TLDs. Some services use calcium sulphate and calcium fluoride detectors. For neutron dosimetry, most services apply pairs of LiF:Mg,Ti TLDs with (6)Li and (7)Li. The characteristics (energy response) of individual dosemeters are mainly related to the energy response of the detectors and filters applied. The construction of filters in dosemeters applied for measurements of H(p)(10) and their energy response are also reviewed.

A catalogue of dosemeters and dosimetric services within Europe--an update.

The catalogue of dosemeters and dosimetric services within the European Union (EU) Member States and Switzerland that was issued by EURADOS in the year 2000 has been updated and extended with information on dosimetric services in the new EU Member States and Bulgaria, Croatia, Romania, Serbia and Montenegro, and Ukraine. The total number of dosimetric services in these European countries is now estimated to be about 200. The present catalogue is based on information collected from 90 European dosimetric services, among which 34 questionnaires from 32 services were obtained over the years 2001-2004 for the first time. This article assesses and updates the present use of personal dosemeters and the extent to which occupationally exposed persons in Europe are monitored with dosemeters able to measure the operational quantity-personal dose equivalent, H(P)(d). The perspective of joining EU by the new countries accelerated the implementation of the EU Basic Safety Standard Directive to their national regulations. As a result, all newly investigated services reported their ability to measure H(P)(d). The catalogue provides information on the dosemeters, dose calculation and background subtraction algorithms, calibration methods, energy and angular response, and performance.

Workplace monitoring for exposures to radon and to other natural sources in Europe: integration of monitoring for internal and external exposures.

Part of the action of the EURADOS working group (European Radiation Dosimetry Group) on "Harmonisation of Individual Monitoring in Europe" was to investigate how the results from personal dosemeters for external radiation, from monitoring for internal exposure and from workplace monitoring, can be combined into a complete and consistent system of individual monitoring. To facilitate this work, the "EURADOS questionnaire Q3" relating to radon and other natural sources of radiation in the workplace was distributed to relevant institutes across Europe. A total of 24 countries replied to the questionnaire. This study offers an important overview on actual regulations, national standards and reference levels for protection of employees from radon and other natural sources in different workplace scenarios. Information was also collected on individual monitoring and area monitoring to determine individual doses in workplaces with elevated levels of natural radiation. The article discusses in detail the results obtained showing by country the reference level in workplaces for radon gas and other natural sources. In both instances, exposures in mines, other underground workplaces, industry workplaces/waterworks, offices, schools and day-care homes were considered. The resultant data clearly indicate that there is a need for harmonisation among countries, not least in the areas of regulation and use of reference levels in the workplace.

Individual monitoring for internal exposure in Europe and the integration of dosimetric data.

The European Radiation Dosimetry Group, EURADOS, established a working group consisting of experts whose aim is to assist in the process of harmonisation of individual monitoring as part of the protection of occupationally exposed workers. A catalogue of facilities and internal dosimetric techniques related to individual monitoring in Europe has been completed as a result of this EURADOS study. A questionnaire was sent in 2002 to services requesting information on various topics including type of exposures, techniques used for direct and indirect measurements including calibration and sensitivity data and the methods employed for the assessment of internal doses. Information relating to Quality Control procedures for direct and indirect measurements, Quality Assurance Programmes in the facilities and legal requirements for "approved dosimetric services" were also considered. A total of 71 completed questionnaires were returned by internal dosimetry facilities in 26 countries. This results in an overview of the actual status of the processes used in internal exposure estimation in Europe. In many ways harmonisation is a reality in internal dose assessments, especially when taking into account the measurements of the activity retained or excreted from the body. However, a future study detailing the estimation of minimum detectable activity in the laboratories is highly recommended. Points to focus on in future harmonisation activities are as follows: the process of calculation of doses from measured activity, establishment of guidelines, similar dosimetric tools and application of the same ICRP recommendations. This would lead to a better and more harmonised approach to the estimation of internal exposures in all European facilities.

Present status of the personal neutron dosemeter based on direct ion storage.

In this paper the present status of the Direct Ion Storage Neutron (DIS-N) prototype dosemeter (RADOS) is described. The separation of neutron from photon dose equivalent has been improved by adding tin shieldings. The neutron energy response has been changed by additional plastic covers containing 40% B4C in order to reduce the over-response to thermal neutrons. The responses of the dosemeters were determined for standard photon and neutron fields (monoenergetic neutrons, neutron sources and simulated workplace fields). Irradiations in real workplaces were also performed. The dependence of the neutron response on the angle of incidence was measured for different neutron sources.

Calibration and testing of a TLD dosemeter for area monitoring.

The response of a TLD-600/TLD-700 area dosemeter has been characterized in neutron fields around the 590 MeV cyclotron ring at the Paul Scherrer Institute (PSI). The dosemeter is based on a cylindrical paraffin moderator with three of each type of TLD chip at the centre, and is intended to use for area monitoring around accelerator facilities. The dosemeter is calibrated in terms of ambient dose equivalent using a non-moderated 252Cf neutron source. The ambient dose equivalent response has been tested in five locations where the neutron fields and dose rates have been well characterized by Bonner sphere spectrometer and active neutron monitor measurements. The different spectrum shapes and dose rates in the five locations permit the comparison of the behavior of the active and passive dosemeters in these neutron fields.

Incorporation measurements in Switzerland: the approved internal dosimetry service at PSI.

The Swiss radiation protection regulation requires approval of external and internal dosimetry laboratories. The Swiss Personal Dosimetry Ordinance specifies the terms of approval, the survey methods and the standard interpretation to assess the committed effective dose. Specific information is given for 25 radionuclides concerning metabolism, methods of measurement, survey interval and interpretation of the results. On successful completion of a technical audit by an external expert, the dosimetry service of PSI was approved for internal dosimetry by the Swiss authorities by 1 January 2001. The scope of approval includes five different measuring methods for 30 radionuclides.

Harmonisation (legal, dosimetric, quality aspects) of individual monitoring, and integration of monitoring for external and internal exposures (EURADOS Working Group).

The EURADOS Working Group II on 'Harmonisation of individual monitoring' consists of experts from almost all EU Member States and Newly Associated States (NAS), involved in tasks related to the assessment of doses for internal and external radiation. The final objective is to achieve harmonisation in individual monitoring for occupational exposures. Sub-group 2 activities are focused on investigating how the results from personal dosemeters for external radiation and workplace monitoring and from monitoring for internal exposure can be combined into a complete and consistent system of individual monitoring. Three questionnaires were prepared, covering 'Individual monitoring of external radiation' (Questionnaire 1), 'Internal exposure' (Questionnaire 2) and 'Natural sources of radiation at the workplace' (Questionnaire 3). With the agreement of a 'contact-person', selected in each country, the distribution of the three EURADOS 2002 questionnaires was carried out by e-mail among the dosimetry facilities of 28 European countries. The preliminary results of these actions are presented here.

A legally approved personal dosemeter for photon and beta radiation based on direct ion storage.

The novel DIS-1 dosemeter developed by RADOS is based on ionisation chambers with so-called Direct Ion Storage (DIS). The dosemeter can measure Hp(10) and Hp(0.07) of photon and Hp(0.07) of beta irradiation. The characteristics of the commercially available DIS-1 dosemeter were studied at the Paul Scherrer Institute, particularly in respect to the requirements laid down in the Swiss Dosimetry Ordinance. Detailed tests were carried out in terms of linearity, photon and beta responses, angle dependence, long-term stability of the signal, reproducibility and environmental conditions. The DIS-1 dosemeter has been qualified by the authority to conform to the requirements of the Swiss Dosimetry Ordinance for personal photon and beta dosemeters. It is now used as a legally approved personal dosemeter system at PSI.

Comparison test of electronic dosemeters.

To assist with a planned purchase of electronic dosemeters by the Swiss Federal Office for Civil Protection, the calibration laboratory of the Paul Scherrer Institute performed tests on 11 types of electronic dosemeters manufactured by 10 European and American companies. The technical specifications for the World Trade Organisation (WTO) tendering procedure were largely in accord with the specifications of the international standard IEC 61526. First tests were performed with samples from each type of dosemeter. The reproducibility of a dose of 0.1 mSv generated with 137Cs radiation at a dose rate of 2.1 mSv.h-1 was found adequate for all tested dosemeter types. The response for environmental levels of radiation showed a large variation, indicating insufficient background correction of some dosmeters. A very high dose rate of 10 Sv.h-1 provoked faulty dose readings for more than half of the tested dosemeters. Dosemeter response for low-energy photon radiation was satisfactory for two of the tested dosemeter types. Four dosemeter types were selected for extended technical tests. Three samples of each of these dosemeter types were purchased. For drop and temperature tests the specifications of the WTO tendering procedure outranged the specifications of the IEC standard. Whereas even at a temperature of -25 degrees C the tested dosemeters functioned normally, drops from a height of 2 m onto a wooden surface rendered the samples of two dosemeter types inoperative.

Accreditation of a personal dosimetry service in Switzerland: practical experience and transition from EN 45004 to ISO 17025.

In compliance with the Swiss legislation on radiological protection, the Paul Scherrer Institute (PSI) operates a dosimetry service that is approved by the Swiss Federal Nuclear Safety Inspectorate. In 1997, the dosimetry service was also accredited by the Swiss Federal Office of Metrology and Accreditation as an inspection body for legal personal and environmental dosimetry, according to EN 45004. The accreditation covers determination of personal dose equivalent for photon, neutron and beta radiation, and ambient dose equivalent for photon and neutron radiation, by means of thermoluminescence and solid state track detection techniques. Within this formal accreditation it was confirmed that the relevant requirements of ISO 9002 are also fulfilled. The first re-accreditation will take place in 2001 and work is going on to achieve the transition from EN 45004 to ISO 17025. Accreditation is a feasible, practicable and acceptable way to achieve harmonisation in the field of dosimetry. However, before starting on the path to formal accreditation, a careful analysis should be made, taking into consideration not only cost-benefit aspects but also national legal requirements.