DOSIMETRIC QUALITY ASSURANCE INTERPRETED FOR ISO 17025 IN PUBLIC HEALTH ENGLAND'S PERSONAL DOSIMETRY SERVICE.

Many individual monitoring services (IMSs) have long experience in delivering high-quality dosimetry, and many follow rigorous quality assurance (QA) procedures. Typically, these procedures have been developed through experience and are highly effective in maintaining high-quality dose measurements. However, it is not always clear how the range of QA procedures normally followed by IMSs maps on to the various requirements of ISO 17025. The Personal Dosimetry Service of Public Health England has interpreted its QA procedures both in operating existing services and in developing a new one.

USE OF A SIMPLE THERMALISED NEUTRON FIELD FOR QUALITY ACCEPTANCE OF WHOLE BODY TLDS.

The individual monitoring service of Public Health England (PHE) uses Harshaw™ whole-body and extremity thermoluminescent dosemeters (TLDs) with high-sensitivity lithium fluoride LiF:Mg,Cu,P, together with Harshaw 8800™ automated readers. The neutron-insensitive, (6)Li-depleted variety of TLD material is used by PHE because the service provides separate neutron and photon dosemeters. The neutron dosemeters are not sensitive to photons and vice versa Since insensitivity to neutrons is a supply requirement for TLDs, there is a need to test every new (annual) consignment for this. Because it is thermal neutrons that produce a response in (6)Li TLDs, a thermal field is needed. To this end, PHE has adopted the simple approach of sandwiching the TLDs between two ISO water-filled slab phantoms. In this arrangement, the fast neutrons from an Am-Be source are effectively thermalised. Details of the method are given, together with the results of supporting MCNP calculations and some typical results.

Monte Carlo modelling of 90Sr/90Y and 85Kr beta fields for Hp(3) measurements.

In support of research aimed at developing a thermoluminescence dosemeter capable of accurately measuring ionising radiation doses to the lens of the eye, Monte Carlo modelling of a standard beta exposure set-up has been performed. It was found that electrons with an energy distribution corresponding to the beta emission spectrum from (85)Kr deposit negligible doses at a depth of 3 mm in tissue, but doses from (90)Sr/(90)Y are significant; free in air and fluence-to-Hp(3,θ°) and -Hp(0.07,θ°) conversion coefficient data were found for this field for exposures at 0°, 30° and 60° angles of incidence, and the response characteristics of the new eye dosemeter were evaluated. It was shown that the results were not affected greatly by the shape of the calibration phantom. However, it was demonstrated that the presence of intermediating air and beam flattening filters hardens the energy distribution of the field at the point of test, relative to a raw (90)Sr/(90)Y source, and this impacts dose depositions.

Type testing of a head band dosemeter for measuring eye lens dose in terms of H(P)(3).

A new head band dosemeter, for the measurement of eye lens dose in terms of Hp(3), has been type tested by Public Health England's Centre for Radiation, Environmental and Chemical Hazards [formerly part of the UK Health Protection Agency (HPA)]. The type tests were based on the International Standard ISO 12794, drawing also upon earlier work at HPA. The results show that, unlike many existing dosemeters, the new head band dosemeter correctly measures Hp(3) for beta radiations as well as photons.

Estimating dual-energy X-ray absorptiometry-derived total body skeletal muscle mass using single-slice abdominal magnetic resonance imaging in obese subjects with and without diabetes: a pilot study.

BACKGROUND/OBJECTIVES: Single-slice abdominal computed tomography or magnetic resonance imaging (MRI) performed to measure visceral adipose tissue in individuals with obesity and diabetes mellitus can also image skeletal muscle. The aim of this study was to validate a method developed in cancer patients using a single abdominal cross-sectional image to estimate fat-free mass (FFM) and appendicular lean tissue mass index (LTMI), a total body skeletal muscle mass surrogate, in an obese cohort of subjects with and without type 2 diabetes. SUBJECTS/METHODS: In total, 49 obese subjects (22 with diabetes) recruited into a weight loss study underwent dual-energy X-ray absorptiometry (DXA) and abdominal MRI at baseline. DXA-derived FFM and LTMI were compared with skeletal muscle area at the level of the third lumbar vertebra (L3) on MRI. RESULTS: L3 skeletal muscle area correlated with FFM (R (adj) (2)=0.825; P<0.001) and LTMI (R (adj) (2)=0.6; P<0.001). A simple formula, previously shown to predict LTMI in cancer patients, produced a good estimation of LTMI from L3 skeletal muscle area (95% confidence interval -3.70, 2.56%) in our obese cohort. Equations incorporating age, sex, height, weight and diabetic status improved the relationship between L3 skeletal muscle area and estimated FFM (r=0.976, P<0.001) and LTMI (r=0.879, P<0.001). CONCLUSION: A single-axial slice at the L3 level can be used to estimate FFM and LTMI in obese diabetic and non-diabetic subjects, allowing precise analysis of body composition using a single imaging modality in clinical research and practice.

Long-term stability of Harshaw LiF:Mg,Cu,P TLDS.

The sensitivity of Harshaw™ magnesium/copper/phosphorus-doped lithium fluoride is shown to be stable over long time periods, even when, as is often the case in practical operations, the TLDs are read out only three times a year.

Evaluating the performance of the Harshaw™ DXTRAD LiF:Mg,Cu,P finger ring with two different thickness filters.

Amongst the dosemeters offered by the Health Protection Agency (HPA) Personal Dosimetry Service are finger rings, which use the Harshaw™ DXTRAD element. This paper describes restricted-type testing carried out by HPA on the previously untried combination of the LiF:Mg,Cu,P material and a thicker filter (42 mg cm(-2)). The tests were based on ISO 12794 [International Organization for Standardization. ISO 12794:2000 nuclear energy--radiation protection--individual thermoluminescence dosemeters for the extremities and eyes. ISO (2000)] and included energy and angle dependence of response for photons. The conclusion was, for photon dosimetry applications the thicker filter is acceptable for use in the HPA service.

Type testing of a new TLD for the UK Health Protection Agency.

The UK Health Protection Agency is currently commissioning a new personal dosimetry system based on the use of Harshaw two-element thermoluminescent dosemeter cards using LiF:Mg,Cu,P. Results of extensive type testing carried out with reference to IEC 61066, "Thermoluminescence Dosimetry Systems for Personal and Environmental Monitoring", have been presented.

Comparison of the effects of exposure to light in Harshaw LiF:Mg,Ti and LiF:Mg,Cu,P.

The response of thermoluminescence dosemeters (TLDs) to light, in various conditions, has been studied. TLD cards containing both conventional lithium fluoride (LiF:Mg,Ti) and the high-sensitivity material LiF:Mg,Cu,P were available, so permitting a comparison between the two types. Also available for the tests were Harshaw extremity EXT-RAD (LiF:Mg,Cu,P) dosemeters. The LiF:Mg,Ti body TLD cards and the EXT-RAD extremity dosemeters both showed some response to fluorescent light, while the LiF:Mg,Cu,P cards showed no significant response. It is therefore concluded that LiF:Mg,Cu,P body cards need no special precautions to protect them from the effects of light. For LiF:Mg,Ti cards and extremity dosemeters, effects are small, but steps to avoid excessive light exposure should be considered.

Type testing of an extremity finger stall dosemeter based on Harshaw TLD EXTRAD technology.

A new type of extremity dosemeter, which incorporates the Harshaw TLD EXTRAD dosemeter element into a PVC finger stall, has been developed. The dosemeter uses high-sensitivity lithium fluoride, (7)LiF:Mg,Cu,P (TLD-700H) in a thin 7 mg cm(-2) layer, with alternative coverings of PVC at 10 mg cm(-2) and aluminised polyester at 3.2 mg cm(-2). Results are presented of the type testing of both versions of the finger stall dosemeter against published standards.

Carcinogenicity of radon/radon decay product inhalation in rats--effect of dose, dose rate and unattached fraction.

PURPOSE: The effects of inhalation of radon/radon decay products at different total doses, dose rates and 'unattached' fractions were investigated in a life span study in rats. MATERIALS AND METHODS: 1574 rats inhaled radon/radon decay products in a purpose-built recirculating exposure system that provided stable/reproducible exposure conditions. 501 were maintained as controls. RESULTS: Lung tumour incidences were significantly elevated in most exposed groups. The study power was insufficient to resolve the shape of the dose and dose rate response curves, but combination of this data with that from other studies demonstrated that for high cumulative exposures, the lifetime excess absolute risk increases with increasing exposure durations and for low cumulative exposures the opposite trend occurs. Exposure did not increase leukaemia incidences. A small number of non-lung tumour types including mammary fibroadenoma showed elevated incidences in some exposed groups, however not consistently across all exposure groups and showed no dose or dose rate relationship. CONCLUSIONS: Radon/radon decay product exposure caused excess lung tumours in rats along with limited non-lung effects. The results are consistent with the findings that at low cumulative exposures decreasing exposure concentrations or protracting the time over which the dose is delivered, reduces lung tumour risk. At higher levels, decreasing exposure concentrations or protracting exposure time increases lung tumour risk.

c-Myc represses the murine Nramp1 promoter.

The Nramp1 (natural resistance-associated macrophage protein 1) gene modulates the growth of intracellular pathogens and encodes a divalent cation transporter within lysosomes/late endosomes of macrophages. Nramp1 modulates the cytoplasmic iron pool. Wu, Polack and Dalla-Favera [(1999) Science 283, 676-679] showed reciprocal control of H-ferritin and IRP2 by c-Myc, and suggest that c-Myc regulates genes to increase cytoplasmic iron. A role for c-Myc in Nramp1 regulation was evaluated. Co-transfection studies show that c-Myc represses Nramp1 promoter function. Five non-canonical Myc-max binding sites (E-box) identified within the Nramp1 5'-flanking sequence are not responsible for the inhibitory effects of c-Myc on Nramp1 expression. An initiator(s) adjacent to the transcription-initiation site is a candidate for the inhibition observed. Results are consistent with a role for Nramp1 removing iron from the cytosol and antagonizing c-Myc function.

Nramp1 modulates iron homoeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de-acidification of intracellular vesicles.

Nramp1 controls responses to infection and encodes a biallelic (G169D) macrophage-restricted divalent-cation transporter. Nramp1(D169) is phenotypically null. We demonstrate Nramp1 is implicated in iron regulation in vivo. In spleen, expression is exclusive to Nramp1(G169) strains within the red pulp. By morphometric analysis, the distribution of splenic iron, following systemic overload, correlates with Nramp1 genotype. More iron is located within the red pulp in Nramp1(D169) strains, whereas in Nramp1(G169) strains iron deposits are localized within the marginal-zone metallophilic cells. Nramp1 immunoreactive protein is not present in control brain, but inducible within a hemorrhagic lesion model in Nramp1(G169) strains. Nramp1 protein expression demonstrates an inverse correlation to the presence of iron. Nramp1(G169) strains show no Perl's stain-reactive iron within the lesion. In contrast, Nramp1(D169) strains display iron-staining cells. The process of cellular iron regulation was investigated in vitro in Nramp1(G169) transfectant Raw264.7 macrophages. Greater (30-50%) iron efflux from Nramp1(G169) compared with Nramp1(D169) cells was determined. The extent of Nramp1-dependent iron-release was influenced by bafilomycin A1, and endogenous nitric oxide synthesis, both inhibitors of vacuolar-ATPase. This study demonstrates that Nramp1 regulates macrophage iron handling, and probably facilitates iron release from macrophages undergoing erythrophagocytosis in vivo.

A negative autoregulatory link between Nramp1 function and expression.

Nramp1 (natural resistance-associated macrophage protein) controls resistance to infection by intracellular pathogens in mice. Nramp1 regulates the microenvironment of the invading pathogen by increasing the luminal iron that participates in the Haber-Weiss reaction, producing radicals that attack the pathogen. We have studied the effect of inflammatory stimuli, iron, and sodium nitroprusside on Nramp1 expression in bone marrow macrophages. Investigations show all three up-regulate Nramp1 expression with a parallel increase in immunoreactivity to an amino-terminal antibody and Nramp1 mRNA. Growth rates are reduced in macrophage cell lines expressing Nramp1. This is through a decrease in iron availability, shown by an increase in IRP2 activity and a reciprocal decrease in conventional protein kinase Cbeta-1 expression. We propose that Nramp1 activity may control its own expression via a negative autoregulatory loop that is important for iron homeostasis and maintenance of low cytoplasmic redox active iron levels in the macrophage.

Effects of continuous inhalation exposure of rats to radon and its progeny at various levels of dose and dose rate: interim results.

Studies of rats at Harwell and CEA [Monchaux et al., Radiat. Res. 152 (Suppl.), S137-S140, 1999] are currently in progress to determine the factors affecting the risk of induction of lung tumors after exposure to radon and radon progeny. Knowledge of the effect of dose, dose rate and characteristics of the aerosol on lung tumor induction in rats may be used to improve estimates of risk from domestic exposure. At Harwell, three studies are in progress, studying the effect of dose, dose rate, and dose rate at low total exposures. Approximately 2000 adult male rats have been exposed. A small number of rats were taken to determine deposition in the respiratory tract and the early effects of exposure on cell proliferation and nuclear aberrations. The remaining animals have been held for their life span. To date 65% of the animals in the first study have been examined. Current results (for 421 rats) suggest that exposure to radon and radon progeny causes elevated incidences of both benign and malignant lung tumors. These findings are based on incomplete tumor incidences. Competing causes of death may affect the results, and full statistical analysis is required before firm conclusions can be drawn about the effect of dose and dose rate.

Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens.

Nramp1 (natural resistance-associated macrophage protein one) regulates intracellular pathogen proliferation and macrophage inflammatory responses. Murine Nramp1 exhibits a natural polymorphism with alleles termed resistant and susceptible. Alleles restrict or allow the proliferation of intracellular pathogens, respectively. Structural predictions suggest that Nramp1 encodes the prototypic member of a transporter family. Nramp1 exhibits sequence identity to Nramp2, which regulates intestinal and reticulocyte iron uptake. Based on this sequence identity we have initiated experiments for Nramp1 to investigate its role in macrophage iron homoeostasis and using a transfection approach in the RAW264.7 murine macrophage-like cell line, which lacks a functional Nramp1 gene. Nramp1 expression supports increased acute cytoplasmic influx of iron, detected using the fluorescent iron sensor dye calcein. Analysis of the endogenous iron sensors, iron regulatory protein 1 and 2, reveals a greater flux of iron in Nramp1-expressing cells and in its exclusion from the cytoplasm. Other work supports the prediction that Nramp1 is a phosphoprotein and the extent of phosphorylation changes in response to inflammatory cytokines. Together these data support the hypothesis that control of intracellular iron homoeostasis is a vital element used by phagocytes to control the proliferation of intracellular pathogens.

Value of estradiol response after human chorionic gonadotropin administration in predicting in vitro fertilization success.

OBJECTIVE: To determine whether the serum E2 response after the administration of exogenous hCG is predictive of outcome during IVF. DESIGN: Prospective, noncomparative cohort. SETTING: Two academic centers and one private-practice IVF program. PATIENT(S): Two hundred twenty-two couples undergoing IVF for infertility arising from ovarian dysfunction, asthenoteratospermia, endometriosis, tubal disease, or unexplained infertility. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and miscarriage rates were compared in cycles that demonstrated an increase, decrease, or plateau in the serum E2 level on the day after hCG administration. The effects of age, cause of infertility, and maximum E2 value on outcome were evaluated. RESULT(S): Ninety-two cycles resulted in a clinical pregnancy and 130 cycles failed. Of 115 cycles in which the E2 level rose, 42 (37%) resulted in an ongoing pregnancy; among cycles with plateauing E2 responses, 20 of 69 (29%) resulted in a pregnancy. Fifteen of 38 (39%) of cycles exhibiting a drop in serum E2 resulted in an ongoing pregnancy. No statistically significant differences in ongoing pregnancy rates were noted in the increasing, plateauing, or decreasing E2 response groups. CONCLUSION(S): E2 values obtained on the day after hCG administration are not predictive of outcome in women undergoing IVF.

Intercomparison of measurement techniques used in radon exposure facilities for animals in Europe.

The biological effects of exposure to radon and its progeny are being studied in animals by three laboratories in Europe. The facilities used for such exposures are described, together with the methods used to estimate radon progeny concentrations and the activity deposited in the lungs of exposed animals. As the facilities and methods vary, a series of comparison exercises has been carried out at the three facilities; CEA/COGEMA, Razes, France, TNO, Rijswijk, The Netherlands and AEA Technology, Harwell, U.K. The results of the exercise are presented together with reasons for the discrepancies in results between the groups thus ensuring that estimates of exposure provided by the groups for their studies is directly comparable.

Changes in the rat lung after exposure to radon and its progeny: effects on incorporation of bromodeoxyuridine in epithelial cells and on the incidence of nuclear aberrations in alveolar macrophages.

The aim of this study was to investigate some responses of cells in the rat respiratory tract as a function of time after inhalation exposure to various levels of radon and its progeny. Rats were exposed to a constant concentration of radon and its progeny to give cumulative exposure levels of 120, 225, 440 and 990 working level months (WLM). An additional unexposed group of rats served as controls. The end points selected for investigation were (a) the incorporation of bromodeoxyuridine (BrdU) in epithelial cells of the conducting airways and of the alveolar region of the respiratory tract and (b) the incidence of alveolar macrophages with nuclear aberrations. After exposure, the incidence of epithelial cells incorporating BrdU--the labeling index--increased in all regions of the respiratory tract examined, but the increase occurred later in alveolar than in airway epithelial cells. The highest labeling index was found in bronchial epithelial cells, which probably received the highest radiation dose. After an initial induction period, the incidence of alveolar macrophages with nuclear aberrations also increased. The possibility of using the labeling index of alveolar and airway epithelial cells, and/or the incidence of nuclear aberrations in alveolar macrophages, to estimate the radiation dose to various regions of the respiratory tract after exposure of rats to radon and its progeny is discussed.

Proliferation of mouse lung epithelial cells after inhalation exposure to 239PuO2.

The aim of this study was to investigate cell proliferation in mouse lungs up to 12 weeks after exposure to 239PuO2. CBA mice were exposed (nose-only) to 239PuO2 to give an initial alveolar deposit of 500 Bq. The main morphological change observed was hypertrophy of Type II cells. The labeling index (LI) of alveolar cells, which was monitored by immunocytochemical detection of DNA-incorporated 5-bromo-2'-deoxyuridine (BrdU), increased with time after exposure and was eight times that of controls by the end of the study. The LI of the bronchiolar cells was increased markedly after exposure but declined thereafter. The cell proliferation patterns of the alveolar and bronchiolar cells (mainly Type II and Clara cells, respectively) could be related to the distribution and clearance patterns of the deposited particles of 239PuO2 and to the effects of alpha-particle radiation on these cells. This study showed that significant cellular changes, particularly cell proliferation, occurred at early times after exposure of mouse lung to 239PuO2. However, the relevance of these results to the late carcinogenic effects of 239Pu could not be assessed because of the limited duration of this study.