Uranium Body Clearance Kinetics-A Long-term Follow-up Study of Retired Nuclear Fuel Workers.

ABSTRACT: Nuclear industry workers exposed to uranium aerosols may risk kidney damage and radiation-induced cancer. This warrants the need for well-established dose and risk assessments, which can be greatly improved by using material-specific absorption parameters in the ICRP Human Respiratory Tract Model. The present study focuses on the evaluation of the slow dissolution rate (ss, d-1), a parameter that is difficult to quantify with in vitro dissolution studies, especially for more insoluble uranium compounds. A long-term follow-up of urinary excretion after the cessation of chronic inhalation exposure can provide a better estimate of the slow-rate dissolution. In this study, two workers, previously working for >20 y at a nuclear fuel fabrication plant, provided urine samples regularly for up to 6 y. One individual had worked at the pelletizing workshop with the known presence of uranium dioxide (UO2) and triuranium octoxide (U3O8). The second individual worked at the conversion workshop where multiple compounds, including uranium hexafluoride (UF6), uranium dioxide (UO2), ammonium uranyl carbonate, and AUC [UO2CO3·2(NH4)2CO3], are present. Data on uranium concentration in urine during working years were also available for both workers. The daily excretion of uranium by urine was characterized by applying non-linear least square regression fitting to the urinary data. Material-specific parameters, such as the activity median aerodynamic diameter (AMAD), the respiratory tract absorption parameters, rapid fraction (fr,), rapid dissolution rate (sr, d-1), and slow dissolution rate (ss, d-1) and alimentary tract transfer factor (fA) acquired from previous work along with default absorption types, were applied to urine data, and the goodness of fit was evaluated. Thereafter intake estimates and dose calculations were performed. For the ex-pelletizing worker, a one-compartment model with a clearance half-time of 662 ± 100 d (ss = 0.0010 d-1) best represented the urinary data. For the ex-conversion worker, a two-compartment model with a major [93% of the initial urinary excretion (A0)] fast compartment with a clearance half-time of 1.3 ± 0.4 d (sr = 0.5 d-1) and a minor (7% of A0) slow compartment with a half-time of 394 ± 241 d (ss = 0.002 d-1) provided the best fit. The results from the data-fitting of urinary data to biokinetic models for the ex-conversion worker demonstrated that in vitro derived experimental parameters (AMAD = 20 µm, fr = 0.32, sr = 27 d-1, ss = 0.0008 d-1, f A = 0.005) from our previous work best represented the urinary data. This resulted in an estimated intake rate of 0.66 Bq d-1. The results from the data-fitting of urinary data to biokinetic models for the ex-pelletizing worker indicated that the experimental parameters (AMAD = 10 µm and 20 µm, fr = 0.008, sr = 12 d-1, fA = 0.00019) from our previous dissolution studies with the slow rate parameter step-wise optimized to urine-data (ss = 0.0008 d-1) gave the best fit. This resulted in an estimated intake rate of 5 Bq d-1. Experimental parameters derived from in vitro dissolution studies provided the best fit for the subject retired from work at the conversion workshop, where inhalation exposure to a mix of soluble (e.g., AUC, UF6) and relatively insoluble aerosol (e.g., UO2) can be assumed. For the subject retired from work at the pelletizing workshop, which involved exposure to relatively insoluble aerosols (UO2 and U3O8), a considerably higher ss than obtained in dissolution studies provided a better representation of the urinary data and was comparable to reported ss values for UO2 and U3O8 in other studies. This implies that in vitro dissolution studies of insoluble material can be uncertain. When evaluating the results from the retrospective fitting of urine data, it is evident that the urine samples acquired after cessation of exposure provide less fluctuation. Long-term follow-up of uranium excretion after cessation of exposure is a good alternative for determining absorption parameters and can be considered the most viable way for determining the slow rate for more insoluble material.

What is the margin of error of surgeons and radiological imaging in diagnosing acute appendicitis?

Background: Acute appendicitis is the most common emergency requiring surgical intervention in general surgery. Negative appendectomy is defined as the removal of a pathologically normal appendix. Aim: In this study, we aimed to show our negative appendectomy rate. Materials and Methods: This study was carried out among 2990 patients who were operated on for appendicitis between 2015-2020 at the Health Sciences University, Istanbul Kanuni Sultan Suleyman Training, and Research Hospital. Accrual and historical records of the patients were analyzed using NCSS (Number Cruncher Statistical System) 2007 Statistical Software (Utah, USA) package program. The results were evaluated at the significance level of P < 0.05. Results: The mean age of all patients was 33. Of the patients, 1011 were women and 1979 were men. 27 of the women patients were pregnant. We requested a blood test (WBC count) and an abdominal ultrasound for all our patients who came with the complaint of abdominal pain in the right lower quadrant. Negative appendectomy was performed with ultrasonography in 622 patients with pathological diagnoses of lymphoid hyperplasia and fibrous obliteration (20.8%). We had abdominal computerized tomography (CT) for 285 patients and abdominal magnetic resonance imaging (MRI) for 16 of 27 pregnant women (59.25%) due to unclear clinical picture. Diagnostic laparoscopy was performed in 36 of the patients who underwent CT and 4 of the patients who underwent MRI since the diagnosis could not be made. We performed unnecessary appendectomy in 21.2% of the patients. Conclusion: With the increasing clinical follow-up experience of surgeons and developing technology in radiology, our aim is to minimize the negative appendectomy rate as much as possible.

On the use of dated sediments to investigate historical nuclear discharges.

Studsvik, a Swedish nuclear research facility, has been releasing aquatic radioactive discharges in the Baltic Sea, through the bay Tvären, since 1959. The permissible discharge levels are regulated by the Swedish Radiation Safety Authority (SSM) but only information about 60Co, 137Cs, 152Eu, total alpha and beta activities were reported up to 2002. Since then, the reports cover most a more comprehensive set of radionuclides. In this context, the seabed can be utilized as a chronological archive to investigate historical Studsvik releases. To this end, 23 sediment cores covering the whole area of the bay were studied and 5 of them were dated using 210Pb-dating methods. Since the discharges from Studsvik contain both plutonium and caesium, neither can be used to validate the 210Pb-dating method. Instead, stable lead with maximum deposition, known to be dated to 1970, was used. Cobalt-60, 137Cs, and 152Eu depth distributions were studied from the dated sediment cores and compared with reported levels of aquatic discharges. The expected sediment 137Cs-peak from the fallout from the Chornobyl accident was however smeared out, indicating an ongoing inflow of 137Cs with the Baltic seawater. Our findings show that reported releases of aquatic discharges of 60Co and 152Eu are consistent with measured sediment activity distribution. The sediments from the deepest parts of Tvären, with intact chronology and with a high time resolution, are ideal for investigating historical nuclear discharges and can be a tool to investigate unreported radionuclide releases. Dated sediment can in this way be a tool for nuclear safeguards to evaluate past and present activities in nuclear facilities.

Particle Size Dependent Dissolution of Uranium Aerosols in Simulated Gastrointestinal Fluids.

ABSTRACT: Uranium aerosol exposure can be a health risk factor for workers in the nuclear fuel industry. Good knowledge about aerosol dissolution and absorption characteristics in the gastrointestinal tract is imperative for solid dose assessments and risk management. In this study, an in vitro dissolution model of the GI tract was used to experimentally study solubility of size-fractionated aerosols. The aerosols were collected from four major workshops in a nuclear fuel fabrication plant where uranium compounds such as uranium hexafluoride (UF 6 ), uranium dioxide (UO 2 ), ammonium uranyl carbonate, AUC [UO 2 CO 3 ·2(NH 4 ) 2 CO 3 ] and triuranium octoxide (U 3 O 8 ) are present. The alimentary tract transfer factor, f A , was estimated for the aerosols sampled in the study. The transfer factor was derived from the dissolution in the small intestine in combination with data on absorption of soluble uranium. Results from the conversion workshop indicated a f A in line with what is recommended (0.004) by the ICRP for inhalation exposure to Type M materials. Obtained transfer factors, f A , for the powder preparation and pelletizing workshops where UO 2 and U 3 O 8 are handled are lower for inhalation and much lower for ingestion than those recommended by the ICRP for Type M/S materials f A = 0.00029 and 0.00016 vs. 0.0006 and 0.002, respectively. The results for ingestion and inhalation f A indicate that ICRP's conservative recommendation of f A for inhalation exposure is applicable to both ingestion and inhalation of insoluble material in this study. The dissolution- and subsequent absorption-dependence on particle size showed correlation only for one of the workshops (pelletizing). The absence of correlation at the other workshops may be an effect of multiple chemical compounds with different size distribution and/or the reported presence of agglomerated particles at higher cut points having more impact on the dissolution than particle size. The impact on dose coefficients [committed effective dose (CED) per Bq] of using experimental f A vs. using default f A recommended by the ICRP for the uranium compounds of interest for inhalation exposure was not significant for any of the workshops. However, a significant impact on CED for ingestion exposure was observed for all workshops when comparing with CED estimated for insoluble material using ICRP default f A . This indicates that the use of experimentally derived site-specific f A can improve dose assessments. It is essential to acquire site-specific estimates of the dissolution and absorption of uranium aerosols as this provides more realistic and accurate dose- and risk-estimates of worker exposure. In this study, the results indicate that ICRP's recommendations for ingestion of insoluble material might overestimate absorption and that the lower f A found for inhalation could be more realistic for both inhalation and ingestion of insoluble material.

Particle Size-dependent Dissolution of Uranium Aerosols in Simulated Lung Fluid: A Case Study in a Nuclear Fuel Fabrication Plant.

ABSTRACT: Inhalation exposure to uranium aerosols can be a concern in nuclear fuel fabrication. The ICRP provides default absorption parameters for various uranium compounds but also recommends determination of material-specific absorption parameters to improve dose calculations for individuals exposed to airborne radioactivity. Aerosol particle size influences internal dosimetry calculations in two potentially significant ways: the efficiency of particle deposition in the various regions of the respiratory tract is dependent on aerodynamic particle size, and the dissolution rate of deposited materials can vary according to particle size, shape, and porosity because smaller particles tend to have higher surface-to-volume ratios than larger particles. However, the ICRP model assumes that deposited particles of a given material dissolve at the same rate regardless of size and that uptake to blood of dissolved material normally occurs instantaneously in all parts of the lung (except the anterior portion of the nasal region, where zero absorption is assumed). In the present work, the effect of particle size on dissolution in simulated lung fluid was studied for uranium aerosols collected at the plant, and its influence on internal dosimetry calculations was evaluated. Size fractionated uranium aerosols were sampled at a nuclear fuel fabrication plant using portable cascade impactors. Absorption parameters, describing dissolution of material according to the ICRP Human Respiratory Tract Model, were determined in vitro for different size fractions using simulated lung fluid. Samples were collected at 16 time-points over a 100-d period. Uranium content of samples was determined using inductively coupled plasma mass spectrometry and alpha spectrometry. In addition, supplementary experiments to study the effect of pH drift and uranium adsorption on filter holders were conducted as they could potentially influence the derived absorption parameters. The undissolved fraction over time was observed to vary with impaction stage cut-point at the four main workshops at the plant. A larger fraction of the particle activity tended to dissolve for small cut-points, but exceptions were noted. Absorption parameters (rapid fraction, rapid rate, and slow rate), derived from the undissolved fraction over time, were generally in fair agreement with the ICRP default recommendations for uranium compounds. Differences in absorption parameters were noted across the four main workshops at the plant (i.e., where the aerosol characteristics are expected to vary). The pelletizing workshop was associated with the most insoluble material and the conversion workshop with the most soluble material. The correlation between derived lung absorption parameters and aerodynamic particle size (impactor stage cut-point) was weak. For example, the mean absorption parameters derived from impaction stages with low (taken to be <5 µm) and large (≥5 µm) cut-points did not differ significantly. Drift of pH and adsorption on filter holders appeared to be of secondary importance, but it was found that particle leakage can occur. Undissolved fractions and to some degree derived lung absorption parameters were observed to vary depending on the aerodynamic size fraction studied, suggesting that size fractionation (e.g., using cascade impactors) is appropriate prior to conducting in vitro dissolution rate experiments. The 0.01-0.02 µm and 1-2 µm size ranges are of particular interest as they correspond to alveolar deposition maxima in the Human Respiratory Tract Model (HRTM). In the present work, however, the dependency on aerodynamic size appeared to be of minor importance, but it cannot be ruled out that particle bounce obscured the results for late impaction stages. In addition, it was noted that the time over which simulated lung fluid samples are collected (100 d in our case) influences the curve-fitting procedure used to determine the lung absorption parameters, in particular the slow rate that increased if fewer samples were considered.

Development of 148Gd analysis method using stable Gd.

The analytical method of Gd determination was developed with the aim to analyse 148Gd in environmental and bioassay samples. It involves the use of anion exchange resin, extraction chromatography, and cation exchange resin. Alkaline fusion and calcium oxalate co-precipitation are used for solid samples dissolution and liquid samples preconcentration, respectively. Total method recovery was tested with natural Gd (157Gd) using ICP-QQQ-MS. A maximum total recovery of 75 % was obtained.

Uranium Aerosol Activity Size Distributions at a Nuclear Fuel Fabrication Plant.

Inhalation of uranium aerosols is a concern in nuclear fuel fabrication. Determination of committed effective doses and lung equivalent doses following inhalation intake requires knowledge about aerosol characteristics; e.g., the activity median aerodynamic diameter (AMAD). Cascade impactor sampling of uranium aerosols in the breathing zone of nuclear operators was carried out at a nuclear fuel fabrication plant producing uranium dioxide via ammonium uranyl carbonate. Complementary static sampling was carried out at key process steps. Uranium on impaction substrates was measured using gross alpha counting and alpha spectrometry. Activity size distributions were evaluated for both unimodal and bimodal distributions. When a unimodal distribution was assumed, the average AMAD in the operator breathing zone at the workshops was 12.9-19.3 µm, which is larger than found in previous studies. Certain sampling occasions showed variable isotope ratios (U/U) at different impactor stages, indicating more than one population of particles; i.e., a multimodal activity size distribution. When a bimodal distribution (coarse and fine fraction) was assumed, 75-88% of the activity was associated with an AMAD of 15.2-18.9 µm (coarse fraction). Quantification of the AMAD of the fine fraction was associated with large uncertainties. Values of 1.7-7.1 µm were obtained. Static sampling at key process steps in the workshops showed AMADs of 4.9-17.2 µm, generally lower than obtained by breathing zone sampling, when a unimodal distribution was assumed. When a bimodal distribution was assumed, a smaller fraction of the activity was associated with the coarse fraction compared to breathing zone sampling. This might be due to impactor positioning during sampling and sedimentation of large particles. The average committed effective dose coefficient for breathing zone sampling and a bimodal distribution was 1.6-2.6 µSv Bq for U when Type M/S absorption parameters were assumed (5.0 µSv Bq for an AMAD of 5 µm). The corresponding lung equivalent dose coefficient was 3.6-10.7 µSv Bq (29.9 µSv Bq for an AMAD of 5 µm). The predicted urinary excretion level 100 d after inhalation intake was found to be 13-34% of that corresponding to an AMAD of 5 µm. Uranium aerosols generated at a nuclear fuel fabrication plant using ammonium uranyl carbonate route of conversion were associated with larger AMADs compared to previous work, especially when sampling of aerosols was carried out in the operator breathing zone. A bimodal activity size distribution can be used in calculations of committed effective doses and lung equivalent doses, but parameters associated with the fine fraction must be interpreted with care due to large uncertainties.

Architectural Modification of Conformal PEG-Bottlebrush Coatings Minimizes Anti-PEG Antigenicity While Preserving Stealth Properties.

Poly(ethylene glycol) (PEG), a linear polymer known for its "stealth" properties, is commonly used to passivate the surface of biomedical implants and devices, and it is conjugated to biologic drugs to improve their pharmacokinetics. However, its antigenicity is a growing concern. Here, the antigenicity of PEG is investigated when assembled in a poly(oligoethylene glycol) methacrylate (POEGMA) "bottlebrush" configuration on a planar surface. Using ethylene glycol (EG) repeat lengths of the POEGMA sidechains as a tunable parameter for optimization, POEGMA brushes with sidechain lengths of two and three EG repeats are identified as the optimal polymer architecture to minimize binding of anti-PEG antibodies (APAs), while retaining resistance to nonspecific binding by bovine serum albumin and cultured cells. Binding of backbone- versus endgroup-selective APAs to POEGMA brushes is further investigated, and finally the antigenicity of POEGMA coatings is assessed against APA-positive clinical plasma samples. These results are applied toward fabricating immunoassays on POEGMA surfaces with minimal reactivity toward APAs while retaining a low limit-of-detection for the analyte. Taken together, these results offer useful design concepts to reduce the antigenicity of polymer brush-based surface coatings used in applications involving human or animal matrices.

Highly flexible, wearable, and disposable cardiac biosensors for remote and ambulatory monitoring.

Contemporary cardiac and heart rate monitoring devices capture physiological signals using optical and electrode-based sensors. However, these devices generally lack the form factor and mechanical flexibility necessary for use in ambulatory and home environments. Here, we report an ultrathin (~1 mm average thickness) and highly flexible wearable cardiac sensor (WiSP) designed to be minimal in cost (disposable), light weight (1.2 g), water resistant, and capable of wireless energy harvesting. Theoretical analyses of system-level bending mechanics show the advantages of WiSP's flexible electronics, soft encapsulation layers and bioadhesives, enabling intimate skin coupling. A clinical feasibility study conducted in atrial fibrillation patients demonstrates that the WiSP device effectively measures cardiac signals matching the Holter monitor, and is more comfortable. WiSP's physical attributes and performance results demonstrate its utility for monitoring cardiac signals during daily activity, exertion and sleep, with implications for home-based care.

Isoform-specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans.

Serum alanine aminotransferase (ALT) is used as a clinical marker to detect hepatic damage and hepatoxicity. Two isoforms of ALT have been identified, ALT1 and ALT2, which have identical enzymatic capacities and are detected simultaneously in human serum/plasma using classical clinical chemical assays. Differences exist in the expression patterns of the ALT1 and ALT2 proteins in different organs which suggest that changes in the proportion of ALT1 and ALT2 in plasma may arise and reflect damage to different human organs. However, this has not been previously studied due to the lack of a selective methodology that can quantify both ALT1 and ALT2 isoforms in the total ALT activity normally measured in clinical samples. To the best of our knowledge, our current study reveals for the first time, that under 3 different conditions of liver damage (non-alcoholic fatty liver disease, hepatitis C and during liver surgery) the leakage of ALT1 activity into plasma greatly exceeds that of ALT2, and that the measurement of ALT1 during liver damage is equal to the measurement of total ALT activity. By contrast, during skeletal muscle injury, induced in volunteers by physical exertion, the leakage of ALT2 exceeds that of ALT1 and the proportion of circulating ALT isoforms changes accordingly. The ALT isoform changes occurring in plasma reflect previously demonstrated relative contents of ALT1 and ALT2 activities in human liver and skeletal muscle. These data suggest that assessing the percentage contribution of ALT1 and ALT2 activities to total ALT activity in plasma may distinguish hepatic from extrahepatic injury using the same standard analytical platform.

Detection of the mitochondrial and catalytically active alanine aminotransferase in human tissues and plasma.

Serum alanine aminotransferase (ALT) is used as a clinical marker of hepatotoxicity. Three forms of human ALT have been identified, ALT1 and 2 and an alternative splice variant of ALT2 (herein called ALT2_2). The standard ALT activity assay does not discriminate between ALT from different organs, or the isoforms measured in the plasma. Here, we show that ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values, while recombinant ALT2_2 protein does not possess any enzymatic activity. Isolation of organelles from cultured human skeletal muscle cells, showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. In human hepatocytes, on the other hand, ALT1 was only localised to the cytosol and ER, with no detection in mitochondria. ALT2 was not detected in cultured human hepatocytes, liver extract or tissue using Western blotting or immunohistochemistry. The islet of Langerhans and cardiomyocytes were other examples of cells with high expression of catalytic ALT2. A clinical method for selective measurement of ALT1 and 2 in human plasma is described, and both ALT1 and 2 were immunoprecipitated from human plasma and structurally detected using Western blotting techniques.

On the use of different measures of exposure-experiences from a case-control study on testicular cancer and PVC exposure.

Associations between exposure to PVC plastics and testicular cancer have been reported. To improve the exposure-response analysis in a matched case-control study on testicular cancer and occupational exposures, a self-administered exposure questionnaire and expert assessment was applied and different exposure measures were developed. The questionnaires regarding work histories and employment in PVC production, manufacturing, and handling of PVC products were completed by 1582 subjects (90%). By expert assessment, 360 subjects were considered exposed, and the exposure intensity to PVC plastics for different working periods was determined. Different exposure measures to PVC plastics were then developed, such as ever/never exposed, duration, maximum intensity, median intensity, and cumulative median intensity. The correlation between the different measures of exposure was high for exposure duration and the cumulative median exposure intensity (Spearman rank coefficient r(s) = 0.94), as was the correlation between the maximum intensity and the median intensity (r(s) = 0.94). The agreement between the answers in the questionnaire and the expert assessments was moderate, Kappa value 0.56. The odds ratio for "ever" exposed based on the exposure as reported in the questionnaire was 1.1 (95%, CI 0.82-1.56), and as determined by expert assessment 1.3 (CI 1.05-1.69). The odds ratios for all four different categories of exposure measures varied between 0.86 and 2.6 but decreased by increasing exposure. An overall excess of testicular cancer for the PVC exposed vs. the unexposed was not supported by the pattern seen in a standard exposure-response analysis based on several exposure measures. The findings stress the importance of using several exposure measures as dose surrogates when the underlying toxic mechanisms are unknown and when there are indications of an overall effect.

Impact of fluoride and other aquatic parameters on radon concentration in natural waters.

Radon (222Rn) accumulation in water in relation to stable elements was studied for the purpose of determining factors influencing the transfer of 222Rn to and from water. In 72 groundwater samples, 222Rn and about 70 analytical parameters were analysed using radiometric and ICP-MS techniques. Using multivariate statistics (partial least squares), it was observed that 222Rn has a positive correlation with fluoride and uranium. The correlation with fluoride was further investigated by a laboratory time-scale experiment to measure the emanation of 222Rn from water as a function of fluoride, pH and carbonate. The transfer of 222Rn from water was measured by continuous monitoring in air in a closed loop set-up. It was observed that fluoride in water adhere or trap 222Rn preferably in acidic water (pH 3). It is suspected that natural physical processes (such as diffusion and microbubble phenomenon) are less effective to transport 222Rn in the presence of fluoride.

Epidemiological adaptation of quartz exposure modeling in Swedish aluminum foundries: nested case-control study on lung cancer.

In a recent cohort study in aluminum foundries and remelting plants an unexpectedly high risk of lung cancer was found in workers in sand foundries. On the basis of present and historical measurement data, we developed a statistical model for exposure to total dust and crystalline quartz for different jobs and time periods. Cumulative dose estimates of total dust and crystalline quartz were calculated and used in a nested case-control study in the cohort. From the cohort of foundry workers (n = 5016), 46 cases of lung cancer were identified. The final analysis was performed on 31 cases and 233 controls with one year or more of employment. Historical measurement data from the 1960s and onward were collected, totaling 203 total dust and 103 crystalline quartz exposure observations. Regression models, using the determinants of job title, time period, type of foundry, and size of production, were developed for assessing historical total dust and crystalline quartz air concentrations. These estimates were used to calculate individual cumulative exposure in the case-control study. In the multiple linear regression analysis, the determinants explained much of the variations in dust level (r(2) = 0.58). The explained variation in crystalline quartz was much lower (r(2) = 0.13). The regression coefficients for the type of foundry, time period, and size of production were statistically significant for total dust. On the basis of the regression analysis, the final models were used to calculate individual cumulative exposures. The calculated cumulative dust and quartz exposures averaged 33 mg/m(3) * year and 0.42 mg/m(3) * year, respectively. The odds ratios (ORs) were not significant, but showed dose-response trends for both dust and crystalline quartz.

Risk of extremity fractures in adult outpatients with epilepsy.

PURPOSE: To study the incidence of extremity fractures in a group of adult patients with epilepsy attending an outpatient clinic compared with the incidence of fractures in the general population in the same geographic area. METHODS: We selected 177 consecutive adult patients with epilepsy attending the outpatient clinic at the Department of Neurology at Karolinska Hospital in Stockholm in 1995. This study population was matched with an Injury Registry to identify those epilepsy patients who during 1991 through 1995 attended the emergency department for an extremity fracture. The observed number of fractures in the epilepsy group was compared with the corresponding number of expected cases based on regional fracture rates. Relative-risk estimates for fractures were calculated with respect to the duration of epilepsy, mono- or polytherapy, and history of tonic-clonic seizures. RESULTS: Twenty (11%) of 177 patients sustained 23 fractures that prompted a visit to the emergency department. The incidence of fractures in the epilepsy patients was 23.8/1,000 person-years. The overall Standardized Morbidity Ratio (SMR) was 2.39 (95% CI, 1.52-3.59). A significantly higher risk for fractures was thus found in patients with epilepsy. Risk factors were age 45 years or older, male sex, and occurrence of generalized seizures. It also was found that the relative risk of fractures was higher during the first and second year compared with >or=5 years after diagnosis (RR, 3.71; 95% CI, 1.20-11.48). CONCLUSIONS: Our results highlight the risk of fractures in outpatients with epilepsy. In this patient group, 43% of the fractures were definitely or possibly seizure related. Males 45 years or older are a particular risk group. Special attention is required for this group of patients who are at higher risk for fractures. The risk is apparently higher in the first 2 years after diagnosis, although potential bias in ascertainment of fracture incidents in our study may have underestimated the long-term risk for fractures.