Incidence, therapy, and outcome in the management of chronic subdural hematoma in Switzerland: a population-based multicenter cohort study.

Background: Chronic subdural hematoma (cSDH) is a disease affecting mainly elderly individuals. The reported incidence ranges from 2.0/100,000 to 58 per 100,000 person-years when only considering patients who are over 70 years old, with an overall incidence of 8.2-14.0 per 100,000 persons. Due to an estimated doubling of the population above 65 years old between 2000 and 2030, cSDH will become an even more significant concern. To gain an overview of cSDH hospital admission rates, treatment, and outcome, we performed this multicenter national cohort study of patients requiring surgical treatment of cSDH. Methods: A multicenter cohort study included patients treated in 2013 in a Swiss center accredited for residency. Demographics, medical history, symptoms, and medication were recorded. Imaging at admission was evaluated, and therapy was divided into burr hole craniostomy (BHC), twist drill craniostomy (TDC), and craniotomy. Patients' outcomes were dichotomized into good (mRS, 0-3) and poor (mRS, 4-6) outcomes. A two-sided t-test for unpaired variables was performed, while a chi-square test was performed for categorical variables, and a p-value of <0.05 was considered to be statistically significant. Results: A total of 663 patients were included. The median age was 76 years, and the overall incidence rate was 8.2/100,000. With age, the incidence rate increased to 64.2/100,000 in patients aged 80-89 years. The most prevalent symptoms were gait disturbance in 362 (58.6%) of patients, headache in 286 (46.4%), and focal neurological deficits in 252 (40.7%). CSDH distribution was unilateral in 478 (72.1%) patients, while 185 presented a bilateral hematoma with no difference in the outcome. BHC was the most performed procedure for 758 (97.3%) evacuations. CSDH recurrence was noted in 104 patients (20.1%). A good outcome was seen in almost 81% of patients. Factors associated with poor outcomes were age, GCS and mRS on admission, and the occurrence of multiple deficits present at the diagnosis of the cSDH. Conclusion: As the first multicenter national cohort-based study analyzing the disease burden of cSDH, our study reveals that the hospital admission rate of cSDH was 8.2/100,000, while with age, it rose to 64.2/100,000. A good outcome was seen in 81% of patients, who maintained the same quality of life as before the surgery. However, the mortality rate was 4%.

Specificity of Quantitative Functional Brain Mapping with Arterial Spin-Labeling for Preoperative Assessment.

BACKGROUND AND PURPOSE: Arterial spin-labeling is a noninvasive MR imaging technique allowing direct and quantitative measurement of brain perfusion. Arterial spin-labeling is well-established in clinics for investigating the overall cerebral perfusion, but it is still occasionally employed during tasks. The typical contrast for functional MR imaging is blood oxygen level-dependent (BOLD) imaging, whose specificity could be biased in neurologic patients due to altered neurovascular coupling. This work aimed to validate the use of functional ASL as a noninvasive tool for presurgical functional brain mapping. This is achieved by comparing the spatial accuracy of functional ASL with transcranial magnetic stimulation as the criterion standard. MATERIALS AND METHODS: Twenty-eight healthy participants executed a motor task and received a somatosensory stimulation, while BOLD imaging and arterial spin-labeling were acquired simultaneously. Transcranial magnetic stimulation was subsequently used to define hand somatotopy. RESULTS: Functional ASL was found more adjacent to transcranial magnetic stimulation than BOLD imaging, with a significant shift along the inferior-to-superior direction. With respect to BOLD imaging, functional ASL was localized significantly more laterally, anteriorly, and inferiorly during motor tasks and pneumatic stimulation. CONCLUSIONS: Our results confirm the specificity of functional ASL in targeting the regional neuronal excitability. Functional ASL could be considered as a valid supplementary technique to BOLD imaging for presurgical mapping when spatial accuracy is crucial for delineating eloquent cortex.

Gender disparity in neurosurgery: A multinational survey on gender-related career satisfaction.

Introduction: Women continue to be underrepresented in the majority of surgical specialties, including neurosurgery. Research question: In this multinational survey, we aimed to assess current gender disparities in neurosurgery focusing on job satisfaction and inequity/discrimination at work. Material and methods: Female and male members of the European Association of Neurosurgical Societies were asked to complete an electronic survey (Google Forms, Mountain View) containing demographic baseline data and questions on attitudes regarding gender disparity, personal experience with gender inequity and career satisfaction/work-life balance. Quantitative analyses were performed to analyse the responses, including summary and comparative statistics. Results: We received 168 responses from 40 different countries. Survey responders had a mean age of 40.8 â€‹± â€‹11.5 years; 29.8% were female. There were significant more male than female residents and attending surgeons per department. Eighty-eight percent of female and 38.1% of male responders experienced gender inequity or discrimination at work (adjusted OR 10.8, 95%CI 4.2-27.8, p<0.001). Female neurosurgeons were more likely to be discriminated by colleagues (aOR 4.32, 95%CI 2.1-9.1, p<0.001) and by patients/relatives (aOR 3.65, 95%CI 1.77-7.54, p<0.001). There was a trend towards lower job satisfaction (p=0.012), less satisfaction with career goals (p=0.035) and worse work-life balance (p=0.0021) in female surgeons. Discussion and conclusion: This survey underlines that a significant proportion of neurosurgeons - in particular females - continue to experience gender inequity & discrimination at work, which may translate into lower work-related satisfaction. A better understanding of the gender-related aspects of job satisfaction is an important step to improving gender equity in our profession.

Longitudinal neuropsychological assessment after aneurysmal subarachnoid hemorrhage and its relationship with delayed cerebral ischemia: a prospective Swiss multicenter study.

OBJECTIVE: While prior retrospective studies have suggested that delayed cerebral ischemia (DCI) is a predictor of neuropsychological deficits after aneurysmal subarachnoid hemorrhage (aSAH), all studies to date have shown a high risk of bias. This study was designed to determine the impact of DCI on the longitudinal neuropsychological outcome after aSAH, and importantly, it includes a baseline examination after aSAH but before DCI onset to reduce the risk of bias. METHODS: In a prospective, multicenter study (8 Swiss centers), 112 consecutive alert patients underwent serial neuropsychological assessments (Montreal Cognitive Assessment [MoCA]) before and after the DCI period (first assessment, < 72 hours after aSAH; second, 14 days after aSAH; third, 3 months after aSAH). The authors compared standardized MoCA scores and determined the likelihood for a clinically meaningful decline of ≥ 2 points from baseline in patients with DCI versus those without. RESULTS: The authors screened 519 patients, enrolled 128, and obtained complete data in 112 (87.5%; mean [± SD] age 53.9 ± 13.9 years; 66.1% female; 73% World Federation of Neurosurgical Societies [WFNS] grade I, 17% WFNS grade II, 10% WFNS grades III-V), of whom 30 (26.8%) developed DCI. MoCA z-scores were worse in the DCI group at baseline (-2.6 vs -1.4, p = 0.013) and 14 days (-3.4 vs -0.9, p < 0.001), and 3 months (-0.8 vs 0.0, p = 0.037) after aSAH. Patients with DCI were more likely to experience a decline of ≥ 2 points in MoCA score at 14 days after aSAH (adjusted OR [aOR] 3.02, 95% CI 1.07-8.54; p = 0.037), but the likelihood was similar to that in patients without DCI at 3 months after aSAH (aOR 1.58, 95% CI 0.28-8.89; p = 0.606). CONCLUSIONS: Aneurysmal SAH patients experiencing DCI have worse neuropsychological function before and until 3 months after the DCI period. DCI itself is responsible for a temporary and clinically meaningful decline in neuropsychological function, but its effect on the MoCA score could not be measured at the time of the 3-month follow-up in patients with low-grade aSAH with little or no impairment of consciousness. Whether these findings can be extrapolated to patients with high-grade aSAH remains unclear. Clinical trial registration no.: NCT03032471 (ClinicalTrials.gov).

Objective functional assessment using the "Timed Up and Go" test in patients with lumbar spinal stenosis.

OBJECTIVEPatient-reported outcome measures (PROMs) are standard of care for the assessment of functional impairment. Subjective outcome measures are increasingly complemented by objective ones, such as the "Timed Up and Go" (TUG) test. Currently, only a few studies report pre- and postoperative TUG test assessments in patients with lumbar spinal stenosis (LSS).METHODSA prospective two-center database was reviewed to identify patients with LSS who underwent lumbar decompression with or without fusion. The subjective functional status was estimated using PROMs for pain (visual analog scale [VAS]), disability (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQoL; 12-Item Short-Form Physical Component Summary [SF-12 PCS] and the EQ-5D) preoperatively, as well as on postoperative day 3 (D3) and week 6 (W6). Objective functional impairment (OFI) was measured using age- and sex-standardized TUG test results.RESULTSSixty-four patients (n = 32 [50%] male, mean age 66.8 ± 11.7 years) were included. Preoperatively, they reported a mean VAS back pain score of 4.1 ± 2.7, VAS leg pain score of 5.4 ± 2.7, RMDI of 10.4 ± 5.3, ODI of 41.9 ± 16.2, SF-12 PCS score of 32.7 ± 8.3, and an EQ-5D index of 0.517 ± 0.226. The preoperative rates of severe, moderate, and mild OFI were 4.7% (n = 3), 12.5% (n = 8), and 7.8% (n = 5), respectively, and the mean OFI T-score was 116.3 ± 23.7. At W6, 60 (93.8%) of 64 patients had a TUG test result within the normal population range (no OFI); 3 patients (4.7%) had mild and 1 patient (1.6%) severe OFI. The mean W6 OFI T-score was significantly decreased (103.1 ± 13.6; p < 0.001). Correspondingly, the PROMs showed a decrease in subjective VAS back pain (1.6 ± 1.7, p < 0.001) and leg pain (1.0 ± 1.8, p < 0.001) scores, disability (RMDI 5.3 ± 4.7, p < 0.001; ODI 21.3 ± 16.1, p < 0.001), and increase in HRQoL (SF-12 PCS 40.1 ± 8.3, p < 0.001; EQ-5D 0.737 ± 0.192, p < 0.001) at W6. The W6 responder status (clinically meaningful improvement) ranged between 81.3% (VAS leg pain) and 29.7% (EQ-5D index) of patients.CONCLUSIONSThe TUG test is a quick and easily applicable tool that reliably measures OFI in patients with LSS. Objective tests incorporating longer walking time should be considered if OFI is suspected but fails to be proven by the TUG test, taking into account that neurogenic claudication may not clinically manifest during the brief TUG examination. Objective tests do not replace the subjective PROM-based assessment, but add valuable information to a comprehensive patient evaluation.

Assessment of the Minimum Clinically Important Difference in the Timed Up and Go Test After Surgery for Lumbar Degenerative Disc Disease.

BACKGROUND: The Timed Up and Go Test (TUG Test) has previously been described as a reliable tool to evaluate objective functional impairment in patients with degenerative disc disease. OBJECTIVE: The aim of this study was to assess the minimum clinically important difference (MCID) of the TUG Test. METHODS: The TUG Test (measured in seconds) was correlated with validated patient-reported outcome measures (PROs) of pain intensity (Visual Analog Scale for back and leg pain), functional impairment (Oswestry Disability Index, Roland Morris Disability Index), and health-related quality of life measures (Short Form-12 and EuroQol 5D). Three established methods were used to establish anchor-based MCID values using responders of the following PROs (Visual Analog Scale back and leg pain, Oswestry Disability Index, Roland Morris Disability Index, EuroQol 5D index, and Short Form-12 Physical Component Summary) as anchors: (1) average change, (2) minimum detectable change, and (3) change difference approach. RESULTS: One hundred patients with a mean ± SD age of 56.2 ± 16.1 years, 57 (57%) male, 45 patients undergoing microdiscectomy, 35 undergoing lumbar decompression, and 20 undergoing fusion surgery were studied. The 3 MCID computation methods revealed a range of MCID values according to the PRO used from 0.9 s (Oswestry Disability Index based on the change difference approach) to 6.0 s (EuroQol 5D index based on the minimum detectable change approach), with a mean MCID of 3.4 s for all measured PROs. CONCLUSION: The MCID for the TUG Test time is highly variable depending on the computation technique used. The average TUG Test MCID was 3.4 s using all 3 methods and all anchors.

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

BACKGROUND: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. METHODS: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. RESULTS: We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12 months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. CONCLUSIONS: This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH.

Assessment of intra-aneurysmal flow modification after flow diverter stent placement with four-dimensional flow MRI: a feasibility study.

BACKGROUND: Flow diverter stents (FDS) have been effectively used for the endovascular treatment of sidewall intracranial aneurysms (IAs). Unlike standard endovascular treatments used to exclude directly the aneurysm bulge from the parent vessel, FDS induce reduction in the intra-aneurysmal flow and promote progressive and stable thrombosis therein. The advent of FDS has therefore increased the need for understanding of IA hemodynamics. METHODS: We proposed the use of the most recently evolved four-dimensional (4D) flow MRI technique to evaluate qualitatively and quantitatively post-FDS flow modification in 10 patients. We report intra-aneurysmal velocity measurements and the influence of metal artifacts induced by the stent. RESULTS: An index was defined to quantitatively measure flow changes-namely, the proportional velocity reduction ratio (PVRR)-with ranges from 34.6% to 71.1%. Furthermore, we could compare streamlines characterizing the post-stent flow patterns in five patients in whom the intra-aneurysmal velocity was beyond the visualization threshold of 7.69 cm/s. CONCLUSIONS: Despite metal artifacts and the low velocities involved, 4D flow MRI could be of interest to measure qualitatively and quantitatively flow changes in stented aneurysms. However, further enhancements are required together with further validation work before it can be considered for clinical use.

Augmented reality in the surgery of cerebral arteriovenous malformations: technique assessment and considerations.

BACKGROUND: Augmented reality technology has been used for intraoperative image guidance through the overlay of virtual images, from preoperative imaging studies, onto the real-world surgical field. Although setups based on augmented reality have been used for various neurosurgical pathologies, very few cases have been reported for the surgery of arteriovenous malformations (AVM). We present our experience with AVM surgery using a system designed for image injection of virtual images into the operating microscope's eyepiece, and discuss why augmented reality may be less appealing in this form of surgery. METHODS: N = 5 patients underwent AVM resection assisted by augmented reality. Virtual three-dimensional models of patients' heads, skulls, AVM nidi, and feeder and drainage vessels were selectively segmented and injected into the microscope's eyepiece for intraoperative image guidance, and their usefulness was assessed in each case. RESULTS: Although the setup helped in performing tailored craniotomies, in guiding dissection and in localizing drainage veins, it did not provide the surgeon with useful information concerning feeder arteries, due to the complexity of AVM angioarchitecture. CONCLUSION: The difficulty in intraoperatively conveying useful information on feeder vessels may make augmented reality a less engaging tool in this form of surgery, and might explain its underrepresentation in the literature. Integrating an AVM's hemodynamic characteristics into the augmented rendering could make it more suited to AVM surgery.

Augmented reality in the surgery of cerebral aneurysms: a technical report.

BACKGROUND: Augmented reality is the overlay of computer-generated images on real-world structures. It has previously been used for image guidance during surgical procedures, but it has never been used in the surgery of cerebral aneurysms. OBJECTIVE: To report our experience of cerebral aneurysm surgery aided by augmented reality. METHODS: Twenty-eight patients with 39 unruptured aneurysms were operated on in a prospective manner with augmented reality. Preoperative 3-dimensional image data sets (angio-magnetic resonance imaging, angio-computed tomography, and 3-dimensional digital subtraction angiography) were used to create virtual segmentations of patients' vessels, aneurysms, aneurysm necks, skulls, and heads. These images were injected intraoperatively into the eyepiece of the operating microscope. An example case of an unruptured posterior communicating artery aneurysm clipping is illustrated in a video. RESULTS: The described operating procedure allowed continuous monitoring of the accuracy of patient registration with neuronavigation data and assisted in the performance of tailored surgical approaches and optimal clipping with minimized exposition. CONCLUSION: Augmented reality may add to the performance of a minimally invasive approach, although further studies need to be performed to evaluate whether certain groups of aneurysms are more likely to benefit from it. Further technological development is required to improve its user friendliness.

SPECT-CT Assessment of Pseudarthrosis after Spinal Fusion: Diagnostic Pitfall due to a Broken Screw.

A 43-year-old drug addicted female was referred for a L5-S1 posterolateral in situ fixation with autologous graft because of an L5/S1 severe discopathy with listhesis. After six months, low back pain recurred. A Tc-99m HDP SPECT-CT diagnosed a pseudarthrosis with intense uptake of the L5-S1 endplates and a fracture of the right S1 screw just outside the metal-bone interface without any uptake or bone resorption around the screw. The absence of uptake around a broken screw is a pitfall that the physician should be aware of.

Validation of a new neurological score (FOUR Score) in the assessment of neurosurgical patients with severely impaired consciousness.

BACKGROUND: The Glasgow coma scale (GCS) was introduced as a scoring system for patients with impaired consciousness after traumatic brain injury (TBI). Since, it has become the worldwide standard in TBI assessment. The GCS has repeatedly been criticized for its several failures to reflect verbal reaction in intubated patients, and to test brain stem reflexes. Recently, the full outline of unresponsiveness (FOUR) score was introduced, which is composed of four clinically distinct categories of evaluation: eye reaction, motor function, brainstem reflexes and respiratory pattern. This study aims to validate the FOUR score in neurosurgical patients. METHODS: FOUR score and GCS were assessed in a consecutive series of neurosurgical patients with severely impaired consciousness (GCS < 9). Their correlation with the 30-day Glasgow outcome score (GOS) was compared. Patients admitted for TBI, spontaneous intracranial hemorrhage (intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, cerebellar hemorrhage), or malignant middle cerebral artery infarction were included. RESULTS: We assessed a total of 101 patients (mean age = 64y, SD = 36.1y). The area under the curve (AUC) for mortality was 0.768 (P = 0.0001) for the FOUR Score, and 0.699 (P = 0.001) for the GCS. For poor outcome (GOS = 2-3) the FOUR score AUC was 0.683 (P = 0.018), the GCS AUC was 0.682 (P = 0.019). The FOUR score value for favorable outcome (GOS = 4-5) was 0.748 (P = 0.001), the corresponding GCS value was 0.704 (P = 0.002). CONCLUSIONS: The FOUR score was more robust than the GCS in predicting mortality after 30 days in neurosurgical patients with severely impaired consciousness. There was no relevant difference in predicting poor and good outcome.

Percutaneous absorption of aromatic amines and the risk assessment resulting from the dermal pathway.

Aromatic amines (AA) are compounds of different carcinogenic potency causing occupational bladder cancer. The percutaneous absorption of AA is mostly appraised to be high. Many AA are, therefore, assigned with skin notations. However, for the assessment of the dermal exposure route only little data are available. Additionally, in many studies the skin penetration data for AA are provided as absorbed percentage of applied dose or permeability coefficients, which are less useful in risk assessment. In this overview, the toxicological relevance of percutaneous absorption of AA was evaluated and a percutaneous penetration ranking for some AA is proposed. A continuous skin exposure of hands to AA for a few minutes can exceed the inhalative exposure over 8 hours at occupational threshold limit values in the workplace air. The health risk resulting from the percutaneous absorption of AA can be considerable. Also the dermal exposure to azo dyes, which can be metabolized to AA, should be considered with caution.

The costs of disorders of the brain in Switzerland: an update from the European Brain Council Study for 2010.

BACKGROUND: In 2005, findings of the first "cost of disorders of the brain in Europe" study of the European Brain Council (EBC) showed that these costs cause a substantial economic burden to the Swiss society. In 2010 an improved update with a broader range of disorders has been analysed. This report shows the new findings for Switzerland and discusses changes. METHODS: Data are derived from the EBC 2010 census study that estimates 12-month prevalence of 12 groups of disorders of the brain and calculates costs (direct health-care costs, direct non-medical costs and indirect costs) by combining top-down and bottom up cost approaches using existing data. RESULTS: The most frequent disorder was headache (2.3 million). Anxiety disorders were found in 1 million persons and sleep disorders in 700,000 persons. Annual costs for all assessed disorders total to 14.5 billion Euro corresponding to about 1,900 EUR per inhabitant per year. Mood, psychotic disorders and dementias (appr. 2 billion EUR each) were most costly. Costs per person were highest for neurological/neurosurgery-relevant disorders, e.g. neuromuscular disorders, brain tumour and multiple sclerosis (38,000 to 24,000 EUR). CONCLUSION: The estimates of the EBC 2010 study for Switzerland provide a basis for health care planning. Increase in size and costs compared to 2005 are mostly due to the inclusion of new disorders (e.g., sleep disorders), or the re-definition of others (e.g., headache) and to an increase in younger cohorts. We suggest coordinated research and preventive measures coordinated between governmental bodies, private health-care and pharmaceutical companies.

External quality assessment of human biomonitoring in the range of environmental exposure levels.

The number of human biomonitoring (HBM) applications for identifying and assessing the chemical exposure of the general population from the environment has distinctly increased during the last decade. An appropriate external quality assessment of the applied methods is essential to assure the accuracy and the comparability of HBM results. The international programme of the German External Quality Assessment Scheme (G-EQUAS) provides proficiency testing for most of the HBM parameters, which are commonly used for the assessment of the human exposure to chemicals. Since 1992, G-EQUAS provides intercomparison runs for biological monitoring parameters in the environmental exposure range twice a year, with a successive increase of parameter numbers. In round no. 45 (2010) 18 metals in blood, plasma and urine und 36 organic parameters in urine and plasma were provided. Additionally analyses of 4 haemoglobin adducts were offered. For each parameter, two samples with different concentrations of the biomarker were sent to the participants. The target values as well as the tolerance ranges were estimated on the basis of the results from reference laboratories. The successful participation was certified, if the participant's results were within the tolerance ranges for both samples. The number of participants ranged from 3 to 37 international laboratories according to the individual parameter. The highest interest was observed for the detection of metals in blood, serum and urine, whereas only a few of the participants took part in the analyses of organophosphate metabolites and haemoglobin adducts. The rate of a successful participation ranged from 38 to 100%. Poor success rates were found for organophosphate metabolites, 1-naphthol and cotinine in urine. A training effect was observed for a group of laboratories which participated regularly in the analysis of organochlorinated compounds in serum.

Biological tolerance values: change in a paradigm concept from assessment of a single value to use of an average.

Since 1981 biological tolerance values for occupational exposure (BAT values) have been published in the List of MAK and BAT Values of the Deutsche Forschungsgemeinschaft (DFG). In 2007 the list includes threshold limit values for more than 90 substances. The BAT value was defined as the maximum permissible quantity of a chemical substance or its metabolites or the maximum permissible deviation from the norm of biological parameters induced by these substances. The biological limit values derived by other commissions (ACGIH, SCOEL) are to be understood as averages, which may well be exceeded individually, in contrast to the BAT values that were defined as ceiling values and thus did not allow an excess of values in the individual employee. The DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has now revised the concept of biological limit values. The BAT value describes the concentration of a chemical substance, of its metabolites or of an effect indicator in appropriate biological material derived by occupational medical and toxicological criteria, at which the health of an employee is usually not affected, even after repeated or long-term exposure. In this case, derivation of the BAT value is based on the average internal exposures. With this redefinition of the German BAT value, it will be possible to better harmonize the values with those provided by other commissions, which are also based on an average concept.

Discrepancies between different rat models for the assessment of percutaneous penetration of hazardous substances.

By regulatory authorities the rat is considered to be a suitable animal model to predict the percutaneous absorption of hazardous substances in humans. In our study, the percutaneous penetration of 2-butoxyethanol (BE) and toluene was compared in different rat models. Intradermal microdialysis and static diffusion cells were used in in vivo and in vitro experiments with haired Wistar and hairless Lewis rats. Microdialysis experiments showed a steady-state penetration for BE and a penetration maximum for toluene in both rat strains at approximately 60 min after beginning of exposure. However, in diffusion cell experiments the penetration of the test compounds in both rat strains increased until the end of exposure (4 h). Additionally, in microdialysis experiments BE penetrated in hairless rats in a higher amount than in haired rats (factor: 1.4; P < 0.01), for toluene it was just the opposite (factor: 1.9; P < 0.001). In diffusion cell experiments, the penetrated amounts of both compounds were higher in hairless rats compared to haired rats. The fluxes for BE were in diffusion cell experiments at a factor of 14.5 (haired rat) and 18.1 (hairless rat) higher than in microdialysis experiments, the difference factor for toluene was 2.6 (haired rat) and 12.9 (hairless rat). The lag times indicate a significantly faster penetration in microdialysis experiments compared with diffusion cell experiments (P < 0.001). There are great differences in percutaneous penetration behaviour between the techniques and the rat strains. The diffusion cell method has difficulties to describe the percutaneous penetration kinetics, whereas microdialysis describes it more reliable. Due to these differences the reliability of a conversion factor for the transfer of percutaneous absorption data from rat to human skin, as proposed in the literature, is questionable.