External electrical cardioversion of persistent atrial fibrillation in a patient with a Micra™ Transcatheter Pacing System.

We report a case of a 85-year old woman with a preexisting Transcatheter Pacing System (TPS) (Micra™ VR, Fa. Medtronic, Inc., Minneapolis, MN, USA) undergoing several external electrical cardioversions (CV) for symptomatic persistent atrial fibrillation (persAF). Due to bradycardia in the setting of atrial fibrillation a right apical TPS implantation was performed earlier. Four weeks prior to presentation at our facility an unsuccessful CV with a maximum biphasic energy level of 360J was performed, after which amiodarone was initiated. At the time of presentation three shocks with 100 J, 200 J and 360 J were delivered without sustained restoration of a stable sinus rhythm. Patches were in an anterior-posterior position. No complications and no significant changes in device parameters in comparison to the pre-acquired values were observed. To our knowledge, this is the first case report of an external CV in a patient with a TPS. External CV in patients with a preexisting TPS seems to be safe and feasible.

Incidence of MRI-detected brain lesions and neurocognitive function after electrical cardioversion in anticoagulated patients with persistent atrial fibrillation.

BACKGROUND: After electrical cardioversion (eCV) in patients with atrial fibrillation (AF), the risk for clinically apparent cerebral thromboembolism is increased in the subsequent weeks. To date, there is little evidence on the incidence of acute brain lesions (ABL) detected with cerebral magnetic resonance imaging (MRI) after eCV, in particular in patients treated with the Non-Vitamin K Antagonist oral anticoagulants (NOAC). AIMS: The aim of this pilot study was to evaluate the incidence of MRI-detected ABL, as well as the neuro-cognitive function after eCV in patients with persistent AF using NOACs as compared to phenprocoumon. METHODS AND RESULTS: 50 consecutive patients with persistent AF (mean age 69.6±3.5years, 26 male) were evaluated in this prospective study. Cerebral 3Tesla MRI and neuro-cognitive assessment using the National Institutes of Health Stroke Scale (NIHSS) score and the Montreal Cognitive Assessment Test (MoCA) were performed in all patients within 24h before eCV and after a median follow-up duration of 14days (Q1: 13, Q3: 19days). Patients were treated with an OAC for at least 4weeks after eCV and according to the CHA2DS2-Vasc-score thereafter. Thirty-nine patients were treated with NOACs (Dabigatran 10/50 [20%], Apixaban 21/50 [42%] and Rivaroxaban 8/50 [16]) and 11/50 patients with Phenprocoumon (22%). No patient developed ABL on cerebral MRI at the 2-week follow-up. Neurological as well as cognitive function were similar before and 2weeks after eCV (NIHSS-score: p=0.35; MoCa score: p=0.21). CONCLUSION: Electrical CV in patients with persistent AF, in particular when treated with NOACs, carries a low risk for the development of MRI-detected ABL or neurocognitive decline. CLINICAL TRIALS REGISTRATION: GermanClinicalTrialsRegister number: DRKS00010460.

[Electrical isolation of the left atrial appendage : Benefits and risks]. / Elektrische Isolation des linken Vorhofohrs : Nutzen und Risiko.

The left atrial appendage (LAA) is an extension originating from the body of the left atrium. The LAA is derived from the primary atrium and shows anatomical and physiological deviations from the left atrium. Different LAA morphologies exist. The LAA is not only the most frequent origin of intracardiac thrombi, it also frequently shows triggers responsible for the initiation or maintenance of atrial tachyarrhythmia and atrial fibrillation (AF). Isolation of the LAA using radiofrequency energy in addition to isolation of the pulmonary vein has recently gained importance due to the potential for increasing the clinical success rates, particularly in patients with persistent and long-standing persistent AF; however, after LAA isolation the incidence of LAA thrombi and systemic thromboembolisms might be increased even under treatment with oral anticoagulants, depending on the ablation strategy used. Thus, mechanical occlusion of the LAA should be discussed with patients after electrical isolation of the LAA.

[Telemedicine-assisted treatment of a 76-year-old man with heart failure]. / Telemedizingestützte Behandlung eines 76-Jährigen mit Herzinsuffizienz.

The case of a patient with dilated cardiomyopathy and severely impaired left ventricular function is reported. With existing complete left bundle branch block and the patient being on optimal medical therapy, a cardiac resynchronization device with an integrated defibrillator was implanted and the patient was included in our telemonitoring program. During monitoring, an increase in ventricular premature beats with a decrease in biventricular pacing percentage was noticed. Consequently, radiofrequency ablation of the ventricular premature beats which originated in the left ventricle was performed. After ablation we could demonstrate a significant increase in biventricular pacing percentage. This case shows the importance of telemedicine and the complexity in the rhythmological treatment of heart failure patients.

[Right ventricular outflow tract tachycardia 30 years after surgical correction of tetralogy of Fallot]. / Rechtsventrikuläre Ausflusstrakt-Tachykardie 30 Jahre nach chirurgischer Fallot-Teratologie-Korrektur.

This case report describes a 31-year-old man with a sustained wide complex tachycardia with left bundle brunch block morphology after surgical repair of a tetralogy of Fallot. The tachycardia was inducible after orciprenaline administration after ventricular stimulation with one extra beat. In combination with the three-dimensional electroanatomic mapping system and pace mapping technique the origin of the tachycardia was identified at the lateral free wall of the right ventricular outflow tract tachycardia (RVOT) inferior of the pulmonary valve. Successful radiofrequency ablation was performed and the patient is still free from ventricular tachycardia.

Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure.

This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake-dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6h/day for 5 days to either brake-dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake-dust or crocidolite asbestos. The chrysotile fibers were relatively biosoluble whereas the crocidolite asbestos fibers persisted through the life-time of the animal. This was reflected in the lung and the pleura where no significant pathological response was observed at any time point in the brake dust or chrysotile/brake dust exposure groups through 365 days post exposure. In contrast, crocidolite asbestos produced a rapid inflammatory response in the lung parenchyma and the pleura, inducing a significant increase in fibrotic response in both of these compartments. Crocidolite fibers were observed embedded in the diaphragm with activated mesothelial cells immediately after cessation of exposure. While no chrysotile fibers were found in the mediastinal lymph nodes, crocidolite fibers of up to 35 µm were observed. These results provide support that brake-dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung or the pleural cavity following short term inhalation.

[Heart failure. Cardiovascular autonomic neuropathy in patients with diabetes mellitus]. / Herzinsuffizienz. Kardiale autonome Neuropathie bei Patienten mit Diabetes mellitus.

In spite of new therapy options the life expectancy of patients with diabetes mellitus is clearly reduced compared to the average population. In addition to coronary heart disease and diabetic cardiomyopathy, cardiac autonomic neuropathy (CAN) is also a factor in patients with diabetes mellitus. The CAN is an impairment of cardiovascular control. A reduced variability of heart rate up to the point of a fixed heart rate are symptoms of CAN. In addition symptomatic hypotension, a reduced left ventricular ejection fraction, cardiac arrhythmia and sudden cardiac death are also signs of CAN. Prevalence rates of CAN increase with age and are approximately 38 % in patients 40-70 years old with diabetes mellitus type 1 and 44 % in patients with diabetes mellitus type 2. The disease is usually documented using miscellaneous cardiovascular autonomic tests so that therapy can be started as soon as possible.

Survey of the biological effects of refractory ceramic fibres: overload and its possible consequences.

This paper summarizes the biological effects of refractory ceramic fibres (RCFs). RCFs are aluminosilicate glass insulation wools with similar chemical properties to other synthetic vitreous fibres (SVFs) or 'man-made vitreous fibres' (MMVFs). There is concern that RCFs could be significantly more pathogenic than other SVFs. This paper critically reviews the data on which this perception is based. Morbidity studies on workers in RCF manufacturing indicated that, in the United states, RCF exposure was associated with an increased incidence of pleural plaques and in both the united states and Europe with statistically significant changes in some measures of lung function (though not at present exposure levels). No interstitial fibrosis was found. An ongoing mortality study of limited statistical power has failed to indicate any increased incidence of lung cancer or mesothelioma. Findings in several early animal studies led to a large series of inhalation studies where rats exposed to high levels of RCF developed fibrosis and tumours but not those exposed to other SVFs. Similarly hamsters exposed to one sample (RCF1) developed mesothelioma. Subsequent analyses of the data indicated that the RCF used in these experiments had a significantly greater proportion of non-fibrous particles than those present in the other types of SVFs tested or in workplace air. Short-term studies indicated that pulmonary overload occurred at the same as RCF tissue burdens as those in the long-term animal bioassay. When RCFs were prepared in the same way as the other SVFs, a sample resulted with a more representative ratio of particles to fibres; this sample did not produce overload in short-term tests. SVFs have various abilities to persist in the lung tissue and thus accumulate to varying degrees. It is suggested that biopersistence is a key property. While RCFs are among the more persistent they are similar to many other fibre types. The scientific and regulatory implications of these findings are examined.

Subchronic inhalation study of stone wool fibres in rats.

Pathology results after subchronic inhalation in rats of three separate fibres representing the new biosoluble high-aluminium low-silica HT type stone wool are given, and the results were compared with the results from a similar study done with the traditional stone wool MMVF21. Male Wistar rats were exposed at one exposure level by nose-only inhalation to well-characterized fibre test atmospheres. The fibres had been size selected to be largely rat respirable. The target dose was an exposure to 150 long fibres/ml (length>20 microm) in each group, and this dose was achieved for all the fibres. The negative control groups were exposed to filtered air. The exposure duration was 6 h/day, 5 days/week for 3 months, with a subsequent non-exposure period lasting 3 months. The rats were killed 1 week after the last exposure and additional post-exposure kills were performed at 1.5 and 3 months to monitor the progression of pulmonary change and fibre numbers in the lung. The assessments included bronchoalveolar lavage fluid (BALF) for evaluation of inflammatory response (e.g. protein content, enzymes, increase in polymorphonuclear leucocytes) and measurement of cell proliferation, assessment of early fibrosis through histological examination and comparison of body weight and lung lobe weights. After exposure of rats to the new biosoluble fibres no biologically significant effects were observed except that a statistically significant increase in lung weight was observed up to 1.5 months post-exposure in all three treatment groups. At 3 months post-exposure, the small increase was no longer significant. The increase in lung weight was still present in the MMVF21 group at the 3 months post-exposure kill. After 3 months exposure, lung retention of long fibres (length>20 microm) varied from 0.4 to 5.2 x 10(6) per lung for the biosoluble fibres. At 3 months post-exposure, the long fibre concentration in the lungs had decreased to 1-7% of this figure. The fibre with the relatively highest biopersistence (RIF41001) showed the highest fibre retention. The retention of the more biopersistent traditional stone wool MMVF21 was 5.7 x 10(6) per rat lung after 3 months exposure and had decreased to 64% of this figure at 3 months post-exposure. There was no clear difference in the bronchoalveolar lavage fluid cell concentration and percentage of cells between MMVF21 and the HT groups. Fibre inhalation caused a significant increase after 3 months in all the biochemical parameters measured in the BALF. Cell proliferation was enhanced at the end of exposure for MMVF21 for all three labelling indices, but only for the bronchiolar epithelium in the RIF41001 group and for alveolar parenchymal cells in the RIF43006-1 group. At the termination of the 3 month exposure period, as well as after 1.5 and 3 month recovery periods, minimal morphological changes were diagnosed in the biosoluble fibre groups. These changes included alveolar macrophage aggregation and/or microgranulomas at the bronchiolar-alveolar junction in the few rats affected. No fibrogenic potential was noted for any of the three fibres. No clear-cut difference between the different biosoluble fibre types was noted. In the MMVF21 group, minimal interstitial fibrosis was observed that gradually decreased after the 1.5 and 3 month non-exposure periods. In this study, the pathological changes found in the lungs of exposed rats were in accordance with the pathology previously reported from full lifespan inhalation studies. This may indicate that for fibres belonging to the man-made vitreous fibres group a well conducted biopersistence study is sufficient to predict possible pathogenic effects for new fibre types. The biological parameters examined in a 90 day study may indicate little additional information to contribute to the prediction of the outcome of carcinogenicity studies.

Residual cftr expression varies with age in cftr(tm1Hgu) cystic fibrosis mice: impact on morphology and physiology.

Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the human disease, but the lung disease phenotypes are lacking in most strains. In this work, the issue was addressed whether aging of the respiratory tract leads to lung pathophysiology in the exon 10 insertional mutant cftr(tm1Hgu) mouse. Weight gain, body weight and life-span of cftr(tm1Hgu) mice were significantly reduced compared with control mice. cftr(tm1Hgu) mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr) mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at the age of 2 and 4 months to levels seen in patients with CFTR splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in cftr(tm1Hgu) mice during their first year of life. The alveolar surfactant phospholipid pool was increased in cftr(tm1Hgu) mice by 1.5- to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of gamma-labelled scandium oxide - the first report of lung clearance measurement in living mice - was reduced in cftr(tm1Hgu) mice compared with littermate controls. Although no progressive lung pathology was seen in the cftr expression of cftr(tm1Hgu) mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.

Effects of nonfibrous particles on ceramic fiber (RCF1) toxicity in rats.

In previous investigations a reference test sample of prepared ceramic fibers called RCF1 induced lung tumors in a 2-yr inhalation study in rats. It was hypothesized that nonfibrous particles in RCF1 may have played a significant role. The objective of the present study was to compare lung retention and biological effects of another sample of ceramic fibers, called RCF1a, to the original RCF1. The main difference between these 2 samples was the content of nonfibrous particles: 25% of the mass of RCF1 versus 2% for RCF1a. These nonfibrous particles were chemically identical to the fibers. Female Wistar rats were exposed 6 h/day, 5 days/wk for 3 wk to either RCF1a or RCF1 fiber aerosol at a concentration of about 125 fibers (>20 microm long)/ml. Because of differences in the nonfibrous particle contents, the average gravimetric aerosol concentration differed between the two samples (RCF1, 51.2 mg/m(3); RCF1a, 25.8 mg/m(3)). The posttreatment observation period was 12 mo. Biological effects measured include the clearance function of alveolar macrophages (clearance of fibers and tracer particles), and inflammation and its persistence during the recovery period. Alveolar clearance of tracer particles ((46)Sc(2)O(3)) was barely retarded after RCF1a exposure (80 days clearance half-time compared to 60 days in controls). After RCF1 exposure, however, a severe retardation of clearance was observed (1200 vs. 66 days). In both groups, differential cell counts on pulmonary lavage showed a significant increase of polymorphonuclear leukocytes (PMNs) (about 15%) and lymphocytes 3 days after the end of exposure. The PMN influx persisted longer after exposure to RCF1 than RCF1a. The conclusion of the study is that the particle fraction of RCF1 significantly enhanced any adverse effects. This clearly demonstrates the importance of the physical characteristics of the test material for the degree of toxic effects to be expected. The presence of nonfibrous particulates can enhance the effects on the lung of a mixture of fibrous and nonfibrous particulates following exposure.

Inhalation tolerance study for p-aramid respirable fiber-shaped particulates (RFP) in rats.

This study was designed to assess the lung clearance function in rats after subchronic exposure to p-aramid respirable fiber-shaped particulates (RFP). Male Wistar rats were exposed 6 hrs/day, 5 days/week for 3 months to 50, 200, and 800 RFP/ml measured by scanning electron microscopy (SEM). Recovery effects were followed up through 9 months postexposure. The retention of RFP (length > 5 microm) was about 25 x 10(6) RFPs per lung in the low dose group after 3 months of exposure. The corresponding values in the medium and high dose groups amounted to overproportionally higher values of 122 x 10(6) and 576 x 10(6) RFPs per lung, respectively. A decrease in the length of the retained RFPs over the 9-month recovery period was observed, indicating a breakage of long fibrils. Alveolar clearance half-times measured by gamma tracers indicated a dust overloading of lungs for the high dose group at 0 and 3 months postexposure. Bronchoalveolar lavage parameters revealed that p-aramid RFPs induced pronounced inflammatory effects in the high and medium dose groups. Histopathologically, slight fibrotic and hyperplastic lesions were observed in the medium and high dose groups directly after the end of exposure. The findings at the 3-month postexposure interval resulted in a reduction of inflammatory changes in the medium and high dose groups compared to the sacrifices upon cessation of exposure. No histopathologic effects were detected in the low dose group. In the high dose group the maximum functionally tolerated dose was exceeded. The No Observed Adverse Effect Level (NOAEL) of RFP was 50 RFP/ml as measured by SEM.

Investigation of Chronic Toxic and Carcinogenic Effects of Gasoline Engine Exhausts Deriving from Fuel without and with Ferrocene Additive.

Chronic toxic and carcinogenic effects of gasoline engine exhaust inhalation were investigated in rats. The exhaust from the combustion of commercial fuel containing 30 ppm ferrocene additive was compared to exhaust from the same fuel without ferrocene. This study was part of a procedure to get a special authorization for the use of ferrocene as gasoline additive according to the German Gasoline Lead Act. To generate the exhausts, pairs of engines of the same type and age were operated on computer-controlled test benches in a combined urban-freeway driving cycle. The engines were equipped with three-way catalysts and lambda sensors. Rats inhaled the exhausts after dilution at ratios of about 1.20 and 1:40 for 18 h/day, 5 days/wk for 12 mo (chronic toxicity study) or for 24 mo followed by 6 mo of clean air (carcinogenicity study). The limiting factor for the exhaust concentration was the relative humidity of the exposure atmosphere. At defined intervals, body weight and food consumption, parameters of clinical chemistry, hematology, bronchoalveolar lavage (BAL), and mechanical lung function were measured, as well as lung clearance and particle retention in the lungs. In the high-dose groups and the controls the complete organ/tissue spectrum was investigated histopathologically, and in the low-dose groups the respiratory tract. Only slight exposure-related effects could be detected, like a loss in the background iron content of the cell pellet of the bronchoalveolar lavage fluid and cytoplasmic inclusions and goblet-cell hyperplasias in the nasal cavity. Between the clean-air controls and the exhaust-exposed groups, no exposure-related differences occurred in body weight development, mortality incidences, or any of the clinical investigations. Ninety-two to 94% of the animals developed age-related tumors, predominantly in the mammary glands, uterus, adrenals, thyroid, and pituitary. In the respiratory tract a total of five tumors was found: one in the controls and four in the low-dose groups. No physical, chemical, or toxicological differences between the exhausts from fuel without or with ferrocene were demonstrated.

Particle Contamination in Experimental Fiber Preparations.

Two samples of refractory ceramic fibers (RCF1 and RCF1a) were tested in rats exposed by inhalation for 3 wk and followed thereafter for 12 mo. RCF1 and RCFIa have similar fiber chemistry but differ in the fiber size distributions and the contents of nonfibrous particles (2% for RCFIa, 25% for RCFli. For both test samples the target aerosol concentration was 130 fibers/ml > 20 µm but the RCF1 aerosol contained more short fibers (less than 20 µm long) and more nonfibrous particles. Radioactive tracer measurements carried out during a period of 90 days after exposure demonstrated an almost complete abolition of alveolar clearance in RCFI-exposed animals. With RCFIa the half-time of(46)Sc2O3 particles was 80 days, compared to 60 days for controls (not statistically different). Biochemical and cytological analyses were carried out in bronchoalveolar lavage at days 3, 17, 31, 94, and 365 postexposure. They revealed a more important and more persistent inflammation in RCFI-exposed animals compared to RCFIa. These observations show that the biological activity of synthetic vitreous fibers (SVFs) assessed by inhalation experiments depends not only on the chemical composition of the fiber type but also on the physical characteristics of the test sample. They are in line with results of previous studies and support the hypothesis of a synergistic effect between fibrous and nonfibrous particles. They raise questions about the interpretation of the so called RCC experiments in which the several SVFs samples tested were not prepared using the same method and differed in their physical characteristics. In particular, these differences existed especially between the RCF and MMV F samples.

Detection of melanoma micrometastases in the sentinel lymph node and in nonsentinel nodes by tyrosinase polymerase chain reaction.

The aim of our study was to investigate the metastatic pathways of melanoma cells in sentinel and other regional lymph nodes. The term "sentinel lymph node" means that the first lymph node of the draining site of a primary tumor is never bypassed in malignant melanoma. In this case lymph node dissection would be necessary only when melanoma cells are detected in the sentinel node. Tyrosinase reverse transcriptase-polymerase chain reaction was applied to search for metastatic melanoma in the sentinel lymph node and in further lymph nodes of a complete lymph node basin in patients who underwent lymph node dissection. In 24 patients with malignant melanoma the draining site of the tumor was marked by lymphoscintigraphy and by intraoperative injection of patent blue V in the area around the primary tumor. The lymph nodes of the affected basin were excised and prepared for histopathologic, immunohistochemical, and molecular biologic examinations. Regarding the sentinel lymph node, 10 of 24 patients showed morphologic evidence for metastases, three additional patients showed only tyrosinase transcripts. In 11 of these 13 cases we found one or more nonsentinel lymph nodes with morphologically detectable melanoma cells and/or tyrosinase mRNA. Interestingly, in seven of 24 patients a positive tyrosinase reverse transcriptase-polymerase chain reaction was received in nonsentinel lymph nodes, whereas the sentinel lymph node was negative, not only for all histologic examinations but also by tyrosinase reverse transcriptase-polymerase chain reaction. In five of seven patients of the latter group, gp100 reverse transcriptase-polymerase chain reaction was carried out, showing also gp100 mRNA in nonsentinel lymph nodes only. Our data indicate that the concept of the sentinel lymph node may miss micrometastases. Whether such micrometastases cause a recurrence or a metastasis of malignant melanoma, or can be destroyed by the immune system, remains to be clarified.

Significance of the biodurability of man-made vitreous fibers to risk assessment.

It is generally agreed that the biodurability of man-made vitreous fibers is a major factor for the characterization of potential health effects. As there is currently no standardization of experimental protocols to determine biodurabilty, the results of the clearance assays have not been used up to now for regulatory purposes. Methods used to analyze biodurability in animal models are short-term inhalational exposure and intratracheal instillation of rat respirable fibers. Both test methods have strengths and limitations for regulatory purposes. We outline recommended procedures for standardized biodurability assays that can be used to compare different fiber types. In animal experiments, biodurability is difficult to separate from biopersistence, as mucociliary and macrophage-mediated clearance occur simultaneously with dissolution and disintegration. For intratracheal instillation, a sized rat respirable sample must be used. Precautions should be taken to prevent aggregation of fibers in the lungs. Although from a scientific point of view questions remain about quantifying the influence of fiber length, diameter, dose, and exposure route, consistent data on the biodurability of vitreous glass fibers are available which may be used for regulatory purposes.

Investigations on health-related properties of two sepiolite samples.

Published i.p. injection studies have shown different biological behavior of different sepiolite samples. There was no evidence for carcinogenic potential of sepiolite from Vicalvaro, Spain, whereas a high tumor incidence was reported for sepiolite from Finland. The low biological activity of the sepiolite from Vicalvaro, compared to the Finnish sample, could be caused by low in vivo persistence or by the short length of the fibers, or both. In this study a further sepiolite sample, obtained as a commercial sample originating from China, was investigated. This sample contained a higher fraction of fibers longer than 5 microns, comparable to the Finnish sepiolite sample. The fraction of fibers with a length > 5 microns was 0.12 and 2.2% for the Vicalvaro and Chinese sepiolite, respectively. For the fiber fraction longer than 8 microns, the corresponding values were 0.0045 and 0.82%. The in vivo persistence of the sepiolite samples from China and Vicalvaro was analyzed after intratracheal instillation of 2 mg in female Wistar rats. Fiber retention in the lungs was analyzed by transmission electron microscopy at different sacrifice dates up to 12 months after application. For the Vicalvaro sepiolite, a splitting of fiber bundles was found during retention time in the lung. Therefore, no half-time of the fiber clearance could be calculated from the number of fibers. The decrease of the calculated retained fiber mass was faster for the Vicalvaro sepiolite (T1/2 = 89 days) compared to the Chinese sepiolite (T1/2 = 129 days). For 2 or 3 rats per group, at sacrifice date 12 months after i.p. injection, the lung was investigated by histopathology. The main difference between both treatment groups was a more pronounced fibrotic response in the Chinese sepiolite-treated rats compared to those treated with Vicalvaro sepiolite. It is concluded that both the higher fraction of long sepiolite fibers and the slower elimination rate of the fiber mass in the Chinese sample were important factors for the different biological reaction in comparison with Vicalvaro sepiolite.

Dose-response relationship of fibrous dusts in intraperitoneal studies.

The relationship between the number of fibers injected intraperitoneally and the occurrence of peritoneal mesotheliomas in rats was investigated using data from a series of carcinogenicity studies with several fibrous dusts. Based on observed tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of dose-response relationships (parallel probit lines in probit analysis) cannot be rejected. In general, parallelism of probit lines is considered an indication of a common mode of action. Analysis of the shape of the dose-response relationship, with one apparent exception, shows virtually linear or superlinear behavior, i.e., from these data, there is no indication of a decrease in carcinogenic potency of an elementary carcinogenic unit at lower doses.