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To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5in the pathogenesis of common idiopathic epilepsies.

Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by paresthesias and an intense urge to move the legs with a considerable familial aggregation. To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5).

I2-binding sites (I2-BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivoand in vitroeffects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2-BS (antazoline, idazoxan, and cirazoline: IC50 20.3, 33.8, and 43.4 ?M ) had a stronger inhibitory effect on MAO activity than did I1-ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50 277, 801, 1,224, and >10,000 ?M ). Substances with the highest inhibitory effects were BDF8082 ( IC50 1.7 ?M ) and 2-(2-benzofuranyl)-2-imidazoline ( BFI; IC50 4.0 ?M ). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity ( IC50 168 ?M ), whereas its precursor, l-arginine, and its metabolite, putrescine, had no effects. In vitroinhibition of MAO and mitochondrial respiration by the IBS-ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivowas significantly reduced only by pargyline (?95), BDF8082 (?68), BFI (?43), and 1-(m-chlorophenyl)-biguanide (?28). Catecholamine content of livers obtained from animals treated with different IBS-ligands was consequently increased. In conclusion, the strong inhibitory effects of I2selective imidazoline ligands confirm the existence of I2-BS as a regulatory site on MAO.

A subchronic inhalation study of a special test toner was conducted by exposure of groups of F-344 SPF (specific pathogen free) rats for 6 hlday, 5 dayslwk for 13 wk. The test material was a special 9000 type xerographic toner, enriched in respirable size particles compared to commercial toner, such that it was about 35% respirable according to the ACGIH criteria. The nominal aerosol exposure concentrations were 0, 7.0, 4.0, 76.0, and 64.0 mg/m3 Body weight, clinical chemistry values, food consumption, and organ weights were normal except for a 40% increase in lung weight for the highest exposure group. Histopathological examination of the lungs indicated an exposure-related accumulation of particle-laden alveolar macrophages. A very slight degree of septal thickening of the alveolar structure was noted in the highest exposure group. Clearance results for the test material and a superimposed spike of 59Fe2O3 were essentially unchanged at exposure concentrations of 0, 1, and 4 mg/m3. At 76 mg/m3, some indications of retarded clearance were noted and at 64 mg/m3, no appreciable toner clearance was observed. The pulmonary changes observed at the two highest exposure levels are interpreted on the basis of the "lung overloading" concept. Based upon the above observations, as well as the increase in lung weight, both the maximum tolerated dose (MTD) and the maximum functionally tolerated dose of test toner (MFTD) in this subchronic study were exceeded at the 64 mg/m3 exposure level.

Male Wistar rats were treated by ozone or carbon black (CB) alone as well as in combination. Intratracheal instillation with various amounts of CB was followed either by an acute 7-day or subchronic 2-month ozone exposure (0.5 ppm). Two functional parameters were investigated in alveolar macrophages from bronchoalveolar lavagates, the phagocytotic capacity and the chemotactic migration capability. In the phagocytosis assay, the percentage of phagocytizing macrophages decreased significantly in the CB-exposed groups whereas the ozone groups remained close to or at the control level after 7 days and 2 months of exposure, respectively. The number of ingested particles per macrophage and the formation of Superoxide anion radicals were not changed after a 7-day exposure to ozone compared to the control group but were increased after a 2-month ozone exposure. However, a reduction was found in the CB groups. A stimulating effect of ozone was observed in the combined groups. Chemotactic migration was generally retarded in the CB-treated groups. From the results it can be concluded that ozone is able to stimulate the phagocytotic and chemotactic activity of alveolar macrophages whereas CB impairs these functions.

The biodurability is one of the essential factors for a carcinogenic potential of mineral fibres. The in vivosolubility of commercial fibre products can be influenced by modifications of the chemical composition.

This article briefly reviews the history of the current threshold limit value and the permissible exposure limit for occupational dusts derived originally from the Nuisance Dust standard. Chronic inhalation studies of appropriate design are described in terms of their key findings and potential impact on the dust standards, especially modern, experimental studies which have been affected by the problem of dust overloading. Many studies show that dust overloading produces a significant and progressive retardation of macrophage-mediated dust removal leading to various dysfunctional and pathologic changes which confound the interpretation of chronic toxicity study findings. Assuming that there may be a human counterpart to this condition at the same milligram dust per gram lung concentration, extrapolation modeling can be used to show that the current occupational dust limits do not protect worker lungs from this eventuality. Several bases for substantially reducing the current occupational standards are discussed.

The analysis of bronchoalveolar lavage fluid has been used as a probe to detect lung injury in texicological studies and to diagnose the disease state of the lung in humans. To determine how variable the content of lavage fluid from different species is, bronchoalveolar lavage fluids from normal individuals of four species (hamster, rat, guinea pig, and rabbit) were compared for enzymatic and cellular content as well as total protein and sialic acid. In addition, lavage fluid from young adult rats and hamsters was compared to that from older animals. Finally, the effect of the method of lavage on lavage fluid content was evaluated by comparing lavage fluid obtained from an excised lung with that from a lavage performed in vivo. In general, lavage fluids from the four species were similar. However, lavage fluid from guinea pigs had higher numbers of granulocytes and higher mean β-glucuronidase activities than fluids from other species. Rats had higher mean alkaline phosphatase activities, reflecting higher serum values of this enzyme. Older hamsters had more protein in their lavage fluid than younger animals, and older rats had lower elastase inhibitory activity than young rats. Performing lavage in vivo, as compared to in vitro, did not greatly alter the lavage fluid except for a trend toward a higher level of sialic acid in fluid taken from the living animal.

Methods for the determination of biodurability of man-made vitreous fibres are reviewed. For mineral wools the first step was the preparation of respirable fibre fractions. Fibres were administered to rats by inhalation or by intratracheal instillation. After serial sacrifice their lungs were digested by low-temperature ashing or by hypochlorite. The total number of fibres per lung and the distributions of length and diameter were analysed by electron microscopy. This resulted in a bivariate distribution of fibres at the various sacrifice dates. If the logarithm of the number of fibres decreased approximately linearly with time after exposure then the elimination kinetics of fibres can be characterized by a half-time. The half-times were compared between various experiments with rats exposed to mineral wool samples. In summary good agreement was found for the elimination of fibres after long-term inhalation and intratraeheal instillation whereas shorter half-times were found after short-term inhalation.

The South-African Orthodontium lineare Schwaegr. (Bryaceae, Musci) is reported from two stations in the Black Forest. Six records from the sandy plains of Northern Germany are given together with eleven from recent dispersion in the Northern Highlands. The total distribution in Europe is reviewed.

Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats. MUHLE, H., BELLMANN, B., CREUTZENBERG, O., DASENBROCK, C., ERNST, H., KILPPER, R., MACKENZIE, J. C., MORROW, P., MOHR, U., TAKENAKA, S., AND MERMELSTEIN, R., Fundam. Appl. Toxicol. 17, 280–299. A chronic inhalation study of a test toner was conducted by exposure of groups of F-344 rats for 6 hr/day, 5 days/week for 24 months The test toner was a special Xerox 9000 type xerographic toner, enriched in respirable-sized particles compared to commercial toner, such that it was about 35% respirable according to the ACGlH criteria. The target test aerosol exposure concentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high) mg/m3. Titamum dioxide (5 mg/m3) and crystalline silicon dioxide (1 mg/m3), used as negative and pasitive controls for fibrogenicity, were also evaluated. Inhalation of the test toner or the control materials showed no signs of overt toxicity. Body weight, clinical chemistry values, food consumption, and organ weights were normal in the toner- and TiO2-exposed groups, except for a 40% increase in lung weight in the toner highexposure group. All of the changes in the toner-exposed groups were restricted to the lungs or associated lymph nodes. A chronic inflammatory response was evident from the bronchoalveolar lavage parameters for the toner high-exposure group. The incidence of primary lung tumors was comparable among the three toner-exposed groups and the TiO2-exposed, and air-only controls, as well as consistent with historical background levels A mild to moderate degree of lung fibrosis was observed in 92% of the rats in the toner high-exposure group, and a minimal to mild degree of fibrosis was noted in 22% of the animals in the toner high-exposure group. The pulmonary changes in the toner high-exposure group were smaller in magnitude than those found in the crystalline silica-exposed group. The comparative fibrogenic potency of TiO2, toner, and SiO2 was estimated to be 1:5:418 using a dasimetric model and assuming a common mechanistic basis. There were no pulmonary changes of any type at the toncr low-exposure level, which is most relevant in regard to potential human exposures The lung alterations in the toner high-exposure group are interpreted in terms of “lung overloading,” a generic response of the respiratory system to saturation of its detoxification capacity. The maximum tolerated dose (MTD) criterion was met at the toner high (16 mg/m3)-exposure level.

Lung Clearance and Retention of Toner, Utilizing a Tracer Technique, during Chronic Inhalation Exposure in Rats. Bellmann, B., Muhle, H., Creutzenberg, O., Dasenbrock, C., Kilpper, R., MacKenzie, J. C., Morrow, P., and Mermelstein, R. Fundum. Appl. Toxicol. 17, 300–313. Male and female F-344 rats were exposed 6 hr/day, 5 days/week for up to 24 months to a special test toner at 0, 1, 4, and 16 mg/m3, TiO2 at 5 mg/m3, or SiO2 at 1 mg/m3 by the inhalation route. 59Fe-labeled iron oxide and 85Sr-labeled polystyrene particles were periodically inhaled by the nose-only route and used to measure alveolar clearance rates during the course of the study. This method was used to describe a maximum functionally tolerated dose (MFTD). Pulmonary retention of toner and control materials (TiO2 and SiO2) was measured after 3, 9, 15, 21, and 24 months of exposure. The quantity of all three materials retained in the lungs and lung-associated lymph nodes increased with exposure duration and level. The final pulmonary burdens of toner at the three exposure levels were 0.22, 1.73, and 15.6 mg/lung, respactively. Alveolar clearana of both tracers was substantially impaired at the toner high-exposure level, and moderately slowed at the toner middle-exposure level. The excessive quantity of toner retained and the substantially retarded clearance in the toner high-exposure group are indicative of “lung overloding.” Alveolar dearance of 85Sr-polystyrene particles was slightly slowd in the TiO2-exposed group and substantmlly impaired in the SiO2-exposed group. The alveolar clearance of the unexposed rats decreased about 30% during the study, a change ascribed to aging For a general description of the toxicokinetics of the various dusts, a semiempirical kinetic model was developed, which could generally be useful for the extrapolation of lung retention of insoluble particles from a subchronic to a chronic inhalation study. Both the maximum tolerated dose (MTD) and the MFTD were exceedes at the toner high-exposure level during the study in rats.

Volume 17, Number 2 (1991), in the article “Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats,” by H. Muhle, B. Bellmann, O. Creutzenberg, C. Dasenbrock, H. Ernst, R. Kilpper, J. C. MacKenzie, P. Morrow, U. Mohr, S. Takenaka, and R. Mermelstein, pages 280–299: On page 280, the author's affiliations are incorrect as printed. For the reader's convenience, the correct affiliations are reprinted here.

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Methods for the determination of biodurability of man-made vitreous fibres are reviewed. For mineral wools the first step was the preparation of respirable fibre fractions. Fibres were administered to rats by inhalation or by intratracheal instillation. After serial sacrifice their lungs were digested by low-temperature ashing or by hypochlorite. The total number of fibres per lung and the distributions of length and diameter were analysed by electron microscopy. This resulted in a bivariate distribution of fibres at the various sacrifice dates. If the logarithm of the number of fibres decreased approximately linearly with time after exposure then the elimination kinetics of fibres can be characterized by a half-time. The half-times were compared between various experiments with rats exposed to mineral wool samples. In summary good agreement was found for the elimination of fibres after long-term inhalation and intratracheal instillation whereas shorter half-times were found after short-term inhalation.