Nonparalytic poliomyelitis in Lyme borreliosis.
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Child↗
Biomedical subjects
H Muhle
Publications and source records attributed to H Muhle.
Classification of man-made vitreous fibers: Comments on the revaluation by an IARC working group.
In 2001, an IARC working group revaluated the carcinogenic risks of man-made vitreous fibers (MMVF). Compared with the IARC evaluation in 1987, the overall evaluations of insulation glass wool, rock (stone) wool, and slag wool were changed from Group 2B to Group 3. These changes ensued from an alteration in the evidence for cancer in humans and in experimental animals: Instead of "sufficient," the evidence for cancer in experimental animals is now looked upon as "limited" if there is a carcinogenic response after intraperitoneal injection but not after recently conducted inhalation experiments. For these studies, it is argued that they did properly address the technological limitations of earlier inhalation experiments. For Maxim and McConnell [Maxim L.D., McConnell E.E., 2001. Interspecies comparisons of the toxicity of asbestos and synthetic vitreous fibers: a weight-of-the-evidence approach. Regul. Toxicol. Pharmacol. 33, 319-342], well-conducted inhalation studies are very sensitive and rats may be more sensitive than humans in detecting the carcinogenic potential of MMVF. However, their arguments are highly questionable. The explanations of the IARC working group for preferring the newer inhalation studies are not sufficiently supported by the published data. Having in mind the higher sensitivity of humans compared to rats after inhalation of asbestos, more emphasis should have been given to the carcinogenic response after intraperitoneal injection.
Animals↗
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.
Air Pollutants, Occupational↗
Inhalation toxicity of mineral particles: critical appraisal of endpoints and study design.
Many of the mineral particles that are of concern in regard to lung toxicity are poorly soluble particles (PSPs). They include biopersistent mineral fibers and dusts containing crystalline silica. The preparation of well-defined test particles of respirable size range and their characterization are an essential step that may require more time and effort than the toxicity study itself. For toxicity studies with mineral particles, an investigation of the toxicokinetics is recommended. Such an investigation will yield information that will help to interpret the results if dust overload conditions occur. For mineral particles such as crystalline silica and mineral fibers, an important endpoint is their potential carcinogenicity. The following parameters are important for the design of chronic toxicity studies, and for the prediction of severe chronic effects: lung retention of inhaled materials for assessing the accumulation of particles, persistent inflammation in lungs, persistent proliferation of epithelial lung cells, progressive fibrogenicity, and genotoxicity in the lung cells. These endpoints should indicate whether the materials investigated are of concern in the health effects on exposed humans, and in the effects of the mineral particles for which chronic studies may be required. In addition, this paper focuses on the effects of PSPs combined with fibers, and on the strategies for investigating the potential carcinogenicity of quartz-containing dusts.
Administration, Inhalation↗
Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects.
We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset holocarboxylase synthetase (HCS, gene symbol HLCS) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype-phenotype correlation that unequivocally exists in HCS deficiency.
Age of Onset↗
The mitochondrial nad2 gene as a novel marker locus for phylogenetic analysis of early land plants: a comparative analysis in mosses.
The mitochondrial nad2 gene is established as a novel marker locus for phylogenetic analyses among early land plants. The potential of this gene for phylogenetic resolution was checked with a broad taxon sampling of 42 mosses (Bryopsida, including the enigmatic genus Takakia) to allow both a comparative analysis with the recently explored nad5 gene and the fusion of independent data sets. The mitochondrial gene sequences provide valuable phylogenetic information on the relationships of classically defined orders and their respective monophylies. The more rapidly diverging sequences of a group I intron in nad5 and of a group II intron in nad2 add information for fine resolution. Although both genes provide phylogenetic information in the same taxonomic range (above family level), the combined sequence alignment results in an approximate doubling in the number of nodes with significant bootstrap support (>90). According to our data, Buxbaumiales are a paraphyletic taxon in a key position between the earliest branching taxa (Sphagnales, Takakiales, Andreaeales, Polytrichales, and Tetraphidales) and all other orders, possibly to be placed in the subclass Bryidae. A dichotomy in the latter recalls two previously suggested superorders Hypnanae and Dicrananae. Both genes independently question the monophyly of the orders Dicranales and Neckerales and reject the inclusion of the genera Schistostega, Timmia, and Encalypta among Eubryales.
Bryopsida↗
Chronic pulmonary effects of respirable methylene diphenyl diisocyanate (MDI) aerosol in rats: combination of findings from two bioassays.
Two independent bioassays are available which have examined the potential carcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate (MDI) following long-term inhalation exposure in rats. These studies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the histopathological findings. This paper presents a definitive overview ofthe pulmonary toxicity of MDI developed following a thorough review of both investigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was conducted by an independent reviewing pathologist. This included the re-examination of the original lung slides, supported by an analysis of the exposure regimens, the results of which were used to develop an accurate profile of the doses received by the animals in the two studies. Histopathological findings were then combined with this information to give an overall dose-response curve for both studies as a whole. The range of total inhalation exposures to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m3. Major pulmonary effects included increased lung weights together with bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicating a very similar qualitative response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the studies were considered as a whole a reasonable overall dose-response relationship was apparent for major lung lesions. Lung tumours (in low incidences) only occurred at the highest dose level in both studies (17,575 and 17,728 mgh/m3). For inflammatory and other non-neoplastic pulmonary changes, the lowest dose examined (559 mgh/m3) was regarded as a no-observed-adverse-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for human risk assessment of MDI.
Adenoma↗
Pacifigorgianes and tamariscene as constituents of Frullania tamarisci and Valeriana officinalis.
The sesquiterpenoid constituents of the essential oils from the liverworts Frullania tamarisci, Frullania fragilifolia and of the angiosperm Valeriana officinalis were investigated. Tamariscene, a compound with a new sesquiterpene skeleton, valerena-4,7(11)-diene and five new pacifigorgiadienes, namely pacifigorgia-1,10-diene, pacifigorgia-1(6),10-diene, pacifigorgia-1(9),10-diene, pacifigorgia-2,10-diene, and pacifigorgia-2(10),11-diene were isolated and identified. Structure elucidation was carried out by NMR spectroscopy and chemical correlations to establish absolute configurations. Compounds present in both the essential oils of the Frullania species and Valeriana officinalis were enantiomeric to each other. A plausible biogenetic relationship between the pacifigorgiane, valerenane and tamariscane skeletons is postulated. Pacifigorgia-6,11-diene, not yet detected in nature, was generated by dehydration and rearrangement of natural (-)-tamariscol.
Magnetic Resonance Spectroscopy↗
Volatile constituents in mosses (Musci).
The essential oils of mosses of the genera Mnium, Plagiomnium, Homalia, Plagiothecium and Taxiphyllum (Musci) have been investigated by gas chromatography and mass spectrometry. The new sesquiterpenes (+)-10-epi-muurola-4,11-diene and 10,11-dihxdro-alpha-cuparenone were isolated by preparative gas chromatography and identified as major constituents of the hydrodistillation products of Mnium hornmum (Hedw.) using NMR and mass spectrometry. In addition, (+)-dauca-8,11-diene and two new butenolides, 3,4,5-trimethyl-5-pentyl-5H-furan-2-one and 3.4-dimethyl-5-pentyl-5H-furan-2-one were identified as constituents in Plagiomnium undulatum (Hedw.) T. Kop. Although the amounts of volatiles present in the investigated mosses are generally smaller than in liverworts, the spectrum of terpenoid compounds is similar. The investigated mosses also generate aliphatic compounds of greater abundance and structural variety.
Bryopsida↗
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.
Administration, Inhalation↗
Asbestos as reference material for fibre-induced cancer.
The objective of this paper is to review published data on the carcinogenicity of asbestos fibres with regard to the elucidation of a potential risk originating from exposure to man-made vitreous fibres (MMVF). Steps in the comparison of the two fibre classes are characterization of the fibres, pulmonary deposition, biodurability and biopersistence and a review of the cancer risk from asbestos fibres after inhalation in rats and humans. Various dust samples of chrysotile, crocidolite, and amosite were used as reference materials in studies with experimental animals. These fibres are normally thinner and shorter than MMVF. These differences in dimensions cause differences in the deposition in the airways. In addition, significant dissimilarities exist in the deposition pattern between rats and humans. Data from biopersistence studies show that focusing only on fibres longer than 20 microm and using weighted half-time for a characterization of risk may be misleading. Inhalation experiments with rats need fibre exposure concentrations over 100 times higher to match the lung cancer risk of asbestos workers, and about 1,000 times higher to reach the same mesothelioma risk. Also, the striking difference between the low lung burden of amphibole fibres of asbestos workers with mesothelioma and the more than 1,000 times higher lung burden of rats with a low mesothelioma risk demonstrates the low sensitivity of the inhalation test model for the carcinogenic potency even of crocidolite fibres. It can be concluded that the rat inhalation model is also not sensitive enough to predict the cancer risk of other fibre types for humans.
Adult↗
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.
Aerosols↗
Modulation of MAO activity by imidazoline and guanidine derivatives.
I2-binding sites (I2-BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects 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 microM) 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 microM). Substances with the highest inhibitory effects were BDF8082 (IC50 = 1.7 microM) and 2-(2-benzofuranyl)-2-imidazoline (BFI; IC50 = 4.0 microM). 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 microM), whereas its precursor, L-arginine, and its metabolite, putrescine, had no effects. In vitro inhibition 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 vivo was 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 I2 selective imidazoline ligands confirm the existence of I2-BS as a regulatory site on MAO.
Animals↗
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.
Administration, Inhalation↗
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.
Administration, Inhalation↗
Biopersistence of man-made vitreous fibres.
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.
Animals↗
Investigation on the biodurability of chemically different stone wool fibres.
The biodurability is one of the essential factors for a carcinogenic potential of mineral fibres. The in vivo solubility of commercial fibre products can be influenced by modifications of the chemical composition. Two types of experimental stone wool samples with new chemical composition were compared to a commercial stone wool sample. Sized fractions of these samples with median lengths of 7.1, 9.3 and 6.7 microns, respectively, and median diameters of 0.76, 1.02 and 0.63 microns, respectively, were intratracheally instilled into female Wistar rats with a single dose of 2 mg in 0.3 ml. 5 animals per group were sacrificed after 2 days, 1, 3, 6, 12 and 18 months. After low-temperature ashing of the lungs about 1,000 fibres per group and sacrifice date were analysed in SEM for length and diameter. The number of fibres in the total lung was calculated. An analysis of fibre number of different length and diameter fractions was used to estimate whether dissolution, breakage or mechanical clearance is responsible for the elimination of fibres from the lung. Results indicate that the breakage of fibres with length above 20 microns and the dissolution of fibres was faster in the experimental stone wool samples compared to the commercial sample.
Animals↗
Phagocytosis and chemotaxis of rat alveolar macrophages after a combined or separate exposure to ozone and carbon black.
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.
Administration, Inhalation↗