Host factors in occupational diisocyanate asthma: a Swiss longitudinal study.

OBJECTIVE: To investigate the usefulness of surrogates for individual susceptibility to organic diisocyanates in occupational asthma. SUBJECTS: All new cases declared to the Swiss National Accident Insurance Company (SUVA) for establishment of a case for compensable occupational disease during 1993. Sixty-nine persons, of whom three were women, were suspected of having occupational asthma due to isocyanates. Of these, 47 subjects fulfilled the criteria to be accepted as an occupational disease case. METHODS: All subjects were studied clinically and gave a blood sample for the phenotyping of their alpha-antitrypsin status and for immunological studies. The subjects were also given a peroral dose of caffeine for the determination of their N-acetylation capacity. Finally, those with an occupational disease were subjected to the methacholine provocation test. RESULTS: Forty-four persons with occupational disease, out of 47, were heterozygous antitrypsin carriers and/or slow acetylators of primary amines. In the bronchial provocation with methacholine, 12 of these subjects had an unaltered response and seven had a mild reaction, 13 a moderate one and 15 a severe reaction. INTERPRETATION: The study confirms the finding that slow N-acetylators are susceptible to asthma from exposure to common diisocyanate monomers at work. The same applies to heterozygous antitrypsin-phenotype carriers. Thus, the use of these markers may reinforce the diagnostic procedure, but they cannot completely replace the immunological tests.

Mutations that reduce sinapoylmalate accumulation in Arabidopsis thaliana define loci with diverse roles in phenylpropanoid metabolism.

The products of phenylpropanoid metabolism in Arabidopsis include the three fluorescent sinapate esters sinapoylglucose, sinapoylmalate, and sinapoylcholine. The sinapoylmalate that accumulates in cotyledons and leaves causes these organs to appear blue-green under ultraviolet (UV) illumination. To find novel genes acting in phenylpropanoid metabolism, Arabidopsis seedlings were screened under UV for altered fluorescence phenotypes caused by changes in sinapoylmalate content. This screen identified recessive mutations at four Reduced Epidermal Fluorescence (REF) loci that reduced leaf sinapoylmalate content. Further analyses showed that the ref mutations affected other aspects of phenylpropanoid metabolism and some led to perturbations in normal plant development. A second class of mutations at the Bright Trichomes 1 (BRT1) locus leads to modest reductions in sinapate ester content; however, the most notable phenotype of brt1 mutants is the development of hyperfluorescent trichomes that appear to contain elevated levels of sinapate esters when compared to the wild type. These results indicate that at least five new loci affecting the developmentally regulated accumulation of phenylpropanoid secondary metabolites in Arabidopsis, and the cell specificity of their distribution, have been identified by screening for altered UV fluorescence phenotypes.

Cloning of the SNG1 gene of Arabidopsis reveals a role for a serine carboxypeptidase-like protein as an acyltransferase in secondary metabolism.

Serine carboxypeptidases contain a conserved catalytic triad of serine, histidine, and aspartic acid active-site residues. These enzymes cleave the peptide bond between the penultimate and C-terminal amino acid residues of their protein or peptide substrates. The Arabidopsis Genome Initiative has revealed that the Arabidopsis genome encodes numerous proteins with homology to serine carboxypeptidases. Although many of these proteins may be involved in protein turnover or processing, the role of virtually all of these serine carboxypeptidase-like (SCPL) proteins in plant metabolism is unknown. We previously identified an Arabidopsis mutant, sng1 (sinapoylglucose accumulator 1), that is defective in synthesis of sinapoylmalate, one of the major phenylpropanoid secondary metabolites accumulated by Arabidopsis and some other members of the Brassicaceae. We have cloned the gene that is defective in sng1 and have found that it encodes a SCPL protein. Expression of SNG1 in Escherichia coli demonstrates that it encodes sinapoylglucose:malate sinapoyltransferase, an enzyme that catalyzes a transesterification instead of functioning like a hydrolase, as do the other carboxypeptidases. This finding suggests that SCPL proteins have acquired novel functions in plant metabolism and provides an insight into the evolution of secondary metabolic pathways in plants.

[Work capacity in the cae of pulmonary diseases]. / Capacité de travail en cas d'affections pulmonaires.

This short review begins by defining some basic medico-legal concepts such as "impairment" and "disability" and gives the corresponding terms in French and German. It is then shown how, in stable obstructive and restrictive respiratory diseases such as COPD and lung fibrosis, the degree of impairment can be assessed on the basis of FEV1 and indices of gas exchange. In the case of bronchial asthma, however, with its typically variable degree of airflow limitation, the amount of reversibility and treatment necessary to achieve optimum bronchodilatation must be taken into account. This can best be done using a score system. Impairment represents a base but in no way equals the final percentage of disability pension or compensation, which are always assessed by the competent administrative authority. However, it is the physician who specifies the amount and type of work an individual patient, with his or her particular degree of disability, can or cannot be expected to do.

Regulation of ferulate-5-hydroxylase expression in Arabidopsis in the context of sinapate ester biosynthesis.

Sinapic acid is an intermediate in syringyl lignin biosynthesis in angiosperms, and in some taxa serves as a precursor for soluble secondary metabolites. The biosynthesis and accumulation of the sinapate esters sinapoylglucose, sinapoylmalate, and sinapoylcholine are developmentally regulated in Arabidopsis and other members of the Brassicaceae. The FAH1 locus of Arabidopsis encodes the enzyme ferulate-5-hydroxylase (F5H), which catalyzes the rate-limiting step in syringyl lignin biosynthesis and is required for the production of sinapate esters. Here we show that F5H expression parallels sinapate ester accumulation in developing siliques and seedlings, but is not rate limiting for their biosynthesis. RNA gel-blot analysis indicated that the tissue-specific and developmentally regulated expression of F5H mRNA is distinct from that of other phenylpropanoid genes. Efforts to identify constructs capable of complementing the sinapate ester-deficient phenotype of fah1 mutants demonstrated that F5H expression in leaves is dependent on sequences 3' of the F5H coding region. In contrast, the positive regulatory function of the downstream region is not required for F5H transcript or sinapoylcholine accumulation in embryos.

The TIR1 protein of Arabidopsis functions in auxin response and is related to human SKP2 and yeast grr1p.

Genetic analysis in Arabidopsis has led to the identification of several genes that are required for auxin response. One of these genes, AXR1, encodes a protein related to yeast Aos1p, a protein that functions to activate the ubiquitin-related protein Smt3p. Here we report the identification of a new gene called TRANSPORT INHIBITOR RESPONSE 1 (TIR1). The tir1 mutants are deficient in a variety of auxin-regulated growth processes including hypocotyl elongation and lateral root formation. These results indicate that TIR1 is also required for normal response to auxin. Further, mutations in TIR1 display a synergistic interaction with mutations in AXR1, suggesting that the two genes function in overlapping pathways. The TIR1 protein contains a series of leucine-rich repeats and a recently identified motif called an F box. Sequence comparisons indicate that TIR1 is related to the yeast protein Grr1p and the human protein SKP2. Because Grr1p and other F-box proteins have been implicated in ubiquitin-mediated processes, we speculate that auxin response depends on the modification of a key regulatory protein(s) by ubiquitin or a ubiquitin-related protein.

Reduced naphthylphthalamic acid binding in the tir3 mutant of Arabidopsis is associated with a reduction in polar auxin transport and diverse morphological defects.

Polar auxin transport plays a key role in the regulation of plant growth and development. To identify genes involved in this process, we have developed a genetic procedure to screen for mutants of Arabidopsis that are altered in their response to auxin transport inhibitors. We recovered a total of 16 independent mutants that defined seven genes, called TRANSPORT INHIBITOR RESPONSE (TIR) genes. Recessive mutations in one of these genes, TIR3, result in altered responses to transport inhibitors, a reduction in polar auxin transport, and a variety of morphological defects that can be ascribed to changes in indole-3-acetic acid distribution. Most dramatically, tir3 seedlings are strongly deficient in lateral root production, a process that is known to depend on polar auxin transport from the shoot into the root. In addition, tir3 plants display a reduction in apical dominance as well as decreased elongation of siliques, pedicels, roots, and the inflorescence. Biochemical studies indicate that tir3 plants have a reduced number of N-1-naphthylphthalamic (NPA) binding sites, suggesting that the TIR3 gene is required for expression, localization, or stabilization of the NPA binding protein (NBP). Alternatively, the TIR3 gene may encode the NBP. Because the tir3 mutants have a substantial defect in NPA binding, their phenotype provides genetic evidence for a role for the NBP in plant growth and development.

[Are artificial mineral fibers harmful to health and unsuitable for asbestos substitute?]. / Sind künstliche Mineralfasern gesundheitsschädigend und untauglich als Asbestersatz?

The increasing knowledge about the carcinogenic properties of asbestos have given rise to an extensive research on possible adverse health effects of alternative materials. Especially man-made mineral fibers (MMMF), i.e. glass fibers, but also glass-, stone- and slag wools turned out to be of unique interest, because they have already been used for several decades for isolation purposes. It is generally accepted that the carcinogenic potential of any fiber is related to its dimension and its biopersistence. Based on series of experiments, it could be demonstrated that only fibers longer than 5 microns, thinner than 3 microns and with a length/diameter ratio of more than 3 are able to reach the periphery of the lung. Excepting the refractory (ceramic) fibers, studies showed that inhalation did not provoke tumors in rodents, whereas the intratracheal, intrapleural and intraperitoneal instillation induced a carcinogenic effect for most kinds of MMMF. Compared to asbestos, MMMF clears out much faster from the lung tissue. Finally, there is no consistent epidemiological evidence for an increased standardized mortality ratio due to malignant tumors of the airways and malignant mesotheliomas in individuals formerly exposed to MMMF. Out of the rather theoretical tumor risk, there is a far more common and itchy skin problem to mention, namely glass-fiber dermatitis, which appears when one is handling without protection thicker and therefore more stinging fibers. In the light of these facts and based on the actual exposure situation, there is no clearcut cancer risk, when one is handling glass fibers and wool; however, the potential risk of exposure to refractory ceramic fibers has to be evaluated with more caution.

Airborne irritant contact dermatitis from metal dust adhering to semisynthetic working suits.

2 workers at an aircraft factory were employed in a plasma sparying unit. Soon after they were equipped with new semisynthetic working suits, they started to complain of pruritic eruptions after heavy exposure to metal dust. They noted that the dust was not as easily blown off the clothes by pressurized air as previously. Clinical findings consisted of discrete macular and papular lesions, partly follicular, on the ventral and medial thighs. Atopy score, IgE level and a standard series of prick tests ruled out atopic disposition. Patch tests revealed no reactions. A diagnosis of occupational airborne irritant contact dermatitis from metal dust was therefore made. To elucidate the role of the working suit, extensive physical investigations of the physical properties of the textile were performed. Microscopic pictures at low magnification showed more dust particles on the semisynthetic working suit, compared to the former pure cotton suit. This impression could not be confirmed by particle count because of too uneven particle distribution at higher magnification. Hairiness of the 2 textiles was low and ruled out irritation by the semisynthetic textile itself. No difference in electrostatic properties between the 2 working suits could be established either. Both textiles showed high static electrical propensity. When use of the semisynthetic overall was discontinued, the patients reported no recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

[Lung disorders due to metals]. / Lungenschäden durch Metalle.

Though metals represent the largest group of elements they rather rarely cause respiratory diseases. This article will therefore review the most important ones caused by inhaled dusts of metals and some of their inorganic compounds, but leaving aside silicosis and silicatosis as well as iatrogenically induced metal pneumopathies. Among toxic inflammatory diseases metal fume fever, an influenza-like condition caused by zinc oxide, ranks as the commonest. Activities such as oxi-acetylene cutting and welding of zinc covered metal pieces account for about 90% of all cases compensated in Switzerland. Due to the non-recurrent character of this type of work, the typical waning of symptoms while exposure is going on has become seldom. Toxic pneumonia caused by inhaled metal fumes occurs rather seldom. However, serious cases have been reported where soldiers were exposed to zinc chloride from smoke bombs. The existence and extent of chronic airflow limitation due to occupational exposure to metallic dusts have not been widely examined but are to be assumed when there is poor occupational hygiene. Concerning asthma, there are at least four metals and several of their compounds which have been proven to cause variable airway narrowing, namely chromium, nickel, platinum and cobalt (the latter as hardmetal). Platinum complex salts (chloro-compounds) are very potent sensitizers leading to a notable prevalence of asthma among exposed workforces. Nevertheless, there have been no such cases in Switzerland for more than ten years. Hard-metal not only causes asthma but also an alveolitis-like interstitial lung disease progressing to fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Narcotic gas burden of personnel in pediatric anesthesia]. / Narkosegasbelastung des Personals in der Kinderanästhesie.

METHODS: To assess the occupational exposure of the anaesthetist to anaesthetic gases, a total of 1 German and 25 Swiss hospitals were investigated. A Brüel & Kjaer Type 1302 multi-gas monitor was used to measure concentrations of nitrous oxide and halogenated anaesthetic agents in the anaesthetist's breathing zone. Measurements were performed during 114 general anaesthetic, 55 of which were in patients under 11 years of age. In these 55 patients, the influence of various factors on the exposure (time-weighted average concentrations) was estimated by comparing different data groups. The efficiency of the applied scavenging equipment was examined by surveying the exhalation valve with a leak detector (type TIF 5600, TIF Instruments, Miami). RESULTS: Sessions with patients under 11 years of age revealed much higher anaesthetic gas exposures compared to older patients. The concentrations of nitrous oxide were on average threefold (Fig. 1), those of the halogenated anaesthetics fivefold higher (Fig. 2) for the younger patients. In 11- to 16-year-old patients the exposure level was the same as in adult patients. The measurements showed a reduction of 85% in exposure if an efficient scavenging system (i.e., no waste gas discharge to room air through the exhalation valve) or lower fresh gas flow were used (Fig. 4); 42% of the inspected scavengers were inefficient, and reduced the exposure on average by only 30%. In operating theatres with a ventilation rate of at least ten air changes per h, the measured concentrations of anaesthetic gases in the inhalation zone of the anaesthetists were reduced more than 50% compared to poorly ventilated rooms (Figs. 4 and 5). The use of tracheal intubation or laryngeal mask airway (LMA) anaesthesia resulted in a reduction of 80% in exposure compared to standard face masks if efficient scavenging was used. The exposures during sessions with inefficiently scavenged Bain coaxial systems or unscavenged semi-open delivery systems of the Jackson-Rees type were tenfold higher than with scavenged rebreathing circuit systems (Fig. 6). During anaesthesia with IV or double-mask induction, the average levels of inhalation anaesthetics were reduced by about 80% compared to inhalational induction with standard masks (Fig. 7). The anaesthetist's working technique is a very important factor that strongly influences the concentrations. Poor work practices, like lifting off the face mask with anaesthetic gas flow turned on, increased the exposure of the anaesthetist and other operating room personnel drastically, even if the other conditions (scavenger and room ventilation) were good. DISCUSSION: The exposure levels of anaesthetic gases are generally higher during anaesthesia in children up to 10 years of age than in older patients. Nevertheless, the measurements showed that exposure during paediatric anaesthesia can be kept below the recommended limit (8-h TWA in Switzerland) of 100 ppm nitrous oxide and 5 ppm halothane or 10 ppm enflurane or isoflurane. Causes of high exposures were particularly high fresh gas flows often applied without scavenging or together with inefficient scavenging devices and the high part of mask anaesthesia and inhalation induction with a loosely held mask. To achieve an effective reduction of occupational exposure, well-adjusted and maintained scavenging systems and low-leakage work practices are of primary importance. As leakage can never be completely avoided, a ventilation rate of at least ten air changes per h should be maintained in operating rooms and rooms where anaesthesia is induced to keep down concentrations of waste anaesthetic gases. High exposure during mask anaesthesia and inhalation induction can be prevented by further measures. Using a LMA instead of a standard mask reduces the exposure to the same level as endotracheal intubation.

[Smoking in the workplace]. / Rauchen am Arbeitsplatz.

Both, smoking and certain work place emissions can cause similar disorders. Among those are chronic obstructive bronchitis and--more rarely--cancer of the lung. If both risk factors are associated their relative noxious effects have sometimes to be weighed and assessed separately. As a rule the greater importance has to be attributed to smoking. Rarer and thus less known are work related noxious substances (mainly nitroglycols, carbon sulfur, carbon monoxide) that lead to or at least accelerate cardiovascular diseases. These substances can thereby interact with concomitant nicotine abuse. While it is now accepted that passive smoking in general increases the risk for cancer, investigations on the exclusive effects of passive smoking at the work place are scarce. In daily life complaints about the various molestations prevail in the working environment. These can only be resolved in mutual openness and a factual comprehension. To this end certain legal prescriptions may prove helpful. Non smoking in institutions not only furthers the working climate but cautious estimates suggest that corporations may hereby economize resources. From this latter point of view the introduction of 'no smoking rules' could thus be rewarding as well.

Pulmonary hemorrhage due to inhalation of vapor containing pyromellitic dianhydride.

Pulmonary hemorrhage due to inhalation of fumes or powders containing trimellitic anhydride (TMA) is well known. We report pulmonary hemorrhage in a young man exposed to epoxy resin vapor containing pyromellitic dianhydride (PMDA). Serum IgG antibodies to PMDA could be detected. We conclude that the pulmonary hemorrhage was mediated by a reaction to PMDA in analogy to the TMA-induced disease. We suggest that exposure to any acid anhydride should be considered a possible cause of pulmonary hemorrhage since these compounds share structural and functional similarities.

[Peak flow profile and expert testimony. The significance of peakflow self assessment for pneumological expert testimony]. / Peak-flow-Profil und Gutachten. Die Bedeutung der Peak-flow-Selbstmessung für das pneumologische Gutachten.

Quantitative assessment of pulmonary obstructive diseases, such as asthma, may be difficult because of variability of obstruction. This is particularly true with regard to expert evidence pulmonary physicians deliver to insurances. Severity of obstruction, degree of impairment by an obstructive ventilatory defect, and temporal relationship of bronchial obstruction to exposure, may not be detected by physiological measurements in the pulmonary function laboratory. Much of the expert's opinion on these matters will depend on the credibility he assigns to the insured individual. The insured individual, in the other hand, has no other proof available than the description of his complaints, which puts him at a disadvantage. Serial peak flow measurements can be instrumental in clarifying such issues. They add an objective dimension to the case history. Six cases in which expert evidence was commissioned by insurances are described in detail, to exemplify how the thinking of the experts was modified by peak flow profiles. The greater usefulness of serial peak flow measurements in occupational asthma is emphasized and problems that may arise with peak flow measurements are discussed.

[Silo filler's syndrome]. / Siloentladersyndrom.

In 1975 an acute febrile bronchopulmonary illness after massive inhalation of fungal spores in silos was described as "pulmonary mycotoxicosis". Subsequently the disorder was referred to as "silo unloader's syndrome" or as a special form of "organic dust toxic syndrome" (ODTS). In this article the three cases of silo unloader's syndrome recognized by the Swiss National Accident Insurance Company (SUVA) between 1978 and 1989 as being an occupational disease are described. Two of the three patients with ODTS were wrongly diagnosed as suffering from allergic alveolitis and a change of occupation was proposed. Therefore, it is important to recognize ODTS in order to avoid unnecessary treatment and a change of occupation. ODTS can be prevented by technical measures such as prevention of mould formation and, in the case of exposure to fungal spores, use of an adequate breathing mask or a powered dust respirator helmet.

[Occupational asthma]. / Berufsasthma.

The recognition of bronchial asthma as occupational disease is essentially a matter of legislation and not of medical definitions. Swiss law accepts an occupational nature of asthma when its causes derive to more than 50% from the work place. Causes are extremely diverse, whereby in Europe flour (bakers) and isocyanates (spray lacquers) dominate. Together, these causative agents contribute close to 50% of all cases of occupational asthma. The clinical picture is that of classic bronchial asthma. Peculiarities are seen only regarding the temporal dependence between exposition and beginning of airway obstruction. Regarding diagnosis of occupational asthma the following questions should be answered. 1. Is the dyspnea described by the patient real bronchial asthma? 2. Is there a documented temporal connection between exposition and complaints? 3. Is there a causative agent at the work place? Peak-flow measurements are particularly useful for documentation of connection of symptoms with occupation. They demand, however, a certain degree of cooperation by the patient. The prime therapeutic measure is avoidance of further contacts with the responsible agent. The Swiss health authorities (SUVA) have the power to issue decisions of unsuitability for certain workplaces or exposures. Such a measure is however severe and requires therefore a careful diagnosis and an evaluation of risk and benefit for the patient.

[Isocyanate-induced respiratory tract diseases in Switzerland]. / Isocyanatbedingte Atemwegserkrankungen in der Schweiz.

From 1980 to 1986 the Swiss National Accident Insurance Company (SUVA) recognized isocyanate-induced airway diseases as an occupational illness in 245 cases, which are presented retrospectively. Since isocyanates are widely used they are found at a large variety of workplaces. At present, isocyanates are the most frequent cause of occupational asthma in the Swiss industrial field. After complete avoidance of any further exposure respiratory symptoms persisted or airway obstruction could still be documented in one third of patients. An unfavourable prognosis is significantly associated with the following factors: (1) bronchial obstruction (FEVl/VC) at first pulmonary function test; (2) RAST positive for isocyanates; (3) long latency period between onset of symptoms and end of exposure. Therefore, individuals with isocyanate-induced airway diseases must be immediately removed from any further exposure to these substances.

[Occupationally-induced pneumopathies]. / Berufsbedingte Pneumopathien.

Today chronic obstructive airways diseases rank amongst the most important occupational pneumopathies in Switzerland. As far as asthma is concerned, the baker's (flour) and the spray painter's (Isocyanates) types are the most important. Despite their frequent occurrence the two forms of asthma seem to differ in their pathogenetic mechanisms. Due to technical precautions another type of occupational pneumopathology namely pneumoconiosis was considerably reduced. Among asbestos induced diseases the cases of asbestosis are decreasing. However, there still are quite a lot of events of malignant mesotheliomas actually heading the list of occupational malignomas. The most numerous asbestos induced disturbances, however, are pleural plaques which seem to be of no considerable importance. Another group of occupational lung disorders is that of hypersensitivity pneumonitis (extrinsic allergic alveolitis), among which the "farmer's lung" and in more industrial settings the "humidifier lung" are most frequently seen. For the diagnosis and evaluation of occupational pneumopathies work related symptoms and individual work place exposure are of decisive importance.

Smoking pattern of smokers with and without tobacco-smoke-related lung diseases.

The number of cigarettes smoked, the duration of the smoking habit, and the tar content of the smoke influence the occurrence of tobacco-smoke-related lung diseases, as may also patterns of smoke inhalation. We therefore determined the smoking pattern, especially the time relation between cigarette puff and inhalation, in smokers with and without tobacco-smoke-related lung diseases. On the basis of clinical and radiologic findings as well as pulmonary function tests, 91 smokers were classified as smokers without lung disease, with small airway disease, with simple chronic bronchitis, with obstructive bronchitis, with pulmonary emphysema, and with lung cancer. Smoking and breathing patterns were recorded, using a smoke-flow machine and a strain-gauge belt while the subject smoked a cigarette. Blood levels of COHb were determined before and after smoking. Of the smoking characteristics assessed, puff-inhalation time, puff peak pressure, and the venous difference in COHb level before and after smoking varied significantly among the smoker groups. Puff-inhalation time, reflecting the duration of smoke retention in the mouth, was only 0.08 s (i.e., practically zero) in smokers with pulmonary emphysema and differed significantly from the time in the other groups. This puffing characteristic may be the consequence or the cause of emphysema. If the latter is true, smokers with emphysema may perhaps lack the acute airway response to smoke inhalation that normally protects most smokers from immediately inhaling tobacco smoke.