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J Pauluhn

Publications and source records attributed to J Pauluhn.

At least 19 recordsLinked to original sources
PubMed1996

Predictive testing for respiratory sensitisation.

A rat bioassay has been developed to provide an objective approach for the identification and classification of upper and lower respiratory tract irritants, with particular emphasis on the concentration-dependent induction and regression of lesions characteristic of asthma, such as persisting non-specific airway hyperreactivity, inflammation and ensuing mismatch of the ventilation-perfusion relationship. For the identification of respiratory allergy, the established guinea-pig bioassay has been further refined. Refinement focused on procedures making this animal model more robust to changes in study design. Attempts were made to allow differentiation of non-specific and specific bronchial hyperresponsiveness and to minimise the use of hapten-protein conjugates for elicitation of respiratory allergy. It appears that the combined assessment of specific pathologic features such as airway eosinophilia and the evaluation of several breathing parameters during hapten and acetylcholine bronchoprovocation challenge make it easier to distinguish effects caused by irritation and respiratory hypersensitivity. Findings support the conclusion that current guinea-pig models require specific optimisation of sensitisation and challenge procedures for each chemical class tested.

Acetylcholine↗
PubMed1996

Risk assessment of pyrethroids following indoor use.

One notable form of toxicity associated with exposure to high concentrations of synthetic pyrethroids has been a cutaneous paresthesia. This strong excitatory action on the sense organs in the vertebrate skin and upper respiratory tract is characteristic of synthetic pyrethroids, whereas the cyano pyrethroids evoke more intense neuroexcitatory activities than the noncyano pyrethroids. Such facial sensations and irritative symptoms appear to be produced by direct stimulation of peripheral sensory nerve endings rather than by inflammatory mechanisms. Effects related to sensory irritation can be evoked by a wide variety of substances occurring in the indoor environment, and analysis of the etiopathological relationships presents difficult and complex medical and scientific issues. For the appropriate assessment of pyrethroids in the indoor environment, it would be helpful to have an objective laboratory assay to confirm and quantitate the degree of sensory irritation evoked by airborne pyrethroids. A bioassay was established using the nociceptive system of mice and rats to assess the extent of pyrethroid-related sensory irritation to the respiratory tract. For analysis, aerosolized Cyfluthrin was selected due to the greater potency of the alpha-cyano pyrethroids to evoke sensory irritation. Additionally, this pyrethroid was tested in a carpet-model to assess the extent to which pyrethroid-laden dust from carpets is likely to become airborne following continuous brushing. Comparative evaluations of the sensory irritation potential of aerosolized Cyfluthrin in mice and rats revealed that for assessment of the sensory irritant threshold concentration, rats appeared to be more susceptible than mice. Measurements performed repeatedly during subacute exposure to the pyrethroid (6 h/day, 5 days/week for 4 consecutive weeks) did not indicate any alteration in responsiveness, and the magnitude of changes in breathing patterns was similar to those observed following acute 1-h exposure. These findings confirm the conclusion that alpha-cyano-pyrethroids appear to act as "pure" sensory irritants and that the effects observed are non-cumulative and transient in nature. Concomitant respiratory tract inflammation and ensuing changes in susceptibility-common findings in chemical sensory irritants-did not occur. From the studies addressing the dislodgeability of pyrethroid containing dust from carpets, it is apparent that measurement of deposited dust is a poor substitute for airborne dust. Even under worst-case testing conditions (continuous brushing of the carpet for approximately 19 h in a bias-flow compartment), only a very small fraction of the pyrethroid laden dust particles charged to the carpet could be recovered airborne (0.04%/m2 per h). Thus, experimental findings support the conclusion that such agents cannot be dislodged from carpets to an extent that toxicologically significant airborne concentrations are attained. Therefore, assessment of health hazards in the indoor environment based solely on "vacuum cleaner" sampling is prone to a high level of errors and misjudgment.

Administration, Inhalation↗
PubMed1995

Phenyl isocyanate-induced asthma in rats following a 2-week exposure period.

This study was conducted to assess the toxic effects of repeated inhalation exposures to phenyl isocyanate vapor in male Wistar rats. Rats were exposed to design concentrations of 0, 1, 4, 7, or 10 mg/m3 phenyl isocyanate air for 2 weeks (6 hr/day, 5 days/week). The rats were assessed for normal toxicologic parameters, and pulmonary function tests, blood gas measurements, and analysis of bronchoalveolar lavage fluid (BALF) parameters were utilized shortly after exposures as well as 2 months postexposure. The results indicated that rats exposed to 7 and 10 mg/m3 experienced decreased body weights, hypoactivity, hypothermia, signs of respiratory tract irritation, delayed onset of mortality, and changes in organ weights. In addition, pulmonary function tests demonstrated decreased forced expiratory flow rates and quasistatic lung compliance. Arterial blood gases showed an arterial hypoxemia and changes consistent with a pronounced venous-admixture-like perfusion, suggesting severe mismatch of the ventilation/perfusion relationship. Delayed onset of mortality appeared to be associated with respiratory acidosis and hypoxemia. Biochemical and cellular components in BALF complemented the results of the functional alterations. Remarkable changes were indicated by increased activities of the BALF parameters, gamma-GPT, protein, and sialic acid. Histopathological findings provided evidence of increased secretory cell activity and a concentration-dependent increase in goblet cell hyperplasia at concentrations of 4 mg/m3 and above. In rats exposed to 7 mg/m3 further findings consisted of intraluminal inflammation of airways, hypertrophia of bronchial smooth muscle, epithelial desquamation, and eosinophilia of the airways. A complete regression of morphological lesions was not found in the animals exposed to 4 mg/m3 and above at the 2-month postexposure time period. In conclusion, the damage to the airways comprise most of the features characteristic of chronic airway inflammation or asthma.

Administration, Inhalation↗
PubMed1994

Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4'-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate.

Guinea-pigs were sensitized to monomeric diphenylmethane-4,4'-diisocyanate (MDI) by two intradermal injections (1-10% MDI, injection volumes of 50-100 microliters/day, on days 0, 2 and 4) or by a single brief high-concentration inhalation exposure (135 or 360 mg/m3, 15 min). Starting with day 21 following sensitization the animals were subjected to inhalation-challenge exposures (30 min) with non-irritating and irritating concentrations of the hapten (MDI). MDI-challenge concentrations ranged from 3.4 +/- 0.9 to 60 +/- 14.3 mg/m3 air. In some groups guinea-pigs were also challenged with acetylcholine (ACh) aerosol or the MDI-guinea pig serum albumin (GPSA) conjugate. Experimental findings indicated that from intradermally sensitized animals an immediate onset respiratory hypersensitivity response could only be elicited with concentrations exceeding the irritant threshold concentration for MDI, i.e. with concentrations greater than approximately 20 mg/m3 air. Guinea-pigs challenged with the MDI-GPSA conjugate (35.3 +/- 2.8 mg/m3 air) also experienced a weak immediate-type respiratory hypersensitivity response. An increased non-specific airway hyper-responsiveness following ACh-challenge was only observed from animals challenged with approximately 60 mg MDI/m3 air. The histopathological evaluation of lungs and lung-associated lymph nodes revealed an association of the increase in eosinophilic granulocytes and concentration of MDI used for challenge exposures. It appeared, in most instances, that this influx was more pronounced in animals sensitized with MDI as compared with concurrent controls challenged with the same MDI concentration. Guinea-pigs sensitized by a single 15-min inhalation exposure to either 135 or 360 mg MDI/m3 air were challenged sequentially with 12 +/- 2.1 mg MDI/m3 air, ACh and MDI-GPSA conjugate. Following the inhalation-induction, an airway hyper-responsiveness was elicited both after challenge with MDI and with the MDI-GPSA conjugate. The influx of eosinophilic granulocytes was more pronounced from animals sensitized by inhalation when compared with guinea-pigs sensitized intradermally and challenged with the same concentration of MDI. Thus, experimental findings suggest that elicitation of respiratory hypersensitivity is concentration-dependent and that challenge concentrations should slightly exceed the threshold concentration for irritation (approximately 20 mg/m3). Sensitization by inhalation increased the susceptibility to irritant stimuli and thus confounds the selection of the most appropriate concentration for challenge. However, the combined assessment of specific pathologic features such as airway eosinophilia and the evaluation of several breathing parameters during hapten- and ACh-challenge make it easier to distinguish effects caused by irritation and respiratory hypersensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1994

Respiratory allergy: hazard identification and risk assessment.

Various chemicals and proteins of industrial importance are known to cause respiratory allergy, with occupational asthma being the most important manifestation of the disease. This paper describes clinical syndromes, mechanisms associated with occupational respiratory hypersensitivity, and methods available currently for the prospective identification of potential respiratory allergens. Certain classes of chemicals are commonly associated with occupational respiratory allergy. There is insufficient information, however, to predict respiratory sensitization potential from analysis of structure alone, although reactivity with proteins is likely to be relevant. As yet there exist no fully validated or widely applied predictive methods or internationally harmonized guidelines. The most promising predictive animal methods are the mouse IgE test and guinea pig models. Work in mice has focused upon events occurring during the induction phase of sensitization following primary encounter with the test chemical. In contrast, guinea pig models have been used primarily to identify respiratory allergens (chemicals or proteins) as a function of elicitation reactions induced in previously sensitized animals. Given the possible serious health manifestations of respiratory allergy, early identification of respiratory sensitizers is urgently required. The two methods should, as a priority, be developed further and the production of a detailed protocol for these methods be undertaken to facilitate further validation. Together, this information will allow for two types of risk assessment associated with respiratory allergy: the risk that exposure to a material will (1) induce sensitization in an individual and (2) elicit allergic reactions in a previously sensitized individual.

Allergens↗
PubMed1993

Electroretinographic assessment of early retinopathy in rats.

Amoscanate, a substance which damages photoreceptors, was administered orally to Wistar rats in doses of 10, 40, and 125 mg/kg body weight once daily for 3 or 10 days. At both times electroretinographic, ophthalmological, and histopathological examinations of the retina were carried out to compare the sensitivity of conventional methods and to test electroretinography (ERG) for suitability for use in toxicity studies. Time-dependent and dose-dependent effects were found by electroretinography and light microscopy. However, signs of retinal changes appeared earlier and more distinctly in the electroretinogram. Ophthalmological fundus examination in albino rats yielded no characteristic correlate. In conclusion, electroretinography constitutes a valuable supplement to histopathology and is suitable for use in toxicity studies.

Animals↗
PubMed1992

Altered lung function in rats after subacute exposure to n-butyl isocyanate.

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m3 air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m3 died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m3 a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasi-static compliance in rats exposed to 26 mg/m3. At the end of the observation period rats exposed to 6.2 and 15 mg/m3 air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship. Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m3 group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m3.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1992

Analysis of alternative methods for determining ocular irritation.

According to classification and labelling requirements, chemicals, dyes, agrochemicals and pharmaceutical formulations have to be evaluated for their potential to induce eye irritancy or corrosion. An attempt was made to analyse the predictive power of the bovine eye-chicken egg chorioallantoic membrane (BE-CAM) assay in comparison with results obtained using the conventional Draize method. In summary, results showed limited correlation between reactions in vitro and responses of eyes in vivo. In a pilot study, ultrasonic pachymetry showed high sensitivity and fairly good correlation between corneal thickness and clinical observations in eyes.

Animals↗
PubMed1992

Modeling of toxicological effects of fire effluents: prediction of toxicity and evaluation of animal model.

Methodology for the prediction of the toxic effects of fire effluents has made considerable progress [1,2]. As emphasized by Hartzell [2] a limiting factor has often been the availability and quality of analytical input data. The Finney model [3] was used to predict the lethal potency and would appear to have utility as a tool in reducing the number of experimental animals used in material testing. However, pilot bioassay data are indispensable to validate the prediction and to categorize fire effluents into narcosis inducing, irritant or of causing unusual or unexpected toxicity. The comparison of predicted and actually observed carboxy-hemoglobin levels is considered to be a sensitive but indirect tool to assess whether major effects on respiration occurred. All laboratory combustion toxicity methods suffer from several types of limitations. However, they might be expected to be relatable to at least some stages of actual fires. Due to a lack of a clearly defined 'generation process'--if compared with conventional inhalation toxicity studies--the classification into broad categories of relative toxic potency seemed to be more appropriate than an absolute classification scheme.

Animals↗
PubMed1991

Validation of a non-invasive technique to assess immediate or delayed onset of airway hypersensitivity in guinea-pigs.

Conscious Hartley guinea-pigs were sensitized with trimellitic anhydride (TMA) or trimeric hexamethylene diisocyanate biuret (Des-N) by repeated intradermal injections or by inhalation exposure. Immediate- and delayed-onset pulmonary reactions were recorded during/after challenges with the hapten or protein conjugate of the hapten, respectively. The positive control was sensitized and challenged with ovalbumin (OA) by inhalation. Homocytotropic antibodies of the IgG1 type were determined to correlate antibody titres and pulmonary responses. Immediate-onset pulmonary reactions were apparent in guinea-pigs sensitized by inhalation of TMA and OA. Animals sensitized intradermally with TMA demonstrated more vigorous immediate-onset reactions than animals sensitized by inhalation. The measurement of breathing parameters demonstrated that the ability to detect immediate-onset airway hyperreactivity was best when the breathing rate and tidal and minute volumes were measured. None of the measurements for delayed-onset reactions presented conclusive results, since sensitized as well as naive guinea-pigs demonstrated a delayed increase of breathing frequency. Antigen-specific IgG1 antibodies were several orders of magnitude higher in intradermally sensitized animals compared with animals sensitized by inhalation. Although Des-N-sensitized guinea-pigs experienced high IgG1-antibody titres, no response of pulmonary hypersensitivity could be elicited after hapten or conjugate challenge. In summary, it would appear that pulmonary hypersensitivity depends on factors other than IgG1 antibody titres. For the screening of chemicals, the dermal induction and inhalation challenge protocol was revealed to be more sensitive than the inhalation induction and inhalation challenge protocol.

Administration, Inhalation↗
PubMed1990

Functional, biochemical, and histopathological evidence of airway obstruction in rats following a four-hour acute inhalation exposure to n-butyl isocyanate.

Pulmonary function, arterial blood gases, acid-base status, and bronchoalveolar lavage fluid (BALF) composition were assessed in male Wistar rats after a single 4-h exposure to 0, 7.6, 23.5 or 55.2 mg n-butyl isocyanate (n-BIC)/m3 air. No significant changes other than transient clinical signs were observed in the rats exposed to 7.6 mg/m3 air. Four weeks after exposure the animals of the 55.2 mg/m3 group showed significant effects: those were pronounced histopathological changes of airways and parenchyma, and elevated relative lung weight. The neutrophils, LDH, and protein in BALF were elevated. Quasi-static lung compliance, peak expiratory flow rate, mean mid expiratory flow rate were decreased whereas lung resistance, residual volume, and single breath CO-diffusing capacity were increased. Blood gas measurements revealed an elevation in hemoglobin, pH, arterio-alveolar oxygen difference, and venous admixture. Arterial pO2 and pCO2 were decreased. In animals exposed to 23.5 mg/m3 only marginal effects were detectable.

Acid-Base Equilibrium↗
PubMed1989

A new method for long-term inhalation toxicity studies for bronchospasmolytic aerosol formulations in dogs.

In routine inhalation toxicity studies laboratory animals are exposed under dynamic exposure conditions to different steady-state concentrations of a test compound. The relevant exposure concentration is the analytically determined time-weighted average concentration in the vicinity of the breathing zone of the animals. If the intended use of a bronchospasmolytic aerosol is taken into account, a non-steady-state exposure regimen might be more appropriate. Using this approach local effects of high aerosol concentrations on the respiratory tract were investigated in dogs by daily head/nose-only exposure for 1 h for 4 weeks. Four groups of four dogs were exposed to 20, 40 and 80 bursts of a bronchodilator formulation using a modified metered dose inhaler. The analytically determined mean concentration of the active ingredient (prostaglandin) in the breathing zone was 43.1, 92.2 and 193.9 micrograms l-1 air, respectively. Maximum concentrations were determined by simulation. The aerosol was in the respirable range (mass median aerodynamic diameter approximately 1.2 microns, geometric standard deviation approximately 1.4). A kinetic model was developed to simulate the mean and maximum non-steady-state concentration for an exposure regimen of 20, 40 and 80 bursts per hour under dynamic exposure conditions. The model was based on first-order inhalation chamber kinetics. The kinetic model was validated experimentally by comparing measured mean and simulated mean concentrations. In all exposure groups the simulated maximum concentrations were ca. 80 mg of test compound (formulation) per litre of air. Plasma levels were elevated in a dose-dependent manner as evidence of the validity of the test model employed.

Administration, Inhalation↗
PubMed1988

Methodological aspects of the determination of the acute inhalation toxicity of spray-can ingredients.

Spray-can ingredients, if liberated in confined spaces, are potential health hazards for man. Thus, appropriate inhalation toxicity studies have to be performed in accordance with internationally recognized guidelines, e.g. the US Environmental Protection Agency: Federal Insecticide, Fungicide and Rodenticide Act (FIFRA no. 81-3) or OECD no. 403. One of the essential requirements of such guidelines is that test animals (preferably rats) be exposed to a steady-state concentration in a dynamic inhalation chamber for at least 4 hours. This is not easy to achieve with vapours released from a pressurized spray-can. The method described here makes it possible to expose experimental animals in an inhalation chamber to a steady-state concentration of intermittently released spray jets of constant doses per jet. Animal experiments and theoretical considerations (computer simulations) have shown that the method presented allows an up-to-date determination of the acute inhalation toxicity of spray-can ingredients.

Administration, Inhalation↗
PubMed1988

Inhalation hazard test. Interlaboratory trial with OECD method 403.

Six industrial laboratories validated the Inhalation Hazard Test (OECD Method 403) using eight volatile chemicals. The test gave similar results in all laboratories, despite variation in inhalation exposure systems and strain of rat used. Detailed atmosphere analyses are not necessary, since nominal atmosphere concentrations were close to the analysed values. The method gives reproducible results directly applicable to hazard evaluation, and is quicker and cheaper and uses fewer animals than the conventional LC50 test.

Administration, Inhalation↗
PubMed1987

Effects of inhaled cholinesterase inhibitors on bronchial tonus and on plasma and erythrocyte acetylcholine esterase activity in rats.

Young adult male and female Wistar rats were inhalationally exposed head-only for 1 or 4 h to different anticholinesterase aerosols. The compounds tested were dichlorvos, fenamiphos, methamidophos, parathion, a pyrimidine thiophosphate and the carbamate propoxur. These compounds are direct or indirect inhibitors of cholinesterase activity. Immediately after termination of exposure to the compounds, the rats were anesthetized with barbiturate and subjected to pulmonary function tests. An acetylcholine provocation test was performed to correlate the effect of the cholinesterase inhibition and lung resistance. The results basically revealed that by inhalation exposure bronchoconstriction in the absence of acetylcholine provocation did not occur at toxicologically significant doses of the pesticides. An increase in lung resistance was observed only after provocation. However, measurements of plasma cholinesterase activity proved to be more sensitive than the provocation test. With regard to their diagnostic value, the results of the reported study may be summarized as follows (beginning with the most sensitive parameter): plasma cholinesterase activity depression greater than or equal to acetylcholine-induced bronchoconstriction greater than or equal to cholinergic symptoms greater than erythrocyte cholinesterase activity depression greater than pulmonary resistance without acetylcholine provocation.

Acetylcholinesterase↗