Respiratory effects of a synthetic metalworking fluid and its components

 A synthetic metalworking fluid, MWF “A”, and its major components were evaluated using a previously developed mouse bioassay. This fluid and its components evoked sensory (S) and pulmonary (P) irritation in mice. For MWF “A” and each of its components, a concentration-response relationship was developed on the basis of respiratory frequency (f_R) responses. From such relationships, the concentration capable of evoking a 50% decrease in mean f_R was determined for MWF “A” and each component (RD₅₀). RD₅₀S or RD₅₀P was used to distinguish decreases in f_R that were due to sensory irritation (S) from those due to pulmonary irritation (P). From RD₅₀P values, it was concluded that the fatty acid alkanolamide condensates, tolutriazole, and triazine-type biocide components were similar in potency to one another and similar in potency to MWF “A”. By examining potency and fractional composition, it was concluded that the fatty acid alkanolamide condensates and the triazine-type biocide largely contributed to the irritancy of MWF “A”. From RD₅₀P values, occupational exposure limits were proposed for MWF “A” and each of its components. The current Threshold Limit Value of 10 mg/m³ established by the American Conference of Governmental Industrial Hygienists for “particulates not otherwise classified” (PNOC) would be inadequate to protect workers from the irritating properties of MWF “A” and most of its components. Received: 16 March 1995 / Accepted: 21 August 1995     

Acute airway irritation of methyl formate in mice

Methyl formate (MF) is a volatile solvent with several industrial applications. The acute airway effects of MF were evaluated in a mouse bioassay, allowing the assessment of sensory irritation of the upper airways, airflow limitation of the conducting airways and deep lung (pulmonary) irritation. MF was studied at vapour concentrations of 202–1,168 ppm. Sensory irritation was the only effect observed, which developed slowly over the 30-min exposure period. The potency at steady state was at least 10-fold higher than expected from a hypothetically similar, but non-reactive compound. Methyl formate may be hydrolysed in vivo to formic acid, a potent sensory irritant, and methanol, a low-potent sensory irritant. Hydrolysis may be catalysed by carboxyesterases, and therefore, the role of the esterases was studied using the esterase inhibitor tri-ortho-cresyl phosphate (TOCP). TOCP pre-treatment reduced the irritation response of MF, suggesting that carboxyesterase-mediated hydrolysis plays a role in the irritative effect. However, even after administration of TOCP, MF was considerably more irritating than expected from a quantitative structure–activity relationship (QSAR) model. The slope of the concentration–effect relationship for formic acid was lower than that for the MF in the low-dose range, suggesting that different receptor activation mechanisms may occur, which may include an effect of MF itself, in addition to an effect of formic acid and potentially an effect from formaldehyde.     

Computer-based bioassay for evaluation of sensory irritation of airborne chemicals and its limit of detection

We expanded a previously described rule-based computerized method to recognize the sensory irritating effect of airborne chemicals. Using 2-chlorobenzylchloride (CBC) as a sensory irritant, characteristic modifications of the normal breathing pattern of exposed mice were evaluated by measuring the duration of braking (TB) after inspiration and the resulting decrease in breathing frequency. From the measurement of TB, each breath was then classified as normal (N) or sensory irritation (S). Using increasing exposure concentrations, the classification S increased from ≤2% (equivalent to sham-exposure) to 100% within a narrow exposure concentration range. The potency of CBC was then evaluated by calculating the concentration necessary to produce 50% of the breaths classified as S, i.e., S₅₀. This approach is easier to use than obtaining RD₅₀ (decrease in respiratory frequency by 50%) when high exposure concentrations are difficult to achieve. Detection limits were also established for this bioassay and experiments were conducted to obtain a level of response just around these limits, in order to delineate the practicality of using this bioassay at low exposure concentrations. Using this approach, sensory irritation was the only effect induced by CBC at low exposure concentrations. However, bronchoconstriction and pulmonary irritation were superimposed on this effect at higher exposure concentrations. Received: 9 December 1997 / Accepted: 6 January 1997     

Skin absorption of six performance amines used in metalworking fluids

Every year, 10 million workers are exposed to metalworking fluids (MWFs) that may be toxic. There are four types of MWFs: neat oils and three water‐based MWFs (soluble oil, semisynthetic and synthetic), which are diluted with water and whose composition varies according to the mineral oils ratio. MWFs also contain various additives. To determine the absorption of six amines used as corrosion inhibitors and biocides in MWFs, porcine skin flow‐through diffusion cell experiments were conducted with hydrophilic ethanolamines (mono‐, di‐ and triethanolamine, MEA, DEA and TEA respectively) and a mixture of lipophilic amines (dibutylethanolamine, dicyclohexylamine and diphenylamine). The six amines were dosed in four vehicles (water and three generic water‐based MWF formulations) and analyzed using a scintillation counter or gas chromatography/mass spectrometry. These 24 h studies showed that dermal absorption significantly (P < 0.05) increased from water for the six amines (e.g. 1.15 ± 0.29% dose; DEA in water) compared to other formulations (e.g. 0.13 ± 0.01% dose; DEA in semisynthetic MWF) and absorption was greatest for dibutylethanolamine in all the formulations. The soluble oil formulation tended to increase the dermal absorption of the hydrophilic amines. The permeability coefficient was significantly higher (P < 0.05) with TEA relative to the other hydrophilic amines (e.g. 4.22 × 10^–4 ± 0.53 × 10^–4 cm h^–1 [TEA in synthetic MWF] vs. 1.23 × 10^–4 ± 0.10 × 10^–4 cm h^–1 [MEA in synthetic MWF]), except for MEA in soluble oil formulation. Future research will confirm these findings in an in vivo pig model along with dermatotoxicity studies. These results should help MWF industries choose safer additives for their formulations to protect the health of metalworkers. Copyright © 2014 John Wiley & Sons, Ltd.     

DERMAL AND SYSTEMIC TOXICITY AFTER APPLICATION OF SEMISYNTHETIC METAL-WORKING FLUIDS IN B6C3F1 MICE

About 10 million industrial workers of both sexes are exposed to metal-working fluids (MWFs) via inhalation, skin or both. Our preliminary results, following dermal application of 200 µl of 50% unused (neat) semisynthetic MWF (pH 7 or pH 9.7) to the unshaved backs of 6-wk-old B6C3F1 mice, twice a week for 6 wk, produced significant increase in weights of the liver of both sexes. The purpose of the present study was to determine if this weight change was related to oxidative stress subsequent to MWF exposure and also to determine whether ethanol intake influences this effect. Therefore, 6-mo-old mice of both sexes were exposed to MWFs following the protocol just described, except that the topical application was with 5% MWFs (pH 7 and 9.7, 5 d/wk) with or without adding 5% ethanol to their drinking water (7 d/wk) for 13 wk. The skin histamine levels and mast-cell numbers were significantly increased in the female group treated with 5% MWF (pH 7). The ascorbic acid levels in the liver (both sexes) (all groups except 5% MWF pH 9.7 males) and testes were reduced significantly. Malondialdehyde levels in the male liver were significantly increased with topical MWF exposure. Glutathione levels were reduced significantly in both male and female liver after 5% MWF (pH 7). Alcohol dehydrogenase activity of the male liver increased significantly after MWF (pH 7). These results suggest that MWFs are absorbed through the skin and produce toxicity in the liver of both sexes and in the male gonads. This may represent an important health risk to MWF-exposed industrial workers, and ethanol may exacerbate this risk.     

Dermal and systemic toxicity after application of semisynthetic metal-working fluids in B6C3F1 mice

About 10 million industrial workers of both sexes are exposed to metal-working fluids (MWFs) via inhalation, skin or both. Our preliminary results, following dermal application of 200 microl of 50% unused (neat) semisynthetic MWF (pH 7 or pH 9.7) to the unshaved backs of 6-wk-old B6C3F1 mice, twice a week for 6 wk, produced significant increase in weights of the liver of both sexes. The purpose of the present study was to determine if this weight change was related to oxidative stress subsequent to MWF exposure and also to determine whether ethanol intake influences this effect. Therefore, 6-mo-old mice of both sexes were exposed to MWFs following the protocol just described, except that the topical application was with 5% MWFs (pH 7 and 9.7, 5 d/wk) with or without adding 5% ethanol to their drinking water (7 d/wk) for 13 wk. The skin histamine levels and mast-cell numbers were significantly increased in the female group treated with 55% MWF (pH 7). The ascorbic acid levels in the liver (both sexes) (all groups except 5%, MWF pH 9.7 males) and testes were reduced significantly. Malondialdehyde levels in the male liver were significantly increased with topical MWF exposure. Glutathione levels were reduced significantly in both male and female liver after 5% MWF (pH 7). Alcohol dehydrogenase activity of the male liver increased significantly after MWF (pH 7). These results suggest that MWFs are absorbed through the skin and produce toxicity in the liver of both sexes and in the male gonads. This may represent an important health risk to MWF-exposed industrial workers, and ethanol may exacerbate this risk.     

Metal working fluids: sub-chronic effects on pulmonary functions in B6C3F1 mice given vitamin E deficient and sufficient diets

Metal working fluids (MWFs) have been widely known to cause asthma and neoplasia of the larynx, pancreas, rectum, skin and urinary bladder (Textbook of Clinical Occupational and Environmental Medicine (1994) 814; Am. J. Ind. Med. 32 (1997) 240; Am. J. Ind. Med. 33 (1997) 282; Am. J. Ind. Med. 22 (1994) 185). Other non-neoplastic respiratory effects in industrial workers attributed to MWFs include increased rates of cough, phlegm production, wheeze, chronic bronchitis and chest tightness (Eur. J. Resir. Dis. 63(118) (1982), 79; J. Occup. Med. 24 (1982) 473; Am. J. Ind. Med. 32 (1997) 450). The epidemic and endemic nature of immune mediated lung morbidity commonly known as hypersensitivity pneumonitis in workers from several different industries using MWFs has been well documented (J. Allergy clin. Immunol. 91 (1993) 311; Chest 108 (1995) 636; MMWR45 (1996) 606; Am. J. Ind. Med. 32 (1997) 423). We studied morphological/functional and antioxidant outcomes in lungs after inhalation exposure of vitamin E deficient mice to MWF (27 mg m(-3) 17 weeks, 5 days a week, 6 h a day). Mice were given vitamin E deficient (<10 IU kg(-1) vitamin E) or basal diets (50 IU kg(-1) vitamin E) for 35 weeks. Inhalation exposure to MWF started after 18 weeks on diet. Microscopic observation of lungs from mice given vitamin E deficient or sufficient diets revealed no inflammation or morphological alteration after exposure to MWF. Mice given vitamin E deficient diet exhibited a significant decrease (P<0.05) in breathing rate, peak inspiratory/expiratory flow, minute ventilation, and tidal volume compared with sufficient controls. However, no differences were found after exposure to MWF in pulmonary function, with the exception of tidal volume which also significantly decreased (P<0.05). Exposure to MWF reduced vitamin E, protein thiol and ascorbate level in lungs. Exposure to MWF in combination with a vitamin E deficient diet resulted in significantly enhanced accumulation of peroxidative products compared with vitamin E deficient controls. This is the first report that describes the increase of oxidative stress in the lungs after MWF exposure.     

Evaluation of the Acute Respiratory Effects of Aerosolized Machining Fluids in Mice

Using a previously developed bioassay, the sensory and pulmonaryirritating properties of a group of 10 aerosolized machiningfluids were evaluated in mice. Single, 3-hr inhalation exposureswere conducted with the fluids at exposure concentrations-rangingfrom 20 to 2000 mg/m³. The results have shown that all 10 werecapable of inducing sensory and pulmonary irritation, with littleor no change in pulmonary histopathology. A concentration-responserelationship was developed for each fluid which revealed that,for the 10 fluids studied here, the synthetic/semisyntheticand soluble fluids were more potent irritants than the straightoils. Also, 3 of the 10 fluids which had been collected fromworkplace operations (i.e., "in use" fluids) were found to besimilar in potency to the same fluids prior to their introductioninto the workplace (i.e., "neat" fluids). From concentration-responserelationships, the RD50 value (i.e., concentration inducinga 50% response) was obtained for each of the 10 fluids. TheRD50 values ranged from 100 to 1000 mg/m³ for all fluids exceptthe straight oils whose RD50 values were over 100,000 mg/m³.Using these values, exposure limits were then suggested forworkers in industry to prevent irritation. This bioassay maybe a good first step in evaluating new machining fluids whoseformulations may change depending upon the current industrialneeds.     

The local lymph node assay being too sensitive?

The local lymph node assay (LLNA) and modifications thereof were recently recognized by the OECD as stand-alone methods for the detection of skin-sensitizing potential. However, although the validity of the LLNA was acknowledged by the ICCVAM, attention was drawn to one major problem, i.e., the possibility of false positive results caused by non-specific cell activation as a result of inflammatory processes in the skin (irritation). This is based on the fact that inflammatory processes in the skin may lead to non-specific activation of dendritic cells, cell migration and non-specific proliferation of lymph node cells. Measuring cell proliferation by radioactive or non-radioactive methods, without taking the irritating properties of test items into account, leads thus to false positive reactions. In this paper, we have compared both endpoints: (1) cell proliferation alone and (2) cell proliferation in combination with inflammatory (irritating) processes. It turned out that a considerable number of tests were “false positive” to the definition mentioned above. By excluding such false positive results the LLNA seems not to be more sensitive than relevant guinea pig assays. These various methods and results are described here.     

Inflammatory and immunological responses to subchronic exposure to endotoxin-contaminated metalworking fluid aerosols in F344 rats

Rats were exposed for 6 h per day in inhalation chambers to a 10 mg/m(3) concentration of metalworking fluid (MWF) contaminated with endotoxin at concentrations of 1813 (low dose) and 20,250 eu/m(3) (high dose) 5 days per week for 8 weeks. It was found that 94.7% of the MWF aerosol particles had diameters in the range of 0.42-4.6 microm, with geometric mean diameter of 1.56 microm. The body weight and pulmonary function parameters were measured every week during the 8 weeks of exposure, whereas bronchoalveolar lavage (BAL) fluid was prepared to measure the inflammatory markers and cytokines after the 8 weeks of exposure. There were no changes in body weight and respiratory function (tidal volume and respiratory frequency) during the 8 weeks of exposure to the MWF containing endotoxins, yet lung weight increased significantly (P < 0.05) in the rats exposed to the MWF both with and without endotoxins. The number of polymorphonuclear (PMN) cells in the BAL fluid increased significantly (P < 0.05) in the rats exposed to MWF with endotoxins, and the levels of cytokines such as IL-4, INF-gamma, IL-1beta, and TNF-alpha also were significantly increased (P < 0.05) compared to the control. The NOx production activity of the BAL cells increased significantly (P < 0.05) in the rats exposed to the MWF with and without endotoxins. Increases in lung weight, number of PMN cells, and levels of extracellular cytokines and NOx were all more significant in the rats exposed to the MWF with endotoxins rather than in those exposed to MWF without endotoxins. In spleen cell cultures, T-cell proliferation activity was decreased, yet cytokine levels (INF-gamma, IL-1beta, IL-4, and TNF-alpha) remained unchanged after repeated exposure to MWF with and without endotoxins. Although the levels of total IgG(1), IgG(2a), and IgE antibodies in the serum were not changed, the levels of endotoxin-specific antibodies, including IgG(2a) and IgE, were increased significantly (P < 0.05) in the rats exposed to endotoxins, but there was not a significant increase in endotoxin-specific IgG(1). When taken together, the results indicate that lung inflammatory responses can be induced without changing pulmonary function after repeated exposure to MWFs contaminated with endotoxins. In addition, endotoxin-specific IgG(2a) and IgE may be effective biomarkers for workers exposed to MWFs contaminated with endotoxins in the workplace.     

Sensory and pulmonary irritation with exposure to methyl isocyanate

Methyl isocyanate (MIC) was tested for its potency as a sensory irritant and as a pulmonary irritant in mice. To evaluate sensory irritation, animals were exposed to MIC at concentrations between 0.5 and 7.6 ppm for a period of 90 min. A characteristic reflex decrease in respiratory rate indicating sensory irritation was observed. The concentration evoking a 50% decrease in respiratory rate (RD50) was found to be 1.3 ppm. To evaluate pulmonary irritation, animals were first anesthetized and fitted with a tracheal cannula. Following recovery from anesthesia, they were exposed to MIC at concentrations between 0.4 and 7.3 ppm for a period of 90 min. A characteristic decrease in respiratory rate indicating pulmonary irritation in tracheally cannulated (TC) mice was observed. The concentration evoking a 50% decrease in respiratory rate (RD50TC) was found to be 1.9 ppm. Thus, MIC was found to be a potent sensory and pulmonary irritant.     

Enhanced oxidative stress in the skin of vitamin E deficient mice exposed to semisynthetic metal working fluids

Metal working fluids (MWFs) are widely used in industry for metal cutting, drilling, shaping, lubricating, and milling. Many occupational health concerns have arisen for workers exposed to MWFs. It has been reported earlier that occupational exposure to MWFs causes allergic and irritant contact dermatitis. Previously, we have shown that dermal exposure of female and male B6C3F1 mice to 5% MWFs for 3 months resulted in accumulation of mast cells and elevation of histamine in the skin. Topical exposure to MWFs also resulted in elevated oxidative stress in the liver of both sexes and the testes in males. The goal of this study was to evaluate whether preexisting oxidative stress in the skin exacerbated mast cell influx after MWFs treatment. Oxidative stress in the skin of B6C3F1 mice was generated by dietary vitamin E deprivation. Mice were given vitamin E deficient (5-10 i.v./kg of vitamin E) or basal (50 i.v./kg of vitamin E) diets for 34 weeks. Topical treatment with MWFs (100 microl, 30%) started after 18 weeks of alimentary vitamin E deprivation. Histology of the skin after 16 weeks of exposure to MWFs revealed a 53% increase in mast cell accumulation in vitamin E deficient diets compared to mice given a vitamin E sufficient diet. Total antioxidant reserve in skin of vitamin E deprived mice treated with MWFs was decreased by 66% as compared to those mice given a vitamin E sufficient diet. GSH and protein thiols in the dermis of vitamin E deprived mice exposed to MWFs were also decreased 39 and 42%, respectively, as compared to mice given basal diet. This study clearly delineates the role of oxidative stress in enhancing mast cell accumulation caused by topical exposure to MWFs.     

Sensory irritation,pulmonary irritation,and respiratory stimulation by airborne benzene and alkylbenzenes: Prediction of safe industrial exposure levels and correlation with their thermodynamic properties

The alkylbenzenes, toluene, ethylbenzene, n-propylbenzene, isopropylbenzene, n-butylbenzene, tert-butylbenzene, n-amylbenzene, n-hexylbenzene, and p-tert-butyltoluene were investigated for their property as sensory irritants in mice. The concentrations of these chemicals necessary to depress the respiratory rate by 50% (RD₅₀) due to sensory irritation of the upper respiratory tract were 5300, 4060, 1530, 2490, 710, 760, 230, 125, and 360 ppm, respectively. The potency of the alkylbenzenes increased with chain length. However, the ratio of equipotent concentration/saturated vapor concentration for these alkylbenzenes varied very little. Knowing the vapor pressure enabled prediction of sensory irritation potency up to a chain length of C₆. As previously suggested (Y. Alarie, 1981, Food Cosmet. Toxicol.19, 623–626), RD₅₀ values multiplied by 0.03 gave values for toluene, ethylbenzene, isopropylbenzene, and p-tert-butyltoluene in close agreement with established threshold limit value (TLV) for industrial exposure. No established TLV values exist for the other alkylbenzenes investigated. Using 0.03 RD₅₀, acceptable TLVs for n-propylbenzene, n-butylbenzene, tert-butylbenzene, n-amylbenzene, and n-hexylbenzene would be 50, 20, 20, 10, and 5 ppm, respectively. Minimal or no pulmonary irritation was observed with these alkylbenzenes. Benzene was inactive as a sensory irritant or pulmonary irritant up to 8500 ppm. Benzene in particular, and to some extent toluene, stimulated the respiratory rate. The effect was maximum approximately 10 to 20 min after onset of exposure. A model for the sensory irritating action of alkylbenzenes is proposed on the basis of their physical interaction with a receptor protein in a lipid layer.     

Multivariate statistical interpretation of laboratory clinical data

Laboratory aids are extensively used in the diagnosis of diseases, in preventive medicine, and as management tools. Reference values of clinically healthy people serve as a guide to the clinician in evaluating biochemical parameters. Determination of 21 biochemical parameters of healthy persons using standard methods of analysis. Cluster analysis and principal components analysis were applied on the above 21 biochemical parameters data. The application of a typical classification approach as cluster analysis proved that four major groups of similarity between all 21 clinical parameters are formed, which correspond to the authors assumption of the existence of several summarizing pattern of clinical parameters such as “enzyme,” “major component excretion”, “general health state,” and “blood specific” pattern. These patterns appear also in the subsets obtained by separation of the general dataset into “male”, “female”, “young”, and “adult” healthy groups. The results obtained from principal components analysis have additionally proved the validity of a similar assumption. The intelligent data analysis on the clinical parameter dataset has shown that when a complex system is considered as a multivariate one, the information about the system substantially increases. All these results support an idea that probably a general health indicator could be constructed taking into account the existing classification groups in the list of clinical parameters.     

Effects of Fly Ash and its Constituents on Sensory Irritation in Mice

Effects of Fly Ash and its Constituents on Sensory Irritationin Mice. Hatch, G.E., Boykin, E., Miller, F.J. and Graham, J.A.(1982). Fundam. Appl. Toxicol. 2:77–81. Sensory irritationcaused by fly ash from oil-fired (OF), fluidized bed coal (FB)combustion and conventional coal (CC) combustion power plants,and from Mt. St. Helens volcano (VA) was studied in mice. Theirritating sensation due to contact with fly ash or its constituentswas quantitated by observing a characteristic flexing of thedorsal musculature of the mouse following intraperitoneal injectionof the ash suspension. Construction of dose-effect curves wasbased on the percentage of animals showing a positive responseat each ash concentration. The order of irritant potency offly ash samples was as follows: OF and OF leachate >>FB > CC > VA. Saline leachates of ash samples other thanOF fly ash showed no irritating effects. OF fly ash was about160xmore irritating than VA and 5x more irritating than thereference detergent compound, sodium dodecyl sulfate. Studyof chemicals known to be present in fly ash or chemicals similarto those present indicated that acidic or basic compounds, heavymetal ions and metal oxides, and insoluble particles could allcontribute to the irritancy of an ash. Soluble heavy metalsappeared to be mainly responsible for the irritant effects ofOF ash, while insoluble particles including metal oxides couldhave accounted for the irritancy of the other fly ash samplesstudied. Comparison of data from the peritoneal irritation testused here with previously published data from the upper respiratorytract irritation test of Alarie confirmed the previously notedcorrelation between these two tests for chemicals in solution.     

Sensitization to the motor effects of contingent infusions of heroin but not of κ agonist RU 51599

It has been postulated that behavioral sensitization could reflect drug-induced changes that are central to the development of drug abuse; however, it is still unknown whether behavioral sensitization can arise during a “voluntary” and “self-controlled” consumption of drugs and consequently play a role in drug abuse. For this reason, we studied the possible sensitization of motor activity during ten consecutive intravenous self-administration (SA) sessions of one of the most largely abused opiates the μ agonist heroin [30 μg/infusion (inf)]. We also studied in similar conditions the new κ agonist RU 51599 (6.5, 20 and 100 μg/inf). Heroin and RU 51599 were compared because both drugs are self-administered by rodents, but the reinforcing properties of RU 51599 are very weak compared to those of heroin. At low ratio requirement rats developed SA of both heroin and RU 51599; however, a progressive increase in drug-induced locomotor activity over subsequent sessions was observed only for heroin but not for RU 51599. Sensitization of the motor effects of heroin developed over a period of time during which the intake of the drug was constant. In conclusion, sensitization can develop during the voluntary consumption of an addictive drug such as heroin. These results are in line with the hypothesis that sensitization could play a role in the etiology of drug abuse. Received: 27 December 1997/Final version: 8 May 1998     

Sensory irritating effects of allyl halides and a role for hydrogen bonding as a likely feature at the receptor site

Allyl chloride, bromide and iodide were investigated for their properties as sensory irritants in mice. The concentrations of the chemicals necessary to depress the respiratory rate by 50% (RD50) within the first 10 min. of exposure due to irritation of the upper respiratory tract were 2330, 257 and 79.8 p.p.m., respectively. No pulmonary irritation was observed. In the period 20 to 30 min., however, pulmonary irritation was observed for allyl bromide and iodide. The effect was not prominent in non-cannulated mice probably due to the scrubbing effect of the nose. According to RD50 values, thermodynamic activity as well as apparent association rate with the receptor the sensory irritating potencies of the halides were low compared to those of allyl alcohol, acetate, and ether. A mechanistic explantation could not be ascribed to metabolites, lipophilicity or chemical reactivity. Only a hydrogen bond donor ability of the receptor offered an explanation. As many industrial chemicals e.g. alcohols, ketones and esters can function as hydrogen bond acceptors this receptor-feature cannot be overemphasized.     

Statistical interpretation of medical data of patients with alcohol abuse

An attempt is made to assess a set of biochemical, kinetic and anthropometric data for patients suffering from alcohol abuse (alcoholics) and healthy patients (non-alcoholics). The main goal is to identify the data set structure, finding groups of similarity among the clinical parameters or among the patients. Multivariate statistical methods (cluster analysis and principal components analysis) were used to assess the data collection. Several significant patterns of related parameters were found to be representative of the role of the liver function, kinetic and anthropometric indicators (conditionally named “liver function factor”, “ethanol metabolism factor”, “body weight factor”, and “acetaldehyde metabolic factor”). An effort is made to connect the role of kinetic parameters for acetaldehyde metabolism with biochemical, ethanol kinetic and anthropometric data in parallel.     

Mechanisms of acute inhalation effects of (+) and (-)-alpha-pinene in BALB/c mice

The effects of (+)-alpha-pinene and (-)-alpha-pinene vapours were studied for respiratory effects in BALB/c mice. The (+) enantiomer showed persistent sensory irritation effect on the upper respiratory tract during exposures in the range of 100 to 3691 ppm. The threshold concentration for this effect was calculated to be about 70 ppm, which is close to the no-effect level of about 40 ppm in humans. A significant airflow limitation occurred from exposure concentrations of 200 ppm and higher. No irritating effect was observed at the alveolar level and no central nervous system effect was obvious. In the exposure range from 218 to 5213 ppm, the (-) enantiomer produced only a short-lasting sensory irritation effect during the first 10 min. of exposure and only at concentrations above 2900 ppm. The tidal volume decreased significantly from approximately 400 ppm, but it was first conspicuous above 1000 ppm. Airflow limitation appeared consistently from approximately 2000 ppm. The (-) enantiomer also induced anesthesia/and or pulmonary irritation as well as sudden death at concentrations above 2600 ppm. Overall, the enantiomers showed different time-dependent and stereoselective effects. The lower sensory irritation effect of the (-) enantiomer probably being due to less of the molecule being adsorbed to a sensory irritant receptor.