Biomedical subjects

E Frantík

Publications and source records attributed to E Frantík.

At least 19 recordsLinked to original sources

PubMed1998

Cytochrome P450 catalyzed oxidation of monochlorobenzene, 1,2- and 1,4-dichlorobenzene in rat, mouse, and human liver microsomes.

We studied metabolism of monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2-DCB) and 1,4-DCB in liver microsomes from untreated male and female Wistar rats and B6C3F1 mice or in those after the induction of CYP3A or 2E1 as well as in human male liver microsomes. MCB and 1,2-DCB were oxidised mainly by rat and human CYP2E1. It was found that 1,4-DCB was oxidised by rat and human CYP2E1 at a several-fold lower rate than 1,2-DCB, but a greater part to covalently binding products. In contrast to previous studies showing rat CYP3A1 as the main CYP form oxidising both DCBs, our experiments indicate only a certain role of rat and human CYP3A in MCB, 1,2-DCB and 1,4-DCB oxidation to covalently bound products. The relative roles of human liver CYP2E1 and 3A4 in the metabolism of 1,4-DCB seem to be individually different. Metabolic rates of MCB, 1,2-DCB and 1,4-DCB correlated with CYP2E1 immunochemical level in microsomes from 11 different human livers and with metabolic rates of CYP2E1 substrates. These rates in different human livers were up to 10-fold different and were generally several-fold higher than those in untreated rats or mice. Metabolic activation of MCB and 1,2-DCB to products binding covalently to microsomal proteins and to calf-thymus DNA, respectively, mostly corresponded to production of water-soluble metabolites. Significant species and sex differences in the oxidation of MCB, 1,2-DCB and 1,4-DCB were reflected in a markedly higher oxidation in male mice than male rats and higher oxidation in male than female mice. The formation of covalently bound products generally corresponded to production of soluble metabolites, but female rats formed significantly less covalently bound products of 1,4-DCB (and also of 1,2-DCB and MCB) than male rats and mice of both sexes, in possible reflection of the fact that 1,4-DCB is not carcinogenic in female rats despite its carcinogenicity for male rats and both sexes of mice.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening. I. Background and genesis.

Numerous events over several years culminated in recognition of the need to explicitly evaluate the nervous system as a potential target for environmental chemicals. Based on recommendations from several international expert panels, the International Programme on Chemical Safety (IPCS) sponsored the Collaborative Study on Neurobehavioral Screening Methods. A Steering Committee was created to oversee the project, develop the testing protocol, recruit participating laboratories and review and analyze the data. The protocol specified the tests, the chemicals (supplied from a common source) and the exposure conditions (acute and repeated dosing). Test methods were based upon existing practices in toxicological screening as well as recent advances in neurotoxicity screening. Chemicals were selected to produce different profiles of neurobehavioral effects. Considerable latitude was afforded the participating laboratories in the choice of several key variables (e.g., strain of rat, testing device for motor activity assessment) that could potentially affect the results of the experiments. The approach therefore provided a standardized yet flexible protocol for evaluating the reproducibility of neurobehavioral screening data in diverse laboratory settings.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: II. Protocol design and testing procedures.

This paper describes the development of the protocol for the International Programme on Chemical Safety (IPCS)-sponsored Collaborative Study on Neurobehavioral Screening Methods, including background on the methods and chemicals selected, as well as details concerning the conduct of the collaborative study, including proficiency testing, range-finding and main study. Participating laboratories in the collaborative study received training in the conduct and scoring of the behavioral tests and each laboratory received a video training film to train additional personnel as needed. Each of the eight laboratories that chose to participate in the study completed proficiency testing and assessed seven representative chemicals using a functional observational battery and automated motor activity assessment. The seven chemicals studied were acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples of the chemicals from a common source. Each laboratory derived doses for single and repeated administration based on the determination of a within-laboratory acute "top dose." Animal strains were not standardized and laboratory conditions were standardized to a limited degree in order to judge the general utility and robustness of these procedures in a diversity of testing situations.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: VII. Summary and conclusions.

In the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods, eight participating laboratories used a standard battery of behavioral tests to determine, in rats, the effects of seven representative chemicals following acute and repeated dosing. The results of the collaborative study indicate good agreement across laboratories with regard to the data collected in vehicle controls. It was clear, however, that some behavioral measures had significantly more variability than other tests. The laboratories also demonstrated the ability to detect known neurotoxic chemicals and identify profiles of effects that differed from non-neurotoxic agents. The results of the study suggest that appropriate training of personnel is crucial to ensure the reliability of the test battery. The results also underscore the importance of dose selection in behavioral screening studies, since it is sometimes difficult to determine the specificity of behavioral changes in animals receiving high doses of some chemicals. The collaborative study also emphasizes the need to utilize a battery of tests in screening a wide range of potential neurotoxic agents. Analysis of data from such studies poses unique challenges due to the large number of tests and test times, and the consequent possibility of false positives. Some statistical concerns may be alleviated by grouping the results from tests that measure similar functions into neurobiological domains. Although this approach improves confidence in the biological relevance of chemical-induced changes in behavior, it may also lead to false negatives. The exploration of other statistical approaches to analyze data from experiments using a test battery is encouraged. Nevertheless, results of the collaborative study strongly support the use of behavioral tests in hazard identification.

Animals↗

PubMed1996

Biotransformation of acrolein in rat: excretion of mercapturic acids after inhalation and intraperitoneal injection.

Biotransformation of acrolein (ACR) was studied in vivo in the rat following inhalation and ip administration. The major and minor urinary metabolites were 3-hydroxypropylmercapturic acid (HPMA) and 2-carboxyethylmercapturic acid (CEMA), respectively. Male Wistar rats were exposed to ACR, 23, 42, 77 and 126 mg/m3, for 1 hr. The sum of mercapturic acids HPMA and CEMA excreted within 24 hr after the exposure amounted to 0.87 +/- 0.12, 1.34 +/- 0.5, 2.81 +/- 1.15, and 7.13 +/- 1.56 mumol/kg, i.e., 10.9 +/- 1.5, 13.3 +/- 5.0, 16.7 +/- 6.9, and 21.5 +/- 4.8% of the estimated absorbed dose, respectively. The dose estimate was based on reported values of minute respiratory volume and respiratory tract retention and was corrected for the ACR-induced changes in minute respiratory volume. In the relevant dose range (8.9 to 35.7 mumol/kg) the portion of mercapturic acids excreted was nearly constant for ip exposed rats. The sum of HPMA and CEMA amounted to 29.1 +/- 6.5% of the dose. These results indicate that the deficiency in rat lung metabolism of ACR to acrylic acid previously observed is not compensated by the other detoxication pathway in vivo, mercapturic acid formation. The health hazard arising from inhalation of ACR is likely to be higher than that from other routes of exposure.

Acetylcysteine↗

PubMed1996

Pattern of inhalation exposure: blood levels and acute subnarcotic effects of toluene and acetone in rats.

Solvent blood concentrations and subnarcotic effects (inhibition of electrically evoked seizures) were measured in rats exposed to constant or fluctuating air concentrations of toluene or acetone. A 4 hour exposure of resting rats to toluene at an air concentration of 1 and 2 mg/l, or to acetone at 4 and 10 mg/l, led to blood levels of 6.7 and 12.8 mg/l of toluene, or 183 and 520 mg/l of acetone: seizure inhibition amounted to 18% and 40+, or 10% and 50%, respectively. Blood level and effect attained 1/2 of the final values after 40 min and 60 min of exposure to 2 mg/l toluene, respectively, and dropped to 1/2 70 min and 90 min after exposure cessation: respective values for acetone 10 mg/l were 80 and 120 min, and more than 4 hours. A steep rise and a rapid drop was characteristic also for the course of blood level and effect during an exposure to fluctuating concentrations of toluene: ten minute fivefold jump in the air concentration induced a shortlasting seizure inhibition by more than 80%; the curves for acetone were flat.

Acetone↗

PubMed1995

Neutrotropic effects and blood levels of solvents at combined exposures: binary mixtures of toluene, o-xylene and acetone in rats and mice.

Male rats and female mice were exposed to vapours of toluene, o-xylene and acetone in basic or double concentrations or to binary combinations of basic concentrations, for 4 and 2 hours, respectively. Basic air concentrations were for rats and mice (in ppm): toluene 270 and 380, o-xylene 230 and 320, acetone 1700 and 1530, respectively. The CNS effect-inhibition of electrically evoked seizure discharge-was measured immediately after exposure and blood levels of solvents were monitored during the desaturation phase. The effect of all binary mixtures was lower than that of double concentrations of each single component, the difference being significant only in mice, and lower than the additive effects predicted on the basis of regressions of the effect on air or on blood concentrations of individual components. On the target site in the neuronal membrane, the effects of mixtures were substantially less than additive. Blood concentrations of solvents immediately after the exposure to a mixture were generally higher in aromatics and lower in acetone than after exposure to individual solvents. The decline of blood toluene and even more so that of xylene after exposure was slowed down by acetone. Presumption of additivity seems to protect safely from acute neurotropic effects of solvents at realistic exposure levels. On the other hand, substantially protracted late phases of desaturation of aromatic solvents in the presence of slowly eliminated polar solvent points to a possible underestimation of exposure by biological exposure tests.

Acetone↗

PubMed1994

Relative acute neurotoxicity of solvents: isoeffective air concentrations of 48 compounds evaluated in rats and mice.

Effect-air concentration regressions of 48 common solvents (aromatic, aliphatic, and chlorinated hydrocarbons, alcohols, ketones, acetates) were determined for 4-hr inhalation exposures in male rats and for 2-hr exposures in female mice. Inhibition of propagation and maintenance of the electrically evoked seizure discharge was used as a criterion of the acute neurotropic effect. The isoeffective concentrations in air were estimated by interpolation on the level of one-third of the maximum effect (ECC). ECC estimates ranged from 90 to 24,000 ppm and were several times lower than concentrations evoking behavioral inhibition and by one to two orders lower than concentrations inducing narcosis. Correlations between corresponding values in both species were high (r > 0.9), indicating a relative independence of the estimates from experimental conditions. The relative potency estimates had only negligible correlation with octanol:water distribution coefficients or other physicochemical predictors for the whole sample of solvents, but moderate to high correlation (r = 0.5 to 0.9) in homogenous groups of nonpolar solvents, permitting cautious predictions. When applied to known effective concentrations of some solvents on human performance and subjective state, the comparative potency procedure suggests that ceiling and STEL values of some solvents may not reliably protect workers from acute nervous depression.

Air Pollutants↗

PubMed1993

Exposure to various benzene derivatives differently induces cytochromes P450 2B1 and P450 2E1 in rat liver.

Benzene (B), toluene (T), ethylbenzene (EB), styrene (S) and xylene isomers (oX, mX, pX) are important environmental pollutants and B is a proved human carcinogen. Their inhalation by male Wistar rats (4 mg/l, 20 h/day, 4 days) caused cytochrome P450 (P450) induction. The degree of P450 2B1 induction increased and that of 2E1 decreased in the series B, T, EB, S, oX, mX and pX, as estimated by Western blots, while neither solvent was as effective for 2B1 induction as phenobarbital and B was more effective for 2E1 than ethanol. The levels of several other P450s decreased after exposure to these solvents, B being most effective. Exposure to these solvents increased in vitro hepatic microsomal oxidation of B and aniline (AN) (2E1 substrates) 3 to 6-fold, indicating induction of this P450. T oxidation was increased 2 to 4-fold and chlorobenzene (ClB) oxidation 3-fold. Sodium phenobarbital (PB, 80 mg/kg/day, 4 days, i.p.) did not increase ethylmorphine (EM) and benzphetamine (BZP) demethylation (2B1 substrates), neither of the B derivatives did so, and oX decreased it; however, pentoxyresorufin O-dealkylation was well related to the immunochemically detected 2B1 levels in control, PB and B microsomes. PB did not increase B, but increased T and ClB oxidation 2-4 and 3-fold, respectively, indicating possible 2B1 role in their oxidation. B oxidation after various inducers was related to immunochemical 2E1 levels, T and ClB oxidation to both 2B1 and 2E1 and AN oxidation to 2E1 and 1A2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Integration of behavioral and neurophysiological approaches in neurotoxicology.

The validity of behavioral and neurophysiological models can only be assessed with respect to the type of the modelled effect: for acute changes in activation level as well as for chronic motor or sensory deficits both approaches are equally prone to misinterpretation. Validation of behavioral criteria supported by neurophysiological correlates and vice versa is the best protection. In the cognitive and emotional sphere, a shift to testing of the readiness ("fluidity") dimension seems to be promising both in human and animal studies, permitting also more reliable extrapolations and efficient cooperation of behavioral and neurophysiological approaches.

Animals↗

PubMed1990

Effects of inhaled acrylic acid derivatives in rats.

Chemical reactivity with glutathione, urinary thioether excretion, total (T-SH) and non-protein-SH (NP-SH) groups in tissues and blood glucose were studied in male Wistar rats exposed to acrylic acid derivatives. The 6-h inhalation of acrylonitrile (AN), methyl acrylate (MA), ethyl acrylate (EA), n-butyl acrylate (BA) and 2-ethylhexyl acrylate (2-EHA) in several concentrations increased the urinary thioether excretion; the portion metabolized to thioethers was 35-18% of the acrylonitrile dose, but only 1.5-8% for the acrylates. Total-SH levels in the liver significantly decreased after the inhalation of AN, EA, BA and 2-EHA. In blood there was a decrease only after EA. Most pronounced NP-SH depletion was in the liver, less in blood and moderate in brain and lungs. There was an exponential relationship between the tissue NP-SH and the inhaled concentrations. Calculated concentrations inducing 50% NP-SH depletion indicated that reaction of acrylic acid derivatives with SH groups was decreasing in the order AN much greater than 2-EHA greater than EA = BA for the chemicals and liver greater than blood greater than lungs greater than brain for the tissues. All inhaled acrylates induced hyperglycemia, but acrylic acid was without effect. The chemical reactivity of acrylates with glutathione (GSH) decreased in the order EA greater than BA greater than MA greater than AN greater than 2-EHA. The results suggest that GSH depletion may participate in acute lethal and biochemical toxic effects of acrylic acid esters.

Acrylates↗

PubMed1990