Study of the genotoxicity of toluene.

Chromosome analysis was conducted for peripheral lymphocytes of 23 printers exposed to toluene concentrations of 590 mg/m3 in a rotary machine workshop and to rotogravure printing inks. The percentages of aberrant cells were 2.30 in the printers and 1.46 in the control group (n = 22) (p < .05). The concentration of hippuric acid in printers was significantly higher than in the control group (p < .01), and the level of blood toluene at the end of the workshift was 0.500 mg/l. The authors also examined rotogravure printing inks-considered a potential source of genotoxic polycyclic aromatic hydrocarbons because they contained carbon black-their use in printing plants, and previous documentation of increased chromosomal aberrations in rotogravure printers. Only milligrams of fluorene and phenanthrene per gram of the printing inks were found; no polycyclic aromatic hydrocarbons with carcinogenic properties were discovered in the inks. The authors used Salmonella typhimurium indicator strains TA 98, TA 100, TA 1537, and YG 1041 in spot tests and indicator strains TA 98 and TA 100 in plate-incorporation assays to determine that there was no bacterial mutagenicity of all four colors of rotogravure inks. Urinary mutagenicity, which was evaluated with a microsuspension assay containing YG 1041 indicator strain both in the presence and absence of metabolic activation, was also studied. No significant difference in bacterial mutagenicity was found between the exposed and control groups. The increased percentage of aberrant cells in printers can be explained by exposure to genotoxicants that are not excreted in urine. Toluene was the most likely cause of the aberration.

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.

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.

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.

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.

The influence of a magnetic field on manganese transport into rat brain.

The aim of this study was to detect the effect of a magnetic field on manganese transport into rat brains. An experimental group of Female Wistar rats was given 0.48 mg Mn2+ per kg body weight intratracheally twice a week for 3 months and simultaneously exposed to a magnetic field: B = 10 mT, f = 50 Hz for 1 hr. Rats in one control group of rats received the same dose of manganese as the experimental group but were not exposed to the magnetic field. Rats in a second control group had neither exposure to manganese nor exposure to the magnetic field. After the last dose, all rats were sacrificed and their brains and other tissues were analyzed for manganese content. The results indicated that the magnetic field had a positive effect on increasing the manganese content in the brains of rats in the experimental group relative to those of the control groups. Visual evoked potentials (VEP) measured at the end of the exposure periods on randomly selected experimental and control rats showed a shortened but not statistically significant latency of the P1 peak of VEP in rats that had been exposed to both factors but not in control rats.

Oxidative phenotype polymorphism (P450 2D6) and metabolism of toluene.

Oxidative phenotype P-450 2D6 was examined using sparteine test in 3 groups of persons to determine if there is a coincidence in the defect of the oxidative biotransformation of sparteine and impaired oxidation of toluene, which could explain interindividual differences in the amounts of hippuric acid in the urine in exposed persons. The following groups of persons were examined: 30 rotogravure printers exposed to toluene vapors at concentrations of 8-307 ppm; 20 workers, 2 months after the cessation of the long-term exposure to toluene at concentrations of 104-1,170 ppm; 48 healthy volunteers with no exposure to toluene. Among the 98 persons 5 poor metabolizers (PMs) of sparteine were found, none in the group of printers exposed to toluene. In the experimental exposure chamber 5 PMs and 6 extensive metabolizers (EMs) were exposed to toluene concentration of 245 ppm for 5 hours. Hippuric acid and o-cresol in the urine, and toluene both in blood and in alveolar air were measured. However, no significant differences were found in either of these parameters between the PM and EM groups. Thus, the sparteine test does not appear to be applicable in the identification of persons with higher risk arising from toluene exposure.

Neurotoxicity profile of supermethrin, a new pyrethroid insecticide.

The use of a standard two-tier neurotoxicity screening procedure in the context of risk assessment is exemplified. Testing of a new pyrethroid in rats addressed the following sequence of questions: Does the substance evoke neurotoxic symptoms in sublethal doses? Do these symptoms reflect a primary neurotropic action? What are the dynamic characteristics of injury, the clinical profile of effect, and the relative potency of the tested substance compared to similar compounds? - The testing protocol is an animal analogue of a systematic neurological and psychological examination in man. First tier tests (structured observation, motor activity measurement, simple neurological examination) were applied after the first dose, during repeated dosing phase and in the restitution phase. Facultative tests for the second-tier examination (motor activity pattern, learning/retention test, evoked potentials, dynamic motor performance) were selected on the basis of effects revealed by the first-tier testing. Supermethrin evoked acute neurotoxicity in sublethal doses, ranging from 1/30 to 1/15 of LD50. The clinical pattern was similar to other cyano-substituted pyrethroids. Behavioural inhibition was transient and complete tolerance to it developed after 4-week repeated dosing. No indications of long-lasting changes in neuronal excitability or in learning and memory processes were found. Ataxia and excitomotoric phenomena dominated both the acute and the subchronic picture. Marked and persistent motor disturbances, including symptoms of lower motoneuron injury, were limited to individual animals of the highest, near-lethal dose group (27 mg-kg-1). Compared to lambda-cyhalothrin, the effects of supermethrin were 2 to 3 times weaker, disappeared more rapidly, cumulated less, and had higher tendency to tolerance.

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.