3-(3,4-Dihydroxyphenyl)adenine, a urinary DNA adduct formed in mice exposed to high concentrations of benzene.

Metabolism of benzene, an important environmental and industrial carcinogen, produces three electrophilic intermediates, namely, benzene oxide and 1,2- and 1,4-benzoquinone, capable of reacting with the DNA. Numerous DNA adducts formed by these metabolites in vitro have been reported in the literature, but only one of them was hitherto identified in vivo. In a search for urinary DNA adducts, specific LC-ESI-MS methods have been developed for the determination in urine of six nucleobase adducts, namely, 7-phenylguanine, 3-phenyladenine, 3-hydroxy-3,N(4) -benzethenocytosine, N(2) -(4-hydroxyphenyl)guanine, 7-(3,4-dihydroxyphenyl)guanine and 3-(3,4-dihydroxyphenyl)-adenine (DHPA), with detection limits of 200, 10, 260, 50, 400 and 200 pg ml(-1) , respectively.

Carcinogenic 3-nitrobenzanthrone but not 2-nitrobenzanthrone is metabolised to an unusual mercapturic acid in rats.

3-Nitrobenzanthrone (3-NBA) is an extremely potent mutagen and suspect human carcinogen found in diesel exhaust. Its isomer 2-nitrobenzanthrone (2-NBA) has also been found in ambient air. These isomers differ in mutagenicity in Salmonella by 2-3 orders of magnitude.

Metabolism of N²-(4-hydroxyphenyl)guanine, a DNA adduct formed from p-benzoquinone, in rat.

Among numerous adducts formed by reaction of DNA with p-benzoquinone (p-BQ), an electrophilic metabolite of benzene, only N2-(4-hydroxyphenyl)guanine (N2HPG) has been confirmed in vivo. If excreted in urine N2HPG would be a candidate non-invasive biomarker of the DNA damage caused by benzene. To test this hypothesis, biotransformation of N2HPG was studied in rats.

DNA adducts formed from p-benzoquinone, an electrophilic metabolite of benzene, are extensively metabolized in vivo.

Benzetheno adducts derived from p-benzoquinone (p-BQ), a reactive metabolite of benzene, were reported to be formed by the reaction of p-BQ with DNA in vitro but have never been detected either in vivo or in experiments with living cells. Two of them, 3-hydroxy-3,N(4)-benzetheno-2'-deoxycytidine (DCBQ) and 7-hydroxy-1,N(2)-benzetheno-2'-deoxyguanosine (DGBQ), were administered to rats by single ip injections at the doses of 2 mg/kg each. The excretion of unchanged compounds DCBQ and DGBQ within 2 days amounted to 8.

Excretion of urinary N7 guanine and N3 adenine DNA adducts in mice after inhalation of styrene.

New urinary adenine adducts, 3-(2-hydroxy-1-phenylethyl)adenine (N3alphaA), 3-(2-hydroxy-2-phenylethyl)adenine (N3betaA), were found in the urine of mice exposed to styrene vapour. These styrene 7,8-oxide derived adenine adducts as well as previously identified guanine adducts, 7-(2-hydroxy-1-phenylethyl)guanine (N7alphaG) and 7-(2-hydroxy-2-phenylethyl)guanine (N7betaG) were quantified by HPLC-ESI-MS(2) and the excretion profile during and after a repeated exposure to 600mg/m(3) or 1200mg/m(3) of styrene for 10 consecutive days (6h/day) was determined. The excretion was dose dependent.

Metals - impact and implications.

Impact of metal in vitro administration on rat tissue oxygen consumption is referred in the first part. Toxicological implications of in vivo metal administration to rats and the study of potential penetration of metal into the rat brain, which may eventually result in oxygen radical production are presented in second part.

Cardiovascular reaction to job stress in middle-aged train drivers.

In this study, cardiovascular (CV) response to a standard laboratory challenge was compared to 24-hr noninvasive monitoring of heart rate (HR) and blood pressure (BP) in 30 healthy middle-aged train drivers. Laboratory stress test consisted of the orthostatic test, the cold pressor test, the Valsalva maneuver, the Stroop test, and the numerical square. In addition, the participants completed an extensive questionnaire on their health state and family health history, lifestyle, job stress, social and family support, personality characteristics, and health risk behaviors.

Mobilization of mercury by DMPS in occupationally exposed workers and in model experiments on rats: evaluation of body burden.

The aim of the study was to evaluate the efficacy of DMPS (sodium-2,3-dimercapto-1-propane sulfonate) (Dimaval) administration for mobilizing mercury from the body in occupationally exposed people and experimental animals. Two doses of DMPS were administered at a 24-h interval to: (a) groups of people occupationally exposed to merkury--workers of the chloralkali industry (n = 43), and dentists (n = 12), (b) non-exposed individuals (n = 20), and (c) rats chronically exposed to mercury vapour at the concentration of 0.8 mg/m3 Hg degree (6 h/day, 5 days/week) for 15 weeks.

Subchronic preexposure to carbon monoxide modifies heart response to a combined CO + isoproterenol challenge in rats.

The effect of repeated exposure to carbon monoxide (CO) on the response of middle-age rats to an acute CO exposure combined with a low dose of a sympathomimetic agent was studied. A group of 12 rats (male albino, Wistar, age 9 months) without ECG abnormalities was divided into two subgroups matched for weight, heart rate and ECG: one subgroup was exposed to 500 ppm CO for 6 h/d, 5 d/w, for 6 weeks (peak COHb 31.5%, SD 3.

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.

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 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.

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 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.

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 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.

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.

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.

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.

Vigilance impairment after a single dose of benzodiazepines.

While outpatients or other users of therapeutic drugs have to be informed about the risk of impaired functioning during driving or work, the prescribing physician needs to be familiar with the side effects of alternative drugs in order to select the most suitable treatment. With this aim, several types of benzodiazepine anxiolytics in low anxiolytic doses (diazepam 5 mg or 10 mg, nitrazepam 5 mg, oxazepam 10 mg, medazepam 10 mg, and alprazolam 0.2 or 0.

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.

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).

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.

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.