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Archives of Toxicology (v.76, #3)

No Title by Monika Meyer-Baron; Michael Schaeper; Andreas Seeber (pp. 127-136).

A meta-analysis for neurobehavioural test results of subjects occupationally exposed to mercury was carried out in order to find general tendencies and express possible deficits numerically. Out of 44 studies investigating neurobehavioural functions of occupationally exposed individuals, 12 studies provided the data required and were included in the analysis. In all, 14 neuropsychological tests with 20 different tasks were analysed. The results related to 686 exposed and 579 control subjects. Nine significant performance effects were shown for mean urinary concentrations between 18 and 34 µg Hg/g creatinine. The effects sizes (D^W+) referred to attention (D^W+=–0.40 and –0.46), memory (D^W+=–0.38 and –0.40), construction (D^W+=–0.20) and motor performance (D^W+=–0.24, –0.40, –0.44 and –0.47). Additionally there was evidence for a dose-response relationship of effect sizes, if all test results were taken into account. Whether the effect sizes could be subject to overestimation was discussed, but there were no reasons for such an assumption. The results can be used as suggestions for new discussions about threshold limit values.

Keywords: Inorganic mercury Neurotoxic effects Neuropsychological tests Behavioural toxicology Occupational exposure levels

No Title by Andreas Seeber; Monika Meyer-Baron; Michael Schäper (pp. 137-145).

The conclusions from published results about neurotoxic effects of inorganic lead exposures <700 µg lead/l blood are contradictory at present. Effects measured by neurobehavioural methods are evaluated differently as far as recommendations for a Biological Exposure Index (BEI) of occupational lead exposure are concerned. Arguments against the German BEI of 400 µg/l were put forward in new publications, and discussion of the issues is the aim of this article. It summarizes two different meta-analytical reviews on neurobehavioural effects in order to show the main tendencies of 24 selected publications on the matter. Calculations on effect sizes are compiled for 12 tests analysed in two meta-analyses and of ten tests analysed in one of the meta-analyses. The survey of six tests of learning and memory gives hints on impairments measured with two tests, covering Logical Memory and Visual Reproduction. The survey of seven tests of attention and visuospatial information processing describes impairments in four tests, namely Simple Reaction, Attention Test d2, Block Design, and Picture Completion. The survey of four tests for psychomotor functions shows impairments for three tests, namely Santa Ana, Grooved Pegboard, and Eye-hand Coordination. These test results provide evidence for subtle deficits being associated with average blood lead levels between 370 and 520 µg/l. In evaluating the adversity of such effects it is concluded that the results of both meta-analytical reviews support the recommendation for the German BEI.

Keywords: Inorganic lead Neurotoxic effects Threshold limit setting

No Title by Hirohisa Takano; Rie Yanagisawa; Takamichi Ichinose; Kaori Sadakane; Ken-ichiro Inoue; Sei-ichi Yoshida; Ken Takeda; Shin Yoshino; Toshikazu Yoshikawa; Masatoshi Morita (pp. 146-151).

Polycyclic aromatic hydrocarbons (PAH) and reactive oxygen species (ROS) derived from diesel exhaust particles (DEP) are implicated in the pathophysiology of respiratory diseases. Cytochrome P450 (Cyp) 1A1 can be induced by several kinds of PAH and produce ROS. We determined whether acute inhalation exposure to DEP induced the expression of Cyp 1A1 in murine lung. Intratracheal instillation of DEP dose-dependently increased the lung expression of Cyp 1A1 at the levels of both mRNA and protein, whereas DEP decreased expression in the lung of aryl hydrocarbon receptors in a dose-dependent manner. In contrast, charcoal particles as the control did not affect the expression of these molecules. These results suggest that the lung expression of Cyp 1A1 can be a biomarker of acute inhalation exposure to DEP and may be implicated in an accelerated production of ROS and the subsequent aggravation of lung injury.

Keywords: Diesel exhaust particles Cytochrome P450 1A1 Lung injury Biomarker Polycyclic aromatic hydrocarbons

No Title by Teresa Wronska-Nofer; Julita Chojnowska-Jezierska; Jerzy-Roch Nofer; Tadeusz Halatek; Justyna Wisniewska-Knypl (pp. 152-157).

There is considerable epidemiological evidence that workers exposed to carbon disulfide (CS₂) develop premature atherosclerosis leading to increased rates of coronary heart disease (CHD), but mechanisms underlying this association remain obscure. The present study documents that occupational exposure to CS₂ modifies the oxidative status of plasma, which is a major determinant of the susceptibility to atherosclerosis. Concentrations of thiobarbituric reactive substances (TBARS), which reflect lipid peroxidation processes in plasma, were determined in 29 men who were exposed to CS₂ for more than 20 years, in 24 patients with peripheral atherosclerosis, and in 30 unexposed, healthy control subjects. TBARS concentrations were significantly increased both in CS₂-exposed subjects and in patients with peripheral atherosclerosis. Subjects in both groups presented also with decreased levels of plasma α-tocopherol, a major plasma antioxidant. In addition, decreased activities of two enzymatic antioxidants, glutathion peroxidase and catalase, were noted both in CS₂-exposed subjects and patients with peripheral atherosclerosis. Finally, LDL isolated from both groups showed increased susceptibility to transition metal-induced oxidation in vitro. It is concluded, that occupational exposure to CS₂ produces oxidative stress in plasma. This may favor the development of atherosclerosis and increase the incidence of CHD in workers exposed to CS₂.

Keywords: Carbon disulfide (CS2) Atherosclerosis Oxidative stress Occupational exposure

No Title by Anna Lankoff; Anna Banasik; Monika Nowak (pp. 158-165).

Nodularin is a hepatotoxin from a cyanobacterium, Nodularia spumigena, that inhibits protein phosphatases 1 and 2 and posseses tumor-promoting activity. The aim of this paper was to examine whether nodularin is able to induce oxidative stress in mouse liver tissue and whether melatonin (protective compound against oxidative damage) could supress the activity of nodularin.We studied the effect of nodularin (1, 5, and 10 µg/kg body weight) and melatonin (5, 10, and 15 mg/kg body weight) administration on the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in mouse liver. Intraperitoneal treatment of mice with nodularin per 7 days decreased the activities of all estimated enzymes in a dose-dependent manner. Intraperitoneal treatment of animals with melatonin per 7 days increased the activities of SOD, CAT, and GSH-Px and this effect was concentration-dependent. Co-treatment (nodularin 5 µg/kg body weight + melatonin 5, 10, and15 mg/kg body weight per 7 days) and post-treatment with melatonin (nodularin 5 µg/kg body weight per 7 days + melatonin 5, 10, and 15 mg/kg body weight per next 7 days) increased the activities of SOD, CAT, and GSH-Px in comparison to the nodularin group. No significant differences from the nodularin group were noted in the group after pre-treatment with melatonin. In conclusion, these findings suggest that oxidative damage may be involved in the toxicity of nodularin. Moreover, co-treatment and post-treatment with 10 and 15 mg/kg body weight of melatonin may protect against nodularin-induced oxidative stress. There was no protective effect of pre-treatment with melatonin.

Keywords: Melatonin Nodularin Antioxidant enzymes Liver Mice

No Title by Márcia Carvalho; Félix Carvalho; Fernando Remião; Maria de Lourdes Pereira; Ricardo Pires-das-Neves; Maria de Lourdes Bastos (pp. 166-172).

The consumption of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is known to cause severe hyperthermia and liver damage in humans. The thermogenic response induced by MDMA is complex and partially determined by the prevailing ambient temperature (AT). This is of extreme importance since ecstasy is often consumed at "rave" parties, where dancing takes place in a warm environment, which may exacerbate the effect of MDMA on thermoregulation. In view of the fact that hyperthermia is a well-known pro-oxidant aggressive condition, its potential role in ecstasy-induced hepatocellular toxicity should be further studied. Thus, the present study was performed in order to evaluate the influence of AT on the effects of single administration of MDMA on body temperature and liver toxicity in Charles River mice. Animals were given an acute intraperitoneal dose of MDMA (5, 10 or 20 mg/kg) and placed in AT of 20±2°C or 30±2°C for 24 h. Body temperature was measured during the study using implanted transponders and a temperature probe reading device. Plasma and liver samples were used for biochemical analysis. Liver sections were also taken for histological examination. The parameters evaluated were (1) plasma levels of transaminases and alkaline phosphatase, (2) hepatic glutathione (GSH), (3) hepatic lipid peroxidation, (4) activity of hepatic antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, copper/zinc superoxide dismutase and manganese superoxide dismutase), and (5) liver histology. The hyperthermic response elicited by MDMA was clearly dose-related and potentiated by high AT. Administration of MDMA produced some evidence of oxidative stress, expressed as GSH depletion at both ATs studied, as well as by lipid peroxidation and decreased catalase activity at high AT. High AT, by itself, decreased glutathione peroxidase activity. Histological examination of the liver revealed abnormalities of a dose- and AT-dependent nature. These changes included vacuolation of the hepatocytes, presence of blood clots and loss of typical hepatic cord organisation. The results obtained in the present study suggest that oxidative stress plays a part in the first stage of MDMA-induced liver damage and that liver antioxidant status is aggravated by increased AT. Thus, these findings are in accordance with the hypothesis that high AT may potentiate ecstasy-induced hepatotoxicity by increasing body hyperthermia.

Keywords: 3,4-Methylenedioxymethamphetamine (MDMA) Ambient temperature Hyperthermia Hepatotoxicity Oxidative stress Mice

No Title by Danko Škare; Božica Radić; Ana Lucić; Maja Peraica; Ana-Marija Domijan; Sanja Milković-Kraus; Vlasta Bradamante; Ivan Jukić (pp. 173-177).

The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl-D-aspartate and muscarinic receptors showed low acute toxicity, having LD₅₀ values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD₅₀ of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD₅₀ of aldicarb to >16.00 LD₅₀ for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD₅₀ of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.

Keywords: Adamantanes Tenocyclidines (2-Hydroxyiminomethylpyridinium-1-methyl-4-carbamoyl pyridinium)-1-methyl ether chloride (HI-6) Carbamates Organophosphorus compounds

No Title by Rainer Tuominen; Pawel Baranczewski; Margareta Warholm; Lars Hagmar; Lennart Möller; Agneta Rannug (pp. 178-186).

Formation of DNA adducts as a result of exposure to polycyclic aromatic hydrocarbons (PAH) was studied in 98 potroom workers from an aluminium smelting plant and in 55 blue-collar workers without occupational PAH exposure. DNA from peripheral blood mononuclear cells (PBMC) was used for quantitation of individual PAH-DNA adducts by ³²P-postlabelling/high performance liquid chromatography (HPLC) analysis. Four individual DNA adducts (denoted A, B, C and D) were quantified in 141 of a total of 153 subjects. Genetic polymorphisms for cytochrome P-4501A1 (CYP1A1), microsomal epoxide hydrolase, N-acetyltransferase 2, glutathione transferases M1, P1 and T1 (GSTM1, GSTP1 and GSTT1, respectively) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were analysed. For 52 subjects, analysis of mRNA inducibility of CYP1A1 was performed. No statistically significant differences in the levels of total or individual DNA adducts A, C and D were found between potroom workers and control subjects. All potroom workers and the subgroup of potroom workers who reported to never/sometimes use personal respiratory protection (n=72) were found to have a significantly higher likelihood of having high levels of adduct B than control subjects [odds ratio (OR) =3.4 with 95% confidence interval (CI) of 1.3–9.2, and OR=4.2 with 95% CI 1.6–11.5, respectively]. In the subgroup, levels of adducts A and B were found to be significantly higher among workers with employment time of less than 6 months (n=5). Also, the levels of the individual DNA adducts were to some extent modified by genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and NQO1 and by CYP1A1 inducibility. In conclusion, levels of adduct B, identified by ³²P-postlabelling/HPLC methodology as an indicator of PAH exposure in aluminium production, were modified by the use of respiratory protection, length of employment and genetic polymorphisms.

Keywords: Occupational health DNA adducts Lymphocytes Polycyclic aromatic hydrocarbons Polymorphism

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Archives of Toxicology (v.76, #3)