Human & Experimental Toxicology

All acute, deliberate, drug-poisoning-related emergency department visits over two periods of one year, 1992-1993 (P1) and 2001-2002 (P2), were reviewed to investigate trends in substances used for acute self drug-poisonings over a 10-year period. For P1 and P2 respectively, 804 and 830 episodes of acute self drug-poisonings were compared. For the two studied periods, psycholeptic drugs predominated (78 and 77%); however, benzodiazepines declined (67 to 55%; P <0.01) and antidepressants in-creased (9.5 to 15%; P <0.01). Moreover, the type of antidepressant changed markedly with a decrease of the imipraminic antidepressants (48.4 to 10.7%) and an increase of selective serotonin reuptake inhibitors (31.2 to 74%). The proportion of benzodiazepine-related drugs increased with time (7.9 to 14.1%). The proportion of analgesics was 5.4% for P1 and 7.3% for P2; paracetamol, alone or associated to other compounds, remained the most incriminated. Nevertheless, opioids were more often mentioned during the later period (11.6 to 24.5%). The trend of the different pharmacological families used in acute self drug-poisonings is not fundamentally different over a 10-year period. However, there are some qualitative modifications, which are important for readjusting the emergency physician's toxicological knowledge and public health actions.

This paper presents cytotoxicity data of selected imidazolium ionic liquids evaluated in vitro on the human tumor cell line HeLa. It was found that for 1-n-butyl-3-methylimidazolium entities the toxicity depends strongly on the associated anion; EC₅₀ values are lowest for tetrafluoroborate. No direct dependence of the reduced effect concentration was found on elongating the short, methyl chain to ethyl or n-hexyl. Only for the ionic liquid with an n-decyl chain, the longest one studied, did higher hydrophobicity result in a EC₅₀ one order of magnitude lower than that obtained with the n-butyl entity. The effect concentrations of imidazolium ionic liquids in the HeLa system used are lower than the values obtained for conventional organic solvents such as dichloromethane, toluene or xylene.

Itraconazole and fluconazole are oral antifungal drugs, which have a wide spectrum antifungal activity and better efficacy than the older drugs. However, both drugs have been associated with hepatotoxicity in susceptible patients. The mechanism of antifungal drug-induced hepatotoxicity is largely unknown. Therefore, the aim of this present study was to investigate and compare the hepatotoxicity induced by these drugs in vivo. Rats were treated intraperitoneally with itraconazole or fluconazole either single (0, 10, l00 and 200 mg/kg) or subchronic (0, 10, 50 and loo mg/kg per day for 14 days) doses. Plasma and liver samples were taken at the end of the study. A statistically significant and dose dependent increase of plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were detected in the subchronic itraconazole-treated group. In addition, dose-dependent hepatocellular necrosis, degeneration of periacinar and mizonal hepatocytes, bile duct hyperplasia and biliary cirrhosis and giant cell granuloma were observed histologically in the same group. Interestingly, fluconazole treated rats had no significant increase in transaminases for both single and subchronic groups. In the subchronic fluconazole treated rats, only mild degenerative changes of centrilobular hepatocytes were observed. These results demonstrated that itraconazole was a more potent hepatotoxicant than fluconazole in vivo in rats.

Ethanolic extract of Emblica officinalis (EO) fruit extract was evaluated for protection against genotoxicity induced by the rodent carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA). Oral administration of EO fruit extract in various concentrations (100, 250, 500mg/kg b.wt) for seven consecutive days prior to a single intraperitoneal injection of DMBA decreased the frequency of bone marrow micronuclei induced in Swiss albino mice. Significant increases in the liver antioxidants, such as glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR) and detoxifying enzyme glutathione-S-transferase (GST), were found in the fruit extract treated group. The extract also reduced the hepatic levels of the activating enzymes cytochrome (CYt) P₄₅₀ and Cyt b₅. These increased in the carcinogen treated group, which emphasizes its protective effect against the carcinogen. There was a dose-dependent effect of the extract against the genotoxin with the maximum effect at 500 mg/kg b.wt. The protection afforded by EO may be associated with its antioxidant capacity and through its modulatory effect on hepatic activation and detoxifying enzymes.

Iron overload and enhanced hydroxyl radical (•OH) formation have been implicated as the causative factors of oxidative stress in different organs. Both pro-oxidant and anti-oxidant properties have been reported for nitric oxide (NO) in iron-mediated tissue injury. To determine the contribution of NO to iron-induced renal injury, eight groups of rats (eight in each group) were studied as follows: control (normal saline), L-Arg (L-arginine as a substrate of NO synthase, 400 mg/kg), L-NAME (an inhibitor of NO synthase, 8 mg/kg), Fe (iron dextran, 600 mg/kg), DFO (deferroxamine as a chelator of iron, 150 mg/kg), Fe+L-Arg, Fe+L-NAME, DFO+L-Arg. Twenty-four hours after the injections, blood samples were taken and kidneys removed for biochemical analysis. Plasma creatinine and urea were used to stimulate renal function. Renal tissue and plasma vitamin E levels, the most important endogenous fat soluble antioxidant, were measured by HPLC and UV detection. In this study, renal function was markedly reduced in the Fe group compared to controls (creatinine, 1.02± 0.05 mg/dL versus 0.78±0.04 P <0.05; urea, 49.59±1.69 mg/dL versus 40.75±0.86, P <0.01). Vitamin E levels were significantly lower in the Fe group compared to controls (plasma P <0.01; renal tissue P <0.05). Administration of L-Arg to Fe-treated groups prevented these reductions. L-NAME increased iron-induced toxicity significantly, demonstrated by further reduction in the vitamin E levels and renal function compared to the Fe group alone. We concluded that NO plays an important role in protecting the kidney from iron-induced nephrotoxicity. NO synthase blockade enhances iron-mediated renal toxicity in this model.

Airborne mono-2-ethylhexyl phthalate (MEHP) was studied for acute airway effects using a bioassay with BALB/c mice. Concentration-and time-dependent effects were obtained by continuous monitoring of the breathing pattern during exposure to 0.3-43.6 mg/m³ MEHP for 60 min. Additionally, inflammatory effects of MEHP were studied from bronchoalveolar lavage (BAL) fluid. MEHP showed no upper airway irritating effect. Lower airway irritation was apparent from a concentration-dependent decrease in tidal volume (shallow respiration) with a no-observed effect level (NOEL) of 0.3 mg/m³. The respiratory rate reached a maximum at about 8 mg/m³, demonstrating a rapid shallow breathing pattern. At concentrations above 4.9 mg/m³, the time of pause, another marker of lung irritation, increased concentration-dependently, resulting in a decrease in respiratory rate at high exposure levels. BAL fluid obtained from 0 to 72 hours after a 60 min exposure to 30 mg/m³ MEHP showed that the number of macrophage reached maximum about 16 hours after exposure. The NOEL was 1.7 mg/m³. BAL content of neutrophils, lymphocytes, eosinophils and epithelial cells was normal after exposure to 30 or 1.7 mg/m³ MEHP. Based on worst case inhalation scenario in the general population, no airway irritation is expected from non-occupational levels of MEHP originating from DEHP.