Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.69, #7)

Auditory and vestibular functions after single or combined exposure to toluene: a review by Thais C. Morata; Per Nylén; Ann -Christin Johnson; Derek E. Dunn (pp. 431-443).

Toluene is a widely used organic solvent, heavily employed in many manufacturing industries. Recently, evidence has begun to accumulate on the deleterious effect of toluene exposure has on the auditory and vestibular systems. Although little published information exists regarding these effects, the reported findings indicate a need for further investigation. The results of such investigations may dramatically affect occupational hearing conservation practices and legislation. Both human and animal studies will be summarized in discussing the effects of toluene alone or in combination with noise or other chemicals. Gaps in scientific knowledge are highlighted to assist future research.

Keywords: Balance; Hearing; Organic solvents; Ototoxicity; Toluene; Vestibulotoxicity

Subchronic toxicity of 3-phenylamino alanine, an impurity in l-tryptophan reported to be associated with eosinophilia-myalgia syndrome by Fumiaki Sato; Yuji Hagiwara; Yoshinobu Kawase (pp. 444-449).

Consumption of certain product lots of l-tryptophan (LT) has been reported to be epidemiologically associated with an outbreak of eosinophilia-myalgia syndrome (EMS) in the United States. Since the production lots were found to contain 3-phenylamino alanine (PAA) as an impurity, its effects were studied by administering the substance orally by gavage to 5-week-old Sprague-Dawley rats. Groups of animals were given PAA for 13 consecutive weeks at dose levels of 1, 10 and 100 mg/kg per day. The animals were killed at 4 or 8 weeks. Hematological and blood biochemical tests were performed and detailed histopathological observations were made. No significant abnormalities were observed in the test animals and in particular no EMS-like conditions. A brief summary of other animal studies using several species of rats and mice performed in our laboratory since 1989 on various LT related substances is also presented. No EMS-like effects were observed in these studies.

Keywords: Eosinophilia-myalgia syndrome; l-Tryptophan; 3-(Phenylamino) alanine; Rat; 1, 1′-Ethylidenebis (l-tryptophan)

Phagocytes render chemicals immunogenic: oxidation of gold(I) to the T cell-sensitizing gold(III) metabolite generated by mononuclear phagocytes by Carsten Goebel; Malgorzata Kubicka-Muranyi; Torsten Tonn; José Gonzalez; Ernst Gleichmann (pp. 450-459).

The oxidizing capacity of phagocytic cells is suspected to play a major role in the generation of immunogenic drug metabolites, in particular those that cause extrahepatic immunopathological lesions. In the case of the antirheumatic drug gold(I) disodium thiomalate (Na₂Au(I)TM), oxidation of the Au(I) ion to Au(III) appears to be responsible for the adverse immune reactions which may develop during gold therapy. Here, we show that the reactive metabolite Au(III) may be generated by mononuclear phagocytes (MΦ) exposed to Au(I). The generation of Au(III) was analyzed by means of the adoptive transfer popliteal lymph node assay (PLNA) in mice, using T lumphocytes previously sensitized to Au(III) as a detection probe. Donors of the Au(III)-primed T cells were either directly sensitized to Au(III) by injection of tetrachloroauric acid (HAu(III)Cl₄), or indirectly via chronic treatment with Na₂Au(I)TM. As donors of peritoneal cells (PC), we used mice which had received weekly i.m. injections of Na₂Au(I)TM for 12 weeks and contained increased numbers of activated B cells. The PC of these mice were found to elicit a significant secondary response when used as antigenic material for the restimulation of Au(III)-primed T cells. The immunogenicity of PC obtained from Na₂Au(I)TM-treated mice paralleled the total gold content of these cells. Noteworthily, MΦ exposed to Au(I) in vitro also proved capable of eliciting a specific secondary response of Au(III)-primed T cells. Hence, MΦ exposed to Au(I) generate the reactive intermediate Au(III) which, apparently via oxidation of self proteins, sensitizes T cells. As MΦ are constituents of many different organs and, moreover, communicate with T cells, their capacity to generate Au(III) may account for the various extrahepatic adverse immune reactions induced by Au(I) drugs.

Keywords: Gold disodium thiomalate; Adverse immune reactions; Reactive metabolite; Mononuclear phagocytes; Immunotoxicity

Effects of paraquat, dinoseb and 2,4-D on intracellular calcium and on vasopressin-induced calcium mobilization in isolated hepatocytes by Carlos M. Palmeira; António J. Moreno; Vitor M. C. Madeira (pp. 460-466).

The effects of the herbicides paraquat, dinoseb and 2,4-D on intracellular Ca²⁺ levels and on vasopressin-induced Ca²⁺ mobilization were investigated in intact isolated hepatocytes. Incubation of rat hepatocytes with paraquat (5 mM for 60 min) and dinoseb (10 μM) resulted in a time-dependent loss of viability by approximately 25%. Viability of cells treated with 2,4-D decreased significantly, dropping to about 20% at 10 mM and 60 min incubation. Exposure of hepatocytes to paraquat (1–10 mM) for 60 min had no effect on the basal level of [Ca²⁺] i. Additionally, exposure to paraquat had no effect on the magnitude and on the duration of the [Ca²⁺] i response to vasopressin. In the presence of 2,4-D (1–10 mM), basal [Ca²⁺] i increases as a function of herbicide concentration. The magnitude of the Δ[Ca²⁺] i response decreases from 256± 8nM in control to 220 ± 5nM, at 10mM 2,4-D. Exposure of hepatocytes to dinoseb (1–10 μM) had no effect on the basal level of [Ca²⁺] i. However, a strong concentration-dependent decrease in the magnitude of Δ[Ca²⁺] i in response to vasopressin was noticed at 60 min incubation. Dinoseb markedly inhibited the stimulation of the production of inositol phosphates by vasopressin stimulus. The present study demonstrates that paraquat, 2,4-D and dinoseb cause cell death in hepatocytes by mechanisms not related to an early increase in [Ca²⁺] i. Additionally, it has been shown for the first time that dinoseb disturbs the transduction mechanism promoted by vasopressin by inhibiting the formation of IP₃.

Keywords: Paraquat; Dinoseb; 2,4-D; Intracellular calcium; Rat; Hepatocytes

Assessment of the developmental toxicity of deferoxamine in mice by M. Angeles Bosque; José L. Domingo; Jacinto Corbella (pp. 467-471).

Deferoxamine (DFO), an efficient chelating agent available for the treatment of iron and aluminium overload, was evaluated for developmental toxicity in Swiss mice. Intraperitoneal injections of DFO were given to pregnant animals at 0, 44, 88, 176, and 352 mg/kg per day on gestational days 6 through 15. Maternal clinical status was monitored daily during and after treatment. Fetal parameters, including external, visceral, and skeletal malformations and variations, were assessed. Mice were killed on day 18. No maternal mortality was observed, but dams exhibited reduced body weight gain during treatment at 88, 176, and 352 mg/kg per day. Body weight at termination, corrected body wieght, and food consumption were reduced in all groups. In contrast, the only significant treatment-related embryo/fetal effect was a decrease in the number of live fetuses per litter at 352 mg/kg per day. The no-observable-adverse-effect level (NOAEL) for maternal toxicity of DFO was < 44 mg/kg per day, whereas the NOAEL for developmental toxicity was 176 mg/kg per day. In summary, intraperitoneal administration of DFO to mice during organogenesis produced developmental toxicity in the presence of maternal toxicity. Because of the remarkable maternal toxicity of DFO, extreme caution in the use of this drug is recommended during pregnancy.

Keywords: Maternal toxicity; Developmental toxicity; Deferoxamine; Mice

Development of a suspension organ culture of the fetal rat palate by Nadim Al-Obaidi; Ursula Kastner; Hans -Joachim Merker; Stephan Klug (pp. 472-479).

On the basis of an already established suspension organ culture system of mouse palate anlagen, we developed a corresponding culture system for rat palate anlagen. In order to optimize the culture results we systematically studied the influence of main “culture conditions” such as dissection technique, rotation speed, gassing schedule, and developmental stage at the onset of culture for mice and rat palate anlagen. This system allows culturing rat palate anlagen from day 15 of gestation to day 18+8 h (80 h) under serum- and antibiotic-free conditions using a chemically defined medium, resulting in 90% fused palates. The explants, containing the maxillary vault and the palatal shelves, were cultured in siliconized culture flasks at a rotation speed of 12 rpm and a temperature of 37°C (Table 1).

Keywords: Organ culture; Palatogenesis in vitro; Rat fetus; Mouse fetus

Nephrotic syndrome associated with N-hydroxyureas, inhibitors of 5-lipoxygenase by Nicholas G. Read; Paul J. Astbury; Gareth O. Evans; David A. Goodwin; Ann Rowlands (pp. 480-490).

The N-hydroxyurea derivatives 70C ((E)-N-{3-[3-(4-fluorophenoxy)phenyl]-1-(R,S)-methylprop-2-enyl}-N-hydroxyurea) and its (R) 225C and (S) 404C enantiomers, which were being developed as 5-lipoxygenase inhibitors for the treatment of certain allergic and inflammatory conditions, were found to cause severe glomerulonephropathy in the rat. The lesion appeared to be of greater severity in female rats compared with male rats. In addition, 70C and 225C treated animals appeared more severely affected than 404C treated animals. Detailed examination of the lesion in animals dosed with 225C showed that there was a clear relationship between the onset of the lesion and the dose given, i.e. the higher the dose the sooner the lesion developed. The earliest changes detected in the kidney by transmission electron microscopy were noted in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. In the more advanced lesion, the degree of foot process loss became more obvious and changes in the kidney tubules were seen by light microscopy. The morphological changes were mirrored by a dose-related increase in water consumption, an increased kidney to body weight ratio and gastrointestinal oedema, suggesting impaired renal function. Shortly after the onset of foot process loss, decreases in the total plasma protein and albumin and increases in the plasma cholesterol, triglycerides, urea and creatinine were recorded. These changes, particularly the foot-process loss, together with increased proteinuria, hypoalbuminaemia, hypercholesterolaemia and lipaemia, are all characteristic of “minimal change nephrotic syndrome”. Because of the serious nature of the kidney lesion caused by these N-hydroxyureas in the rat, it was considered that it precluded their development as therapeutic agents for use in man.

Keywords: 5-Lipoxygenase inhibitors; N-Hydroxyureas; Nephrotoxicity; Rat

Altered hepatic eicosanoid concentrations in rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid by Mary W. Wilson; L. Travis Lay; Ching K. Chow; Hsin -Hsiung Tai; Larry W. Robertson; Howard P. Glauert (pp. 491-497).

Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal β-oxidation path-way and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E₂ and F_2α (PGE₂, PGF_2α) thromboxane B₂ (TXB₂), and leukotriene C₄ (LTC₄) were measured by immunoassay. Concentrations of PGE₂, PGF_2α, and TXB₂ were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC₄ concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis.

Keywords: Ciprofibrate; Perfluorodecanoic acid; Eicosanoids; Peroxisome

Modulation of cellular antioxidant defense activities by sodium arsenite in human fibroblasts by Te -Chang Lee; I -Ching Ho (pp. 498-504).

Many studies have shown that oxygen radicals can be produced during arsenic metabolism. We report here that in human fibroblasts (HFW cells) sodium arsenite exposure caused increased formation of fluorescent dichlorofluorescein (DCF) by oxidation of the nonfluorescent form. The enhanced DCF fluorescence was inhibited by a radical scavenger, butylated hydroxytoluene. The effects of sodium arsenite treatment on cellular antioxidant activities were then examined. Treatment of HFW cells with sodium arsenite resulted in a significant increase in heme oxygenase activity and ferritin level. Sodium arsenite-enhanced heme oxygenase synthesis was inhibited by co-treatment of cells with the antioxidants sodium azide and dimethyl sulfoxide. Furthermore, sodium arsenite treatment did not apparently affect glucose-6-phosphate dehydrogenase activity, but resulted in significantly increased glutathione levels and superoxide dismutase activity, slightly decreased glutathione peroxidase activity, and significantly decreased catalase activity. Sodium arsenite toxicity was partly reduced by addition of catalase to the culture medium. These results imply that arsenite can enhance oxidative stress in HFW cells.

Keywords: Arsenite; Glutathione; Antioxidant activities; Heme oxygenase; Ferritin

Glutathione-S-transferase (GST) theta polymorphism influences background SCE rate by K. R. Schröder; F. A. Wiebel; S. Reich; D. Dannappel; H. M. Bolt; E. Hallier (pp. 505-507).

Polymorphism of glutathione S-transferase θ (GSTT1) modulates the toxicity of halogenated alkanes and epoxides in humans. The enzymatic activity of glutathione S-transferase θ and its corresponding gene is lacking in about 30% of the central European population. It has now been demonstrated that the background rate for sister chromatid exchange (SCE) is affected by this particular polymorphism. Smoking as a known inducer of SCE was taken into account. A group of GSTT1-positive subjects exhibited lower SCE rates than GSTT1-negative individuals (7.55±0.77 versus 8.74±1.24 SCE/mitosis, respectively, p<0.005). Non-smoking GSTT1-positive individuals showed the lowest SCE rate (7.26±0.71 SCE/mitosis), significantly lower than the rates of smoking GSTT1-positive and non-smoking GSTT1-negative subjects (8.14±0.55 SCE/mitosis and 8.12±0.88 SCE/mitosis, respectively, p<0.025 in both cases). Smoking GSTT1-negative subjects exhibited the highest SCE rates (9.28±1.3 SCE/mitosis). It is hypothesized that GSTT1 is protective against background genotoxic damage. Since ethylene oxide is a proven substrate of GSTT1, the detoxification of this epoxide arising from endogenous ethylene may modulate SCE background rates.

Keywords: Glutathione-S-transferase; Theta polymorphism; Sister chromatid exchange

Sections

Personal tools

Archives of Toxicology (v.69, #7)

Sections

Personal tools

Local resources

Archives of Toxicology (v.69, #7)