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Archives of Toxicology (v.68, #5)
Acute and subchronic inhalation toxicity of tetraethoxysilane (TEOS) in mice by Hiroshi Nakashima; Kazuyuki Omae; Tohru Sakai; Kazuto Yamazaki; Haruhiko Sakurai (pp. 277-283).
To clarify the acute and subchronic inhalation toxicity of tetraethoxysilane [TEOS, Si(OC2H5)4], groups of ten male ICR mice (SPF grade) were exposed to 1000 ppm TEOS for 1, 2, 4 or 8 h (acute inhalation study), or to 200 ppm of TEOS for 6 h/day, 5 days/week, for 2 or 4 weeks (subchronic inhalation study). The numbers of mice that died during 2 weeks of observation were 0, 1, 1 and 6 in the 1-, 2-, 4- and 8-h inhalation experiments and zero in the subchronic inhalation study. In the acute inhalation study, body weight decreased after TEOS exposure and did not reach the level of control mice during 2 weeks of observation except in the 1-h inhalation study. In the subchronic exposure study, weight gain was suppressed during the exposure period. Body weight in mice exposed for 2 weeks reached the level of non-exposed mice during the 2-week observation period, but did not do so in mice exposed for 4 weeks. Acute tubular necrosis (ATN) and acute splenic atrophy (ASA) were observed in all dead mice in the acute inhalation study, and tubulointerstitial nephritis (TIN) was frequently found in the surviving mice in both the acute and subchronic studies. However, blood biochemical examinations revealed no evidence of renal dysfunction. The olfactory epithelium was necrotic in all dead mice. In the subchronic inhalation study, infiltration of polymorphonuclear neutrophils in the nasal mucosa was observed in all mice killed 1 day after exposure. These results indicate that the LCL0 for 1-h exposure to TEOS and LC50 for 4-h exposure are greater than 1000 ppm, and that the kidney and nasal mucosa are the target organs for TEOS inhalation.
Keywords: Tetraethoxysilane; Semiconductor; Renal lesion; Nasal mucosa; Irritation
Early effects of benzene exposure in mice. Hematological versus genotoxic effects by U. Plappert; E. Barthel; K. Raddatz; H. J. Seidel (pp. 284-290).
Female BDF1 mice were exposed to 100, 300 and 900 ppm benzene 6 h/day, 5 days/week, up to 8 weeks. Hematological studies included peripheral blood data, T4 and T8 lymphocyte counts in the blood and the spleen, hemopoietic stem and progenitor cell assays in the marrow (CFU-S, CFU-C, BFU-E, CFU-E). The single cell gel assay (“comet assay”) was applied in parallel with cells from the peripheral blood, bone marrow, spleen and liver. The results showed minor changes in the stem and progenitor cells and the development of a slight anemia at 4 and 8 weeks, in agreement with reported data. New was the increase of the T4/T8 ratio in the peripheral blood (not in the spleen) at the end of the first week of exposure to 300 and 900 ppm. The results of the “comet assay” indicate a much higher sensitivity of this test system (strand breaks and alkali labile sites of DNA). The tail moment indicative of the damage to DNA increased as early as 3 days with 300 ppm in the peripheral blood cells. Furthermore, the liver cells did react to a much higher extent than the other cells tested. With 100 ppm significant changes were seen in the liver after 5 days, but not in the blood. The repair, studied 24 and 48 h after the end of the exposure, was almost complete after 5-day exposure period in the blood and the liver, but not after 4 weeks of exposure with 300 ppm in the blood, and 100 and 300 ppm in the liver.
Keywords: Benzene; Mice; Hematological effects; Genotoxicity
Metabolism and hepatotoxicity of N,N-dimethylformamide, N-hydroxymethyl-N-methylformamide, and N-methylformamide in the rat by M. Van den Bulcke; M. T. Rosseel; P. Wijnants; W. Buylaert; F. M. Belpaire (pp. 291-295).
The metabolism and hepatotoxicity ofN,N-dimethylformamide (DMF) and two of its metabolites,N-hydroxymethyl-N-methylformamide (HMMF) andN-methylformamide (NMF) were evaluated over a 4-day period in rats. DMF toxicity was dose dependent and delayed toxicity after the administration of a high DMF dose (13.7 mmol/kg) in comparison to a lower dose (4.1 mmol/kg) was observed. Treatment of rats with 13.7 mmol/kg DMF, HMMF, or NMF showed i) that DMF is more toxic than HMMF or NMR, and ii) that hepatotoxicity occurs later for DMF than for HMMF or NMF. Analysis of serum and urine samples demonstrated that DMF is first metabolized to HMMF, which is then partially converted to NMF. After HMMF administration, NMF was found both in serum and in urine. The time course of DMF and HMMF toxicity in relation to NMF formation fitted the hypothesis that the hepatotoxicity of DMF and HMMF is mediated via NMF. The degree of hepatotoxicity after HMMF and NMF treatment is similar. However, the degree of DMF hepatotoxicity is much higher than in the case of NMF or HMMF. The role of NMF as an obligatory intermediate in DMF and HMMF hepatotoxicity is discussed.
Keywords: Hepatotoxicity; Toxicokinetics; N,N-Dimethylformamide; N-Hydroxymethyl-N-methylformamide; N-Methylformamide
Lack of direct immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on human peripheral blood lymphocyte subsets in vitro by Dagmar S. Lang; Susannne Becker; George C. Clark; Robert B. Devlin; Hillel S. Koren (pp. 296-302).
A wide variety of immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in experimental animals has been documented. In contrast, the impact of dioxin on the human immune system remains controversial, although adverse health effects have been reported in humans after occupational or accidental exposure to dioxin. Recently, Neubert et al. (1991) found that a dose-dependent decrease of peripheral blood lymphocyte (PBL) subpopulations in humans and non-human primates, including helper-inducer/memory cells (CD4+CD29+) and B cells (CD20+) occurred in pokeweed mitogen (PWM) stimulated cultures at concentrations as low as 10−12–10−14 M TCDD. Therefore, the direct effects of dioxin on human PBL subpopulations have been studied, in order to determine their usefulness as sensitive biomarkers for human dioxin exposure. Lymphocyte cultures from healthy individuals were treated with 10−7 M–10−14 M TCDD in the absence and presence of stimulation with pokeweed mitogen (PWM) or anti-CD3 monoclonal antibody (moAb; OKT3) for 3 days. Cytochrome P450 (CYP1A1) enzyme induction, one of the best studied direct biological effects of TCDD on numerous cell types, was assayed in parallel by ethoxyresorufin-O-deethylase (EROD) activity. Percentages of the different lymphocytes subsets, including CD2 (T cells); CD4; CD45 RA (suppressor-inducer/virgin T cells); CD4 CD29; CD8; CD19 (B cells) as well as interleukin 2 (IL-2) receptor (CD25) and class II antigen (HLA-DR) expression, were anlayzed by flow cytometry. DNA synthesis was determined by3H-thymidine uptake after 3 days of culture. In the present study, all stimulated lymphocyte cultures showed a dose-dependent significant increase of CYP1A1 activity at dioxin concentrations of 10−7 and 10−9 M. No enzyme activity could be detected at lower concentrations of TCDD. On the other hand, neither alteration in surface marker distribution nor suppression of lymphocyte proliferation could be demonstrated in mitogen-activated cells following any concentration of TCDD treatment. These data suggest that the inducibility of CYP1A1 enzyme activity is not correlated with direct immunotoxic effects in vitro in human PBL. In contrast to a previous report by Neubert et al. (1991), lymphoproliferation and phenotypes of human PBL are resistant to dioxin exposure in vitro and therefore appeared not to be useful as sensitive biomarkers in human exposure studies.
Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Human peripheral blood lymphocytes; Surface antigen expression; Mitogen stimulation in vitro; Cytochrome P450 (CYP1A1) enzyme induction
Transforming growth factor-β1 inhibits TCDD-induced cytochrome P450IA1 expression in human lung cancer A549 cells by Christoph Vogel; Olaf Döhr; Josef Abel (pp. 303-307).
The effect of transforming growth factor-β1 (TGF-β1) on the expression of cytochrome P450IA1 (CYPIA1) was examined in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated human lung cancer A549 cells. Using the reverse transcription-polymerase chain reaction (RT-PCR) it was demonstrated that TGF-β1 inhibits CYPIA1 expression in a dose dependent manner. Based on the inhibitory concentration 50 (IC50) of about 5 pM it is suggested that TGF-β1 has a physiological function in downregulation of this cytochrome. In the presence of cycloheximide, the effect of TGF-β1 on CYPIA1 mRNA disappeared. This finding indicates that protein synthesis may be required for the TGF-β1 mediated response of CYPIA1. The possible mechanisms by which TGF-β1 interacts with TCDD-responsive drug metabolizing enzymes are discussed.
Keywords: 2,3,7,8-TCDD; Transforming growth factor-β1 ; Cytochrome P450IA1; Lung cancer A549 cells
Neuropathology of organophosphate-induced delayed neuropathy (OPIDN) in young chicks by Kathleen A. Funk; John D. Henderson; Chen-Hsuan Liu; Robert J. Higgins; Barry W. Wilson (pp. 308-316).
To examine the phenomenon of apparent age resistance of young chicks to organophosphate-induced delayed neuropathy (OPIDN), groups of either 2- or 10-week-old chicks were exposed subcutaneously daily for 4 days to the neuropathic organophosphate (OP), di-isopropylfluorophosphate (DFP, 1 mg/kg), the non-neuropathic OP, paraoxon (PO, 0.25 mg/kg) or atropine (20 mg/kg). Subsequently, all birds were examined at post-exposure intervals (calculated from the last day of exposure) for up to 56 days for neurological deficits and morphological lesions in the central and peripheral nervous systems (CNS, PNS). Clinically, none of the birds in the 2-week-old groups, or in the 10-week-old PO or atropine exposed groups had neurological deficits. However, all birds in the 10-week-old DFP exposed group developed ataxia by 7 days post-exposure (DPE) and then progressive paralysis. Therefore, all birds in the 10-week-old groups were killed at 14 DPE. Pathologically, the 2-week-old DFP exposed chicks had increasingly severe lesions of Wallerian-like degeneration predominantly in the spinal cord from 7 DPE and subsequently. In the 10-week-old DFP exposed chicks, the degenerative lesions of OPIDN were first detected in the CNS at 3 DPE and then with equally increasing severity in the CNS and PNS up to 14 DPE. A higher incidence of neuronal necrosis and chromatolysis in ventral motor horn neurons of spinal cord grey matter and in dorsal root ganglia occurred in both the DFP exposed age groups compared with those lesions in other groups. These results demonstrate that after neuropathic DFP exposure, 2-week-old chicks develop pathological lesions in the spinal cord without neurological deficits. In both age groups, onset of degenerative lesions in the spinal cord preceeded those in the PNS. The claim of apparent age resistance of chicks to OPIDN needs to be re-evaluated.
Keywords: Organophosphate-induced delayed neuropathy (OPIDN); Avian; Nervous system; Ultrastructure; Di-isopropylfluorophosphate (DFP); Paraoxon; Atropine
Evaluation of mercury in hair, blood and muscle as biomarkers for methylmercury exposure in male and female mice by Jesper Bo Nielsen; Ole Andersen; Philippe Grandjean (pp. 317-321).
Recently established reference intervals demonstrate that blood mercury is significantly higher in women than in men. Mercury in blood and hair are both used as biomarkers for human methylmercury exposure and employed in risk assessment without considering possible sex-related differences in toxicokinetics of methylmercury. In an experimental study using male and female mice of three different strains, the validty of mercury in hair, blood and muscle as indicators of methylmercury exposure was evaluated. Significant sex-related differences in the toxicokinetics of methylmercury were observed in the mice and it is concluded that hair and blood levels of mercury are of questionable relevance as indicators of both body burden and target organ concentrations of mercury. However, blood concentrations might be used as an indicator of brain deposition and the correlation improves after corrections due to sex-related differences in toxicokinetics.
Keywords: Methylmercury; Biomarkers; Sex-related difference; Mice
Early renal effects of occupational exposure to low-level hexavalent chromium by Teruo Nagaya; Noriko Ishikawa; Hideo Hata; Akemi Takahashi; Izumi Yoshida; Yoshinari Okamoto (pp. 322-324).
To detect early renal effects of occupational exposure to hexavalent chromium (Cr), urinary total proteins (U-TP), urinary albumin (U-Alb) and urinary retinol-binding protein (U-RBP) were determined in 166 male Cr platers and 106 male controls. The mean employment time in Cr plating for the platers was 12.6 years. Urinary Cr (U-Cr), which was determined as an index of Cr exposure, ranged from “not detected” to 19.91 μg/g creatinine in the platers. The U-Cr level was lower than those in other previous studies. Age-adjusted U-TP, U-Alb or U-RBP levels were not different between the platers and the controls. In the platers, a significant positive correlation was found between age-adjusted U-TP and U-Cr, but U-Cr had no significant relation to age-adjusted U-Alb or U-RBP level. Employment time had no effect on any age-adjusted urinary proteins. The Cr exposure may have been too low to induce definite renal dysfunction. Early renal effects of low-level Cr exposure may be mild, and may not be specific to renal function.
Keywords: Chromium; Plater; Kidney; Urinary proteins; Healthy worker effect
Mechanism for the decrease in the accumulation of cadmium (Cd) in Cd-resistant Chinese hamster V79 cells by Naoto Tsuchiya; Takafumi Ochi (pp. 325-331).
The mechanism for the decrease in the accumulation of cadmium (Cd) in Cd-resistant Chinese hamster V79 (Cdr) cells in culture was investigated in a comparison with Cd-sensitive (Cds) cells. Both Cdr and Cds cells took up Cd in a time-dependent manner but the rate of uptake of Cd by Cdr cells was about 15% of that by Cds cells. Kinetic studies of the uptake of Cd showed that the Vmax values for Cdr and Cds cells were 0.31 and 0.46 pmol Cd/h per mg protein, respectively. The Km values were 31.95 μM for Cdr cells and 3.15 μM for Cds cells. Mersalyl acid, a sulfhydryl (SH) blocker to which cells are impermeable, inhibited the uptake of Cd by Cds cells at subtoxic concentrations while Cdr cells were insensitive to inhibition by mersalyl acid, suggesting that SH groups in the plasma membrane play a role in the uptake of Cd. Uptake of Cd by Cds cells was dependent on the pH of the incubation medium and the rate of uptake was very high at pH 7.4 and pH 8.0 relative to the rates at pH 6.0 and pH 6.8. By contrast, the uptake of Cd by Cdr cells was lower at all pH values than that by Cds cells. The decrease in the rate of uptake of Cd by Cdr cells could not be ascribed to an increase in the efflux of Cd. A Cd-blotting technique was used to detect plasma membrane proteins with high affinity for Cd. Two major differences in terms of Cd-binding proteins (Cd-BPs) were observed between Cdr and Cds cells. A 110-kDa Cd-BP, detected in Cds cells, was found at a reduced level in Cdr cells, while an 82-kDa Cd-BP, which was not observed in Cds cells, was detected in Cdr cells.
Keywords: Cadmium-resistant V79 cells; Cd transport; Plasma membrane; Cd-binding proteins
Computer programs for calculation of median effective dose (LD50 or ED50) using the method of moving average interpolation by Michelle M. Schaper; Randolph D. Thompson; Carrol S. Weil (pp. 332-337).
Over the past 40 years, toxicologists and pharmacologists have used tables published by Weil for the determination of LD50 (or ED50) values and their associated 95% confidence intervals. With the advances in computer technology, it is now common for investigators to have personal computers in their laboratories. Therefore, two identical programs were developed for determination of the LD50 (or ED50) which may be run on a personal computer. One of these programs was written in BASIC, and the other in FORTRAN. The programs are easy and rapid to use, requiring minimum computer hardware and little, if any, knowledge of programming. They also offer more user flexibility than the previously published tables of Weil, in that there are fewer restrictions on the number of animals and number of dosage levels used in an experiment. The output of the programs may be typed on the screen of a computer monitor, and may be sent to a printer. The two programs calculate the LD50 and 95% confidence intervals for the LD50. These programs should be valuable for many investigators.
Keywords: Computer program; Median effective dose; Moving average interpolation
Excretion of malondialdehyde, formaldehyde, acetaldehyde, acetone and methyl ethyl ketone in the urine of rats given an acute dose of malondialdehyde by Paul I. Akubue; Debasis Bagchi; William J. Ihm; Sidney J. Stohs (pp. 338-341).
A high pressure liquid chromatographic system (HPLC) has recently been developed for the simultaneous detection of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON). We have examined the urinary excretion of these four lipid metabolites in the urine of rats following the acute oral administration of MDA (158 mg/kg body weight). During the first 12 h, increases in the urinary excretion of MDA and ACT of approximately 192- and 70-fold, respectively, were observed. The urinary excretion of both MDA and ACT decreased thereafter. An increase in FA excretion was observed only 12–24 h after MDA administration. A significant decrease in ACON relative to control values was observed 12–48 h after MDA treatment. Two new peaks were present in the HPLC chromatograms of urine samples 0–24 h after MDA administration. Both peaks were shown to be due to methyl ethyl ketone (MEK) which appears to be formed as a result of MDA metabolism. The results demonstrate that orally administered MDA is rapidly excreted in the urine, and alters the metabolism and excretion of other lipid metabolites.
Keywords: Malondialdehyde administration; Formaldehyde; Acetaldehyde; Acetone; Methyl ethyl ketone; Lipid metabolite excretion; High pressure liquid chromatography