[show abstract][hide abstract] ABSTRACT: Systemic and respiratory tract (RT) toxicity of triethanolamine (TEA) was assessed in a 28-day nose-only inhalation study in Wistar rats (10animals/sex, concentrations: 0, 20, 100, 500mg/m3; 5 days/week, 6h/day). In two nose-only 90-day inhalation studies, with similar exposure design, Wistar rats were exposed to 0, 15, 150, 400mg/m3 diethanolamine (DEA) (DEA Study 1:13animals/sex, general subchronic study) and to 0, 1.5, 3, 8mg/m3 (DEA Study 2:10animals/sex) to specifically investigate respiratory tract toxicity. Only DEA induced systemic toxicity at or above 150mg/m3 (body and organ weight changes, clinical- and histo-pathological changes indicative for mild blood, liver, kidney and testicular effects). Neurotoxicity was not observed for both substances. Exposure to both substances resulted in laryngeal epithelial changes starting from 3mg/m3 for DEA (reversible metaplasia at the base of the epiglottis, inflammation at higher concentrations extending into the trachea) or from 20mg/m3 for TEA (focal inflammation, starting in single male animals). TEA appears to be less potent with respect to systemic toxicity and RT irritancy than DEA. The 90-day no adverse effect concentration" (NOAEC) for changes due to TEA exposure in the respiratory tract was 4.7mg/m3 derived by extrapolation from the NOAEC of the 28day study.
Food and Chemical Toxicology 07/2008; 46(6):2173-83. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Administration of an iron-deficient diet to Wistar rats resulted within 14 days in reduced serum iron concentrations, a microcytic hypochromic anemia, characteristic for impaired hemoglobin synthesis, and an increase of duodenal epithelial cell proliferation. After 5 weeks of iron deficiency, hypochromic microcytic anemia and a clear increase of duodenum weight but no pronounced effects on cell proliferation was observed. Increased duodenum weights corresponded to significant increases in mucosal area, indicating a diffuse, simple mucosal hyperplasia. The sequence of events following iron depletion thus appears to be: (1) reduced serum iron levels, (2) induction of hypochromic microcytic anemia, (3) increased duodenal epithelial cell proliferation, and (4) increased duodenal weight (increased mucosal area). Iron deficiency anemia was rapidly reversible after a 2-week recovery period. However, increased duodenum weights were still noted at that time. Intramuscular iron supplementation in animals fed with iron-deficient diet maintained body iron levels not below normal values, and neither anemia nor increased duodenum cell proliferation were detected after 14 days. A 5-week iron supplementation period resulted in slightly increased serum iron values, and slightly decreased duodenal epithelial cell proliferation. Thus, increased duodenum mucosal hyperplasia was shown to be secondary to depletion of body iron and anemia and reflects an attempt to increase iron absorption to counteract iron deficiency.
[show abstract][hide abstract] ABSTRACT: Styrene is not carcinogenic in rats but has caused pneumotoxicity and increased lung tumors after inhalation in mice. This study investigated whether styrene-7,8-oxide, ring-oxidized, and side-chain hydroxylated styrene metabolites induce cell proliferation, apoptosis, pathological changes, and glutathione depletion in mice lungs. Intraperitoneal treatment with phenylacetaldehyde and phenylacetic acid (3 x 100 mg/kg b.w./day) increased the levels of apoptosis and cell proliferation in the alveoli without producing any effects in the terminal bronchioli, the target site of tumor formation in mice. Only styrene-oxide (SO) at 3 x 100 mg/kg b.w./day and 4-vinyl-phenol (4-VP) at 3 x 35 and 3 x 20 mg/kg b.w./day, respectively, caused up to 19-fold increases in cell proliferation in the large/medium bronchi and terminal bronchioles; marginal increases in alveolar cell proliferation were noted with SO (1.6-fold) but not with 4-VP. These compounds also caused glutathione depletion in the bronchiolar epithelium and histomorphological changes of the bronchiolar epithelium in large and medium bronchi and terminal bronchioles. Changes were characterized by flattened cells and a loss of the typical bulging of the "dome-shaped" Clara cells, suggesting that Clara cells were primary target cells. The specific reactions of mouse lung to SO and 4-VP could serve as a verifiable hypothesis for the different response of rats and mice with regard to tumor formation.
Regulatory Toxicology and Pharmacology 07/2005; 42(1):24-36. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Styrene has been shown to cause an increase in the incidence of lung tumors in CD-1 mice following chronic exposure at 40 and 160 ppm, whereas no treatment-related increase in tumors in any organ was seen in rats chronically exposed to up to 1000 ppm styrene. So far most of the mechanistic studies have been performed with male animals. The aim of the present study was to further elucidate the target cell population in mouse lungs exposed to styrene, and to investigate possible differential in vivo effects (e.g., glutathione depletion, increased lipid peroxidation, and oxidative DNA damage). Groups of female CD-1 mice were exposed to styrene at concentrations of 0, 172 or 688 mg/m3 (0, 40 or 160 ppm) for 6 h per day on 1 day, 5 consecutive days or for 20 days during a 4 week period. Groups of female Crl:CD rats were exposed to styrene at concentrations of 0, 688 or 2150 mg/m3 (0, 160 or 500 ppm) for a single 6 h period or for 6 h per day on 5 consecutive days. No signs of lung toxicity were observed in rats. The cytology of cells in lung lavage fluid provided no signs of an inflammatory response in either rats or mice. In mice, both exposure levels caused decreased CC16 protein concentrations in lung lavage fluid after 1 and 5 exposures and in mouse blood serum throughout the study, suggesting that styrene may cause destruction of Clara cells in mice. Degenerative lesions in mouse Clara cells (vacuolar cell degeneration, cell necrosis) were revealed by electronmicroscopy. After 5 and 20 exposures of mice at 160 ppm, cellular crowding, expressed as an irregular epithelial lining and indicative of a very early hyperplasia was noted. Although a depletion of glutathione was noted in mouse lung homogenates after 20 exposures, there was no evidence of oxidative stress as indicated by unchanged concentrations of 8-OH-deoxyguanosine. Malondialdehyde, an indicator of lipid peroxidation, was slightly increased in mice after 1 exposure at 160 ppm only.
Food and Chemical Toxicology 11/2004; 42(10):1655-67. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diethanolamine (DEA) has been shown to induce liver tumours in B6C3F(1) mice in a previous 2-year dermal study. To elucidate the mode of action groups of eight male and eight female B6C3F1 mice were dermally exposed to daily DEA doses of 0 or 160 mg/kg body weight/day for 1 week. Reversibility was assessed after a 3-week treatment-free recovery period. Subsequently groups of 10 male B6C3F(1) mice were dermally exposed to daily DEA doses of 0 or 160 mg/kg body weight for 1, 4 or 13 weeks. Finally, groups of 8 male B6C3F(1) mice were dermally exposed to daily DEA doses of 0, 10, 20, 40, 80, and 160 mg/kg body weight for 1 and 13 weeks. Following a 1-week treatment, DEA caused increased cell proliferation (5-bromo-2'-deoxyuridine (BrdU) method) in zone 3 (central vein region) of the liver lobules at 160 mg/kg body weight. Reversibility of liver cell proliferation was demonstrated in the recovery phase. In the subsequent studies increased cell proliferation was observed at 10 mg/kg body weight or higher after 13 weeks of treatment. These results support the hypothesis that sustained liver cell proliferation is a potential non genotoxic mode of action by which DEA promotes liver tumours in B6C3F(1) mice.
Food and Chemical Toxicology 02/2004; 42(1):127-34. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F(1) mice. Groups of female B6C3F(1) mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m(3) for 6 h per day, for 5 consecutive days. One-half of the animals in each THF exposure group were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) at 100 mg/kg (i.p.) 1 h before the start of each THF exposure period. Treatment with THF at 15,000 mg/m(3) caused marked microsomal enzyme induction in the liver. The cytochrome P450 content was nearly doubled (+98%), pentoxyresorufin-O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities were increased by 600% and 160%, respectively. ABT pretreatment effectively blocked microsomal enzyme induction at 15,000 mg/m(3). THF exposure had no effect on the subcellular morphology of hepatocytes, whereas ABT-pretreatment caused centrilobular fatty change. THF at 15,000 mg/m(3) caused increased cell proliferation in zone 3 (central vein region) of the liver (according to Rappaport), as indicated by a significantly higher PCNA (Proliferating Cell Nuclear Antigen) labelling index, but there were no effects at 5,400 ppm. ABT pretreatment prior to THF exposure at 15,000 mg/m(3) caused an exacerbated proliferative response of mouse liver, significantly higher PCNA labelling indices being observed in zones 2 (midzonal region) and 3. The exacerbated proliferative response of mouse liver under conditions of inhibited THF metabolism suggests that the mitogenic effects are related to prevailing THF tissue concentrations and not to the generation of THF oxidative metabolite(s).
Archive für Toxikologie 09/2003; 77(8):459-64. · 5.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: To elucidate possible mechanism(s) of carcinogenic action of tetrahydrofuran (THF) that had been demonstrated in previous inhalation studies, groups of male F344 rats and female B6C3F(1) mice were exposed to dynamic atmospheric concentrations of 0, 600, 1800, or 5400 mg/m(3) for 6 h per day, either for 5 consecutive days or for a period of 4 weeks (5 days per week). The reversibility of treatment-related changes was investigated in rats and mice exposed for 5 days and sacrificed 21 days after the last exposure. Female B6C3F(1) mice exposed to 5400 mg/m(3) showed significantly increased cytochrome P450 content, increased ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase activities, increased cell proliferation (5-bromo-2'-deoxyuridine-method) and an increased mitotic index in liver zones 2 (midzonal region) and 3 (central vein region). The changes were found to be reversible after a 3-week treatment-free period (cell proliferation examined, only). Male F344 rats showed dose-related alpha2u-globulin (alpha2u) accumulation in the renal cortex after 5 or 20 exposures, and there were no signs of reversal after a 3-week treatment-free period. After 20 exposures at 5400 mg/m(3), the alpha2u accumulation was found to be associated with increased cell proliferation in "hot spots" of the renal cortex and increased apoptosis. Increased cell proliferation was also detected after 20 exposures at 1800 mg/m(3). There were no effects at 600 mg/m(3). It is concluded that THF enhances tumor formation in male rat kidney and female mouse liver via induction of cell proliferation. These features present essential elements that should be taken into account for the carcinogenic risk assessment of THF.
[show abstract][hide abstract] ABSTRACT: Recently several chronic toxicity/carcinogenicity studies of di-isononyl phthalate (DINP) have been reported. These studies defined effect levels for liver tumors in male and female F344 rats at dietary levels exceeding 700 mg/kg/day; the no effect levels were 359 mg/kg/day in males and 442 mg/kg/day in females. Similar results were found in male B6C3F1 mice, but in female mice a significant increase in liver tumors was found at 336 mg/kg/day, making 112 mg/kg/day the NOAEL for liver tumors in that sex and species. DINP induces peroxisomal proliferation, and that, along with evidence that DINP is not mutagenic, is presumptive evidence for peroxisomal proliferation as the underlying mode of action for liver tumor development. To further explore the relationship between peroxisome proliferation and tumor induction in male and female mice, indicators of peroxisomal proliferation including liver weight, peroxisomal volume density, induction of peroxisomal enzyme activity, enhanced replicative DNA synthesis, and rates of apoptosis were measured at all of the dietary levels used in the chronic study in mice (500, 1500, 4000, and 8000 ppm, or approximately 100, 300, 800, and 1600 mg/kg/day). Liver weights, peroxisomal volume, and peroxisomal enzyme activity were significantly elevated in both male and female mice at the tumorigenic levels. Cell proliferation was also elevated in male and female mice, although the increases at levels below 4000 ppm in female mice were not significantly different from control values. Apoptosis was elevated at the 4000 and 8000 ppm levels, paralleling the increases in liver weight. These data along with previous results satisfy the criteria of the International Agency for Research on Cancer (IARC) and demonstrate that peroxisomal proliferation was indeed the mode of action for DINP-induced liver tumor induction in mice.
Regulatory Toxicology and Pharmacology 11/2002; 36(2):175-83. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a study of the 28-day inhalation toxicity of di-(2-ethylhexyl) phthalate (DEHP) aerosols, 9-wk-old Wistar rats, 27 males (mean weight 226 g) and 17 females (mean weight 155 g) per group, were exposed in head-nose inhalation systems to DEHP aerosols of respirable particle size (mass median aerodynamic diameter < or = 1.2 microns) or air (controls). Exposure for 6 hr per day, 5 days per wk for 4 wk to target concentrations of 0, 0.01, 0.05 and 1.0 mg/litre gave estimated doses of 230, 11 and 2.3 mg/kg/day for the males, and 360, 18 and 3.6 mg/kg/day for females, on the assumption of 100% deposition and absorption. Clinical investigation and blood chemistry parameters did not reveal any treatment-related effects. At the end of exposure a statistically significant (16%) increase in relative lung weights, accompanied by increased foam-cell proliferation and thickening of the alveolar septi, was found in the males of the highest dose group. Absolute liver weights were significantly (8.75%) increased in females and relative liver weights were increased in both sexes in the highest dose group, but there were no corresponding histological effects. All these effects were reversed during the 8-wk post-exposure period. No testicular toxicity was observed histologically and no impact on mating performance and male fertility was detected after two matings of treated males with untreated females, 2 and 6 wk after the end of exposure. Electron microscopic examination of liver samples from two male and two female rats per group at the end of exposure and after the 8-wk post-exposure period did not reveal clear substructural changes that could be attributed to exposure or to peroxisome proliferation. The no-observed-effect level for all exposure-related findings was 0.05 mg/litre under the conditions used.
Food and Chemical Toxicology 11/1992; 30(11):915-9. · 3.01 Impact Factor