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Archives of Toxicology (v.81, #2)
A repeated 28-day oral dose toxicity study of nonylphenol in rats, based on the ‘Enhanced OECD Test Guideline 407’ for screening of endocrine-disrupting chemicals by Gye-Hyeong Woo; Makoto Shibutani; Tsutomu Ichiki; Masao Hamamura; Kyoung-Youl Lee; Kaoru Inoue; Masao Hirose (pp. 77-88).
A 28-day repeated oral dose toxicity study of nonylphenol (NP) was performed for an international validation of the ‘Enhanced OECD Test Guideline 407’ paying particular attention to the sensitivity of individual endocrine-related parameters. Sprague-Dawley rats, each group consisting of ten males and ten females, were administered NP once daily by gavage at doses of 0 (control), 10, 50, or 250 mg/kg body weight. At 250 mg/kg, three females died or became moribund during the experiment. At this dose, hepatic and renal toxicity was evident in both sexes with increase of relative liver and kidney weights as well as histopathological changes, such as centrilobular liver cell hypertrophy and a variety of renal tubular lesions, and alteration of serum biochemical parameters, some of them being evident from 50 mg/kg in females (glucose and inorganic phosphates). Hematologically, development of anemia was evident at 250 mg/kg in both sexes. Regarding endocrine-related effects, increase of thyroid weight in males was detected from 50 mg/kg. At 250 mg/kg, males exhibited reduction of relative weights of the ventral prostate and seminal vesicles, and females developed irregular estrous cyclicity and vaginal mucosal hyperplasia. Although changes in serum hormone levels were detected in both sexes, magnitude of the changes was small to be regarded as a low toxicological significance. In summary, repeated oral doses of NP to rats for 28 days resulted in hepato-renal toxicity from 50 mg/kg and anemia at 250 mg/kg. Effects on the endocrine system were observed from 50 mg/kg, and assessment of weights and histopathology of endocrine-related organs and estrous cyclicity may be valid in a battery for detecting endocrine effects of NP. The no-observed-adverse-effect level of NP was estimated to be 10 mg/kg per day.
Keywords: Nonylphenol; Estrogen; Rat; Enhanced OECD Test Guideline 407; Endocrine disrupters
Role of oxidative stress and intracellular calcium in nickel carbonate hydroxide-induced sister-chromatid exchange, and alterations in replication index and mitotic index in cultured human peripheral blood lymphocytes by Prosper M’Bemba-Meka; Nicole Lemieux; Saroj K. Chakrabarti (pp. 89-99).
Human peripheral lymphocytes from whole blood cultures were exposed to either soluble form of nickel carbonate hydroxide (NiCH) (0–60 μM), or of nickel subsulfide (Ni3S2) (0–120 μM), or of nickel oxide (NiO) (0–120 μM), or nickel sulfate (NiSO4) (0–120 μM) for a short duration of 2 h. The treatments occurred 46 h after the beginning of the cultures. The cultures were harvested after a total incubation of 72 h, and sister-chromatid exchange (SCE), replication index (RI), and mitotic index (MI) were measured for each nickel compound. The soluble form of NiCH at 30 μM but those of Ni3S2 and NiO at 120 μM produced significant increase in the SCE per cell compared to the control value, whereas NiSO4 failed to produce any such significant increase. Except NiSO4, the soluble forms of NiCH, Ni3S2, and NiO produced significant cell-cycle delay (as measured by the inhibition of RI) as well as significant inhibition of the MI at respective similar concentrations as mentioned above. Pretreatment of human blood lymphocytes with catalase (H2O2 scavenger), or superoxide dismutase (superoxide anion scavenger), or dimethylthiourea (hydroxyl radical scavenger), or deferoxamine (iron chelator), or N-acetylcysteine (general antioxidant) inhibited NiCH-induced SCE, and changes in RI and MI. This suggests the participation of oxidative stress involving H2O2, the superoxide anion radical, the hydroxyl radical, and iron in the NiCH-induced genotoxic responses. Cotreatment of NiCH with either verapamil (inhibitor of intracellular calcium ion ([Ca2+]i) movement through plasma membranes), or dantrolene (inhibitor of [Ca2+]i release from sarcoplasmic reticulum), or BAPTA (Ca2+ chelator) also inhibited the NiCH-induced responses. These results suggest that [Ca2+]i is also implicated in the genotoxicity of NiCH. Overall these data indicate that various types of oxidative stress including iron-mediated oxidative stress involving the Fenton–Haber/Weiss reaction, and alterations in calcium homeostasis are involved in the genetic damage produced by the soluble form of NiCH.
Keywords: Human blood lymphocytes; Nickel carbonate hydroxide; Sister-chromatid exchange; Replication index; Mitotic index; Oxidative stress; Calcium homeostasis
A physiologically based pharmacokinetic model for lactational transfer of PCB 153 with or without PCB 126 in mice by Sun Ku Lee; Ying C. Ou; Melvin E. Andersen; Raymond S. H. Yang (pp. 101-111).
Chemical exposure via breast milk is one of the great concerns in public health. Previously, we demonstrated that most body burden of PCB 153 can be transferred from the mother to the pups in mice during lactational period. Here we present a physiologically based pharmacokinetic (PBPK) model to describe the lactational transfer of PCB 153 with or without PCB 126 in mice. The model incorporated physiological changes on the volume and the blood flow into mammary tissues, and considered mechanistic information on the movement of PCB 153 from adipose tissue to the mammary gland during lactational period. The mechanistic consideration includes fat volume changes, binding of PCB 153 to very low density lipoprotein (VLDL) and increased uptake of VLDL in mammary tissues. Model parameters depicting physiological changes were obtained from research articles dealing with chemical transfer during lactational period in rodents. Chemical-specific parameters were derived from previous PBPK models focusing on the PCB disposition in rodents. The developed model adequately described the lactational transfer of PCB 153 with or without PCB 126 in mice. Our model will provide a useful mechanistic tool to estimate the disposition of PCBs in diverse experimental designs regarding PCB effects during developmental period and to improve quantitative risk assessment of PCBs in the developing organisms.
Keywords: PCB; Lactational transfer; PBPK; Pharmacokinetic interaction; Risk assessment
An in vitro approach for demonstrating the critical role of serum albumin in the detoxication of the carbamate carbaryl at in vivo toxicologically relevant concentrations by Miguel A. Sogorb; Carlos Álvarez-Escalante; Victoria Carrera; Eugenio Vilanova (pp. 113-119).
The hydrolysis of carbaryl by bovine serum albumin (BSA) was studied at toxicologically relevant concentrations (range 15–300 μM) in order to determine the role of this protein in the detoxication of the carbamate in vivo. The 1-naphthol released during the hydrolysis of carbaryl was monitored using gas chromatography coupled with mass spectrometry. BSA hydrolyzed carbaryl in a time-progressive way. The hydrolysis was also dependent of enzyme (1.0, 2.5, 5.0 and 7.0 mg ml−1) and substrate (range between 15 and 1,000 μM) concentration. The estimated turnover number and Michaelis–Menten constant were 1.6 × 10−4 s−1 and 430 μM, respectively. Thus, the second order rate constant was 0.37 M−1 s−1. At enzyme concentrations of 7.0 mg ml−1 and substrate concentrations ranging between 50 and 300 μM about 80% of substrate was hydrolyzed in 3 h. At lower substrate concentrations (15 and 30 μM carbaryl) also significant hydrolysis was detected at the highest enzyme concentration, even when these substrate concentrations were 30 and 15 times lower than the Michaelis–Menten constant. Although the efficacy of the enzymatic hydrolysis is low, the extrapolation of our results to the physiological albumin high concentrations (around 40 mg ml−1) suggests that the hydrolysis of carbaryl by serum albumins plays a critical role in the detoxication of this carbamate at in vivo toxicologically relevant concentrations.
Keywords: In vivo detoxication; Carbaryl; Serum albumin; Hydrolysis
Effect of direct infusion of acetaldehyde on dopamine and dopamine-derived salsolinol in the striatum of free-moving rats using a reverse microdialysis technique by Weihuan Wang; Kiyoshi Ameno; Mostofa Jamal; Mitsuru Kumihashi; Ikuo Uekita; Setsuko Ameno; Iwao Ijiri (pp. 121-126).
The effects of acetaldehyde (ACD) on dopamine (DA) and DA-derived salsolinol (SAL) levels were investigated in the striatum of freely moving rats. Dialysate levels of DA and SAL were determined using in vivo reverse microdialysis coupled with high-performance liquid chromatography with an electrochemical detector. Perfusion with 1,000 μM ACD decreased DA levels significantly, as compared to baseline value, whereas 250 and 500 μM ACD perfusion did not result in any significant alteration of the DA levels in the striatal dialysates. SAL levels in the dialysates were determined first at 30 or 40 min after ACD perfusion, reached a peak at 150 min, followed by no alterations for 240 min with doses of 250, 500, and 1,000 μM ACD. Our in vivo study suggested that 1,000 μM ACD led to significant decreases in DA levels in the striatum with greater SAL formation, and the examined ACD concentrations induced a dose-dependent elevation in SAL levels in the striatum of freely moving rats.
Keywords: Salsolinol; Dopamine; Acetaldehyde; Reverse microdialysis
Ototoxicity in rats exposed to ethylbenzene and to two technical xylene vapours for 13 weeks by François Gagnaire; Cristina Langlais; Stéphane Grossmann; Pascal Wild (pp. 127-143).
Male Sprague–Dawley rats were exposed to ethylbenzene (200, 400, 600 and 800 ppm) and to two mixed xylenes (250, 500, 1,000 and 2,000 ppm total compounds) by inhalation, 6 h/day, 6 days/week for 13 weeks and sacrificed for morphological investigation 8 weeks after the end of exposure. Brainstem auditory-evoked responses were used to determine auditory thresholds at different frequencies. Ethylbenzene produced moderate to severe ototoxicity in rats exposed to the four concentrations studied. Increased thresholds were observed at 2, 4, 8 and 16 kHz in rats exposed to 400, 600 and 800 ppm ethylbenzene. Moderate to severe losses of outer hair cells of the organ of Corti occurred in animals exposed to the four concentrations studied. Exposure to both mixed xylenes produced ototoxicity characterized by increased auditory thresholds and losses of outer hair cells. Ototoxicity potentiation caused by ethylbenzene was observed. Depending on the mixed xylene studied and the area of the concentration–response curves taken into account, the concentrations of ethylbenzene in mixed xylenes necessary to cause a given ototoxicity were 1.7–2.8 times less than those of pure ethylbenzene. Given the high ototoxicity of ethylbenzene, the safety margin of less or equal to two (LOAEL/TWA) might be too small to protect workers from the potential risk of ototoxicity. Moreover, the enhanced ototoxicity of ethylbenzene and para-xylene observed in mixed xylenes should encourage the production of mixed xylenes with the lowest possible concentrations of ethylbenzene and para-xylene.
Keywords: Ototoxicity; Ethylbenzene; Mixed xylenes; Aromatic solvents; Potentiation; Rat