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Archives of Toxicology (v.82, #1)
Comparative study of aryl hydrocarbon receptor ligand activities of six chemicals in vitro and in vivo by Kazumi Sugihara; Takashige Okayama; Shigeyuki Kitamura; Keisuke Yamashita; Mineo Yasuda; Shinichi Miyairi; Yasushi Minobe; Shigeru Ohta (pp. 5-11).
The aryl hydrocarbon receptor (AhR) ligand activities of six known AhR ligands were compared in vivo and in vitro. The in vivo ligand activity was estimated in terms of induction of cytochrome P450 1A1/2 activities, i.e., ethoxyresorufin-O-dealkylase (EROD) and methoxyresorufin-O-dealkylase (MROD) activities, and in vitro ligand activity was evaluated with a recombinant yeast reporter gene assay. The test chemicals were 3-methylcholanthrene (MC), β-naphthoflavone (β-NF), indirubin, indigo, 3,3′-diindolylmethane (DIM) and diphenyl-p-phenylenediamine (DPPD). The first four showed potent AhR ligand activity in vitro, comparable with that of 2,3,7,8-tetrachlorodibenzo-p-dioxin, while DIM and DPPD showed weaker activity. Administration of MC and β-NF to mice caused significant induction of EROD and MROD activities, while indirubin, indigo and DIM also induced these activities, but less potently. DPPD also induced the activities, but was toxic at higher doses. These enhancing effects were lost or greatly reduced in Ahr-null mice (Ahr −/−). Our results suggest that EROD and MROD activity assays are useful for evaluating the AhR ligand activity of chemicals in vivo, where the biodynamics of the chemicals plays an important role.
Keywords: Aryl hydrocarbon receptor; Induction; Cytochrome P450; Ahr-null mice; Ethoxyresorufin-O-dealkylase; Methoxyresorufin-O-dealkylase; Indirubin
Human volunteer study on the inhalational and dermal absorption of N-methyl-2-pyrrolidone (NMP) from the vapour phase by Michael Bader; Renate Wrbitzky; Meinolf Blaszkewicz; Michael Schäper; Christoph van Thriel (pp. 13-20).
N-Methyl-2-pyrrolidone (NMP) is a versatile organic solvent frequently used for surface cleaning such as paint stripping or graffiti removal. Liquid NMP is rapidly absorbed through the skin but dermal vapour phase absorption might also play an important role for the uptake of the solvent. This particular aspect was investigated in an experimental study with 16 volunteers exposed to 80 mg/m3 NMP for 8 h under either whole-body, i.e. inhalational plus dermal, or dermal-only conditions. Additionally, the influence of moderate physical workload on the uptake of NMP was studied. The urinary concentrations of NMP and its metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) were followed for 48 h and analysed by gas chromatography–mass spectrometry (GC–MS). Percutaneous uptake delayed the elimination peak times and the apparent biological half-lives of NMP and 5-HNMP. Under resting conditions, dermal-only exposure resulted in the elimination of 71 ± 8 mg NMP equivalents as compared to 169 ± 15 mg for whole-body exposure. Moderate workload yielded 79 ± 8 mg NMP (dermal-only) and 238 ± 18 mg (whole-body). Thus, dermal absorption from the vapour phase may contribute significantly to the total uptake of NMP, e.g. from workplace atmospheres. As the concentration of airborne NMP does not reflect the body dose, biomonitoring should be carried out for surveillance purposes.
Keywords: N-Methyl-2-pyrrolidone; Dermal absorption; Biomonitoring; GC–MS
Toxicity potentiation by H2O2 with components of dental restorative materials on human oral cells by Franz-Xaver Reichl; Mario Seiss; Wolfgang Marquardt; Norbert Kleinsasser; Helmut Schweikl; Kai Kehe; Reinhard Hickel (pp. 21-28).
Toxicity potentiation of two monomers [bisphenol-A-glycidyldimethacrylate (BisGMA) and urethanedimethacrylate (UDMA)] as well as two comonomers [triethyleneglycoldimethacrylate (TEGDMA) and 2-hydroxyethylmethacrylate (HEMA)], each in combination with H2O2, was investigated on the viability on human gingival fibroblasts (HGF) and human pulpal fibroblasts (HPF). The applied concentration of H2O2 was 0.06 or 0.1 mmol/l, respectively, corresponding to the EC0 of H2O2 in HGF or HPF. The cell viability was assessed by the XTT test. From this test the half maximum effect concentrations (EC50) were calculated from fitted sigmoidale curves. EC50 values were (HGF; mmol/l; mean ± s.e.m.; n = 5): HEMA 11.9 ± 0.9, TEGDMA 3.7 ± 0.3, H2O2 0.36 ± 0.04, UDMA 0.27 ± 0.08, and BisGMA 0.11 ± 0.03. No significant (P < 0.05) differences in the EC50 values were observed when HGF was exposed to substances, as compared to HPF. No significant decrease of the EC50 values was found when HGF or HPF, respectively, was exposed to HEMA or BisGMA in addition with H2O2 up to the concentration of 0.1 mmol/l, as compared to those EC50 values of each compound without H2O2 addition. A significant decrease of the TEGDMA EC50 value from 3.7 to 2.1 or 0.4 mmol/l, respectively, was found when cells were exposed to TEGDMA in combination with H2O2 (0.06 or 0.1 mmol/l), as compared to that TEGDMA EC50 value without H2O2 addition. A significant decrease of the UDMA EC50 value from 0.27 to 0.11 or 0.08 mmol/l, respectively, was found when HGF or HPF was exposed to UDMA in combination with H2O2 (0.06 or 0.1 mmol/l), as compared to that UDMA EC50 value without H2O2 addition. The addition of H2O2 (0.06 or 0.1 mmol/l) resulted in a toxicity potentiation of TEGDMA and UDMA, but not of HEMA and BisGMA, on HGF or HPF.
Keywords: TEGDMA; HEMA; UDMA; BisGMA; H2O2 ; Toxicity potentiation; Human oral cells
Haplotypes of vitamin D receptor modulate the circulating levels of lead in exposed subjects by Vania B. Rezende; Fernando Barbosa Jr; Marcelo F. Montenegro; Valeria C. Sandrim; Raquel F. Gerlach; Jose E. Tanus-Santos (pp. 29-36).
Genetic factors influence whole blood lead (Pb-B) concentrations in lead exposed subjects. This study aimed at examining the combined effects (haplotype analysis) of three polymorphisms (BsmI, ApaI and FokI) in vitamin D receptor (VDR) gene on Pb-B and on the concentrations of lead in plasma (Pb-P), which is more relevant to lead toxicity, in 150 environmentally exposed subjects. Genotypes were determined by RFLP, and Pb-P and Pb-B were determined by inductively coupled plasma mass spectrometry and by graphite furnace atomic absorption spectrometry, respectively. Subjects with the bb (BsmI polymorphism) or ff (FokI polymorphism) genotypes have lower B-Pb than subjects in the other genotype groups. Subjects with the aa (ApaI polymorphism) or ff genotypes have lower P-Pb than subjects in the other genotype groups. Lower Pb-P, Pb-B, and %Pb-P/Pb-B levels were found in subjects with the haplotype combining the a, b, and f alleles for the ApaI, BsmI, and FokI polymorphisms, respectively, compared with the other haplotype groups, thus suggesting that VDR haplotypes modulate the circulating levels of lead in exposed subjects.
Keywords: Haplotype; Polymorphism; Plasma lead; Toxicogenetics; Vitamin D receptor; Whole blood lead
Selection of micronutrients used along with DMSA in the treatment of moderately lead intoxicated mice by Yingjun Liao; Fei Yu; Yaping Jin; Chunwei Lu; Gexin Li; Xuping Zhi; Li An; Jun Yang (pp. 37-43).
The objective of this study was to explore the optimum combination of micronutrients used with 2,3-dimercaptosuccinic acid (DMSA) in the treatment of moderately lead-intoxicated mice. Experiment was carried out based on the orthogonal design L8(27) setting six factors with two different levels of each, and eight groups of mice were needed. Mice were exposed to lead by drinking water contaminated with 0.1% lead acetate for four consecutive weeks, and then supplemented by gavage with different combinations of micronutrients with and without DMSA as designed in the orthogonal table. Lead levels in blood, liver, kidney, brain and bone and activities of blood δ-aminolevulinic acid dehydratase (ALAD) were analyzed after cessation of supplementation. The results suggested that DMSA was the only factor which could decrease significantly lead levels in blood, liver, kidney and bone; calcium and ascorbic acid were the notable factors decreasing lead levels in blood, liver, kidney, bone and brain; zinc and calcium were the notable factors reversing the lead-inhibited activities of blood ALAD; taurine was the notable factor decreasing lead levels in kidney and brain; and thiamine was the notable factor decreasing lead levels in brain. The lowest lead level in blood, liver, kidney and bone was shown in the mice supplemented with combination of calcium and ascorbic acid along with DMSA. In conclusion, the optimum combination of micronutrients used with DMSA suggested in present study was calcium and ascorbic acid, which seemed to potentiate the chelating efficacy of DMSA in the treatment of moderately lead intoxicated mice.
Keywords: Lead intoxication; 2,3-dimercaptosuccinic acid (DMSA); Micronutrients; Mice; Combined therapy
Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice by P. C. Chan; G. D. Hills; G. E. Kissling; A. Nyska (pp. 45-53).
4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats.
Keywords: 4-Methylimidazole; Toxicity; Carcinogenicity; Rats; Mice
Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice
by P. C. Chan; G. D. Hill; G. E. Kissling; A. Nyska (pp. 55-55).
Perfluorinated compounds (PFC) hit the headlines
by Peter H. Roos; Jürgen Angerer; Hermann Dieter; Michael Wilhelm; Detlef Wölfle; Jan G. Hengstler (pp. 57-59).
Strategy of the scientific committee on occupational exposure limits (SCOEL) in the derivation of occupational exposure limits for carcinogens and mutagens by Hermann M. Bolt; Alicia Huici-Montagud (pp. 61-64).
Setting standards, such as occupational exposure limits (OELs) for carcinogenic substances must consider modes of action. At the European Union level, the scientific committee on occupational exposure limits (SCOEL) has discussed a number of chemical carcinogens and has issued recommendations. For some carcinogens, health-based OELs were recommended, while quantitative assessments of carcinogenic risks were performed for others. For purposes of setting limits this led to the consideration of the following groups of carcinogens. (A) Non-threshold genotoxic carcinogens; for low-dose assessment of risk, the linear non-threshold (LNT) model appears appropriate. For these chemicals, regulations (risk management) may be based on the ALARA principle (“as low as reasonably achievable”), technical feasibility, and other socio-political considerations. (B) Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported at present. In these cases, the LNT model may be used as a default assumption, based on the scientific uncertainty. (C) Genotoxic carcinogens with a practical threshold, as supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established NOAEL (no observed adverse effect level). (D) Non-genotoxic carcinogens and non-DNA-reactive carcinogens; for these compounds a true (“perfect”) threshold is associated with a clearly founded NOAEL. The mechanisms shown by tumour promoters, spindle poisons, topoisomerase II poisons and hormones are typical examples of this category. Health-based OELs are derived for carcinogens of groups C and D, while a risk assessment is carried out for carcinogens of groups A and B. Substantial progress is currently being made in the incorporation of new types of mechanistic data into these regulatory procedures.
Keywords: Occupational exposure limits; Carcinogens; Genotoxicity; Mode of action; Thresholds; Workplace chemicals