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Drinking water contamination by polychlorinated butadienes
Abstracts / Toxicology Letters 189S (2009) S57–S273
F06 Analysis of DNA binding of furan in rat liver by accelerator mass 夽 spectrometry Carolin Hamberger 1,∗ , Sabrina Moro 1 , Mike Malfatti 2 , Ken Turteltaub 2 , Angela Mally 1 , Wolfgang Dekant 1 1
Universität Würzburg, Institut für Pharmakologie und Toxikologie, Würzburg, Germany, 2 Lawrence Livermore National Laboratory, Livermore, CA, United States Furan, a potent hepatotoxicant and liver carcinogen in rodents, was recently shown to be present in a wide variety of heattreated foods. Furan is metabolized by cytochromes P450 to cis-2-butene-1,4-dial, an ␣,-unsaturated dialdehyde which has been demonstrated to react with nucleosides in vitro. However, short-term tests for genotoxicity of furan in mammalian cells are inconclusive. The aim of this study was to assess the potential of furan to covalently bind to DNA in rat liver. Male F344 rats (n = 5) were administered 0, 0.1 or 2.0 mg/kg bw [3,4-14 C]-furan (20 mCi/mmol) by oral gavage and were sacrificed 2 h later. DNA was isolated from liver by ion exchange chromatography and analyzed by accelerator mass spectrometry. The 14 C-content in DNA was significantly increased in a dose-dependent manner, ranging from 5 to 8 amol 14 C/g DNA (corresponding to 10–16 adducts/109 nucleotides) and 123 to 383 amol 14 C/g DNA (corresponding to 3–8 adducts/107 nucleotides) in left liver lobes of rats treated with 0.1 and 2.0 mg/kg bw, respectively. A similar degree of DNA binding was observed in DNA extracted from the more susceptible caudate liver lobes. While these results indicate that furan may form covalent DNA adducts, current work is aimed to exclude the possibility that the increased 14 C content may be due to metabolic incorporation. 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.486
F07
夽 Drinking water contamination by polychlorinated butadienes Beat Brüschweiler 1,∗ , Wolfgang Märki 2 , Richard Wülser 3 1
Swiss Federal Office of Public Health, Food Safety Division, Zürich, Switzerland, 2 Hardwasser AG, Pratteln, Switzerland, 3 IWB, Quality Assurance DW, Basel, Switzerland Tetrachlorinated butadienes, pentachlorinated butadienes and 1,1,2,3,4,4-hexachloro-1,3-butadiene (HCBD) were measured up to 157 ng/L (sum), 15 ng/L (sum), and <50 ng/L, respectively, in the wells of the drinking water production by Hardwasser AG for Basel in 2006. HCBD is known as a solvent and an undesired but unavoidable industrial by-product that arises during the manufacture of chlorinated hydrocarbons. Tetra- and pentachlorinated butadienes are supposed to be environmental degradation products of HCBD. For HCBD, the WHO has derived a tolerable daily intake (TDI) of 0.2 g/kg body weight (b.w.)/day and a drinking water guideline value of 600 ng/L, based on a NOAEL of 0.2 mg/kg b.w./day for renal toxicity in a 2-year feeding study in rats. No toxicity data for the tetra- and pentachlorinated butadienes are available. Therefore, the threshold of toxicological concern (TTC) approach was applied to assess these compounds. According to the structure–activity relationship (SAR) software Derek for Windows, these compounds are predicted to be carcinogenic in mammals and may react with DNA
S229
or cellular proteins. Based on the TTC value of 150 ng/person/day for substances with structural alerts for genotoxicity, a daily water consumption of 2 L/person, 60 kg b.w./person and 100% allocation of intake through drinking water, 75 ng/L would represent a drinking water concentration which would not raise concern. Consequently, appropriate risk reduction measures were taken in Basel and the concentrations of tetra- and pentachlorinated butadienes as well as HCBD in the drinking water could be reduced well below 8 ng/L (detection limit) by activated carbon adsorption. In the meantime, in vitro genotoxicity was tested in the Bacterial Reverse Mutation Test (brmt) as well as in the Mammalian Chromosome Aberration Test (mcat) for 1,1,3,4-tetrachloro1,3-butadiene (brmt+/mcat+), 1,1,4,4-tetrachloro-1,3-butadiene (brmt−/mcat+), 1,2,3,4-tetrachloro-1,3-butadiene (brmt+/mcat+), 1,1,2,3,4-pentachloro-1,3-butadiene (brmt−/mcat+), 1,1,2,4,4,pentachloro-1,3-butadiene (brmt−/mcat+) and HCBD (brmt−/ mcat+). 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.487
F08 Effects of purity-controlled PCB52 and PCB180 on dopamine夽 dependent behavior in rat offspring after maternal exposure Hellmuth Lilienthal 1,∗ , Paivi Heikkinen 2 , Conny Danielsson 3 , Patrik Andersson 3 , Matti Viluksela 2 1 BGFA-Research Institute of Occupational Medicine, Toxicology, Bochum, Germany, 2 THL-National Institute for Health and Welfare, Environmental Health, Kuopio, Finland, 3 Umea University, Chemistry, Umea, Sweden
In contrast to dioxin-like polychlorinated biphenyls (PCBs), systematic knowledge is lacking about non-dioxin-like PCB congeners (NDL-PCBs). Previous studies of single congeners have mostly used NDL-PCBs which were not highly purified. Thus, the outcome of these studies may have been influenced by Ah receptor-active contaminants. The EU-funded program ATHON was initiated to address this issue by exploring various toxicological aspects of highly purified NDL-PCBs. Rat dams were orally given six dose levels of PCB180 (0–1000 mg/kg b wt, total dose, prenatal) or PCB52 (0–3000 mg/kg, total dose, pre- and postnatal). Since previous results indicated pronounced effects of NDL-PCBs on dopamine concentrations in different brain areas, adult offspring were tested for dopamine-dependent behavior, using haloperidol-induced catalepsy. Rats were placed in unusual body postures 30 and 60 min after the injection with haloperidol. Latencies to movement onset were determined, namely, descent latency from a horizontal bar, paw movement on a steep grid, and leg retraction from holes on a box. Male offspring exposed to PCB180 exhibited reduced latencies with significant dose–response relations (p < 0.05). In contrast, increased latencies were detected in female offspring exposed to PCB52, but a significant dose–response relation was found only in one part of the test (foreleg retraction on the box, p < 0.05). Effects in PCB180 exposed males may be due to induction of metabolizing liver enzymes, thereby causing more rapid depletion of haloperidol, whereas latency increases in females exposed to PCB52 may result from reduced dopaminergic activity in the brain.
F06 Analysis of DNA binding of furan in rat liver by accelerator mass 夽 spectrometry Carolin Hamberger 1,∗ , Sabrina Moro 1 , Mike Malfatti 2 , Ken Turteltaub 2 , Angela Mally 1 , Wolfgang Dekant 1 1
Universität Würzburg, Institut für Pharmakologie und Toxikologie, Würzburg, Germany, 2 Lawrence Livermore National Laboratory, Livermore, CA, United States Furan, a potent hepatotoxicant and liver carcinogen in rodents, was recently shown to be present in a wide variety of heattreated foods. Furan is metabolized by cytochromes P450 to cis-2-butene-1,4-dial, an ␣,-unsaturated dialdehyde which has been demonstrated to react with nucleosides in vitro. However, short-term tests for genotoxicity of furan in mammalian cells are inconclusive. The aim of this study was to assess the potential of furan to covalently bind to DNA in rat liver. Male F344 rats (n = 5) were administered 0, 0.1 or 2.0 mg/kg bw [3,4-14 C]-furan (20 mCi/mmol) by oral gavage and were sacrificed 2 h later. DNA was isolated from liver by ion exchange chromatography and analyzed by accelerator mass spectrometry. The 14 C-content in DNA was significantly increased in a dose-dependent manner, ranging from 5 to 8 amol 14 C/g DNA (corresponding to 10–16 adducts/109 nucleotides) and 123 to 383 amol 14 C/g DNA (corresponding to 3–8 adducts/107 nucleotides) in left liver lobes of rats treated with 0.1 and 2.0 mg/kg bw, respectively. A similar degree of DNA binding was observed in DNA extracted from the more susceptible caudate liver lobes. While these results indicate that furan may form covalent DNA adducts, current work is aimed to exclude the possibility that the increased 14 C content may be due to metabolic incorporation. 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.486
F07
夽 Drinking water contamination by polychlorinated butadienes Beat Brüschweiler 1,∗ , Wolfgang Märki 2 , Richard Wülser 3 1
Swiss Federal Office of Public Health, Food Safety Division, Zürich, Switzerland, 2 Hardwasser AG, Pratteln, Switzerland, 3 IWB, Quality Assurance DW, Basel, Switzerland Tetrachlorinated butadienes, pentachlorinated butadienes and 1,1,2,3,4,4-hexachloro-1,3-butadiene (HCBD) were measured up to 157 ng/L (sum), 15 ng/L (sum), and <50 ng/L, respectively, in the wells of the drinking water production by Hardwasser AG for Basel in 2006. HCBD is known as a solvent and an undesired but unavoidable industrial by-product that arises during the manufacture of chlorinated hydrocarbons. Tetra- and pentachlorinated butadienes are supposed to be environmental degradation products of HCBD. For HCBD, the WHO has derived a tolerable daily intake (TDI) of 0.2 g/kg body weight (b.w.)/day and a drinking water guideline value of 600 ng/L, based on a NOAEL of 0.2 mg/kg b.w./day for renal toxicity in a 2-year feeding study in rats. No toxicity data for the tetra- and pentachlorinated butadienes are available. Therefore, the threshold of toxicological concern (TTC) approach was applied to assess these compounds. According to the structure–activity relationship (SAR) software Derek for Windows, these compounds are predicted to be carcinogenic in mammals and may react with DNA
S229
or cellular proteins. Based on the TTC value of 150 ng/person/day for substances with structural alerts for genotoxicity, a daily water consumption of 2 L/person, 60 kg b.w./person and 100% allocation of intake through drinking water, 75 ng/L would represent a drinking water concentration which would not raise concern. Consequently, appropriate risk reduction measures were taken in Basel and the concentrations of tetra- and pentachlorinated butadienes as well as HCBD in the drinking water could be reduced well below 8 ng/L (detection limit) by activated carbon adsorption. In the meantime, in vitro genotoxicity was tested in the Bacterial Reverse Mutation Test (brmt) as well as in the Mammalian Chromosome Aberration Test (mcat) for 1,1,3,4-tetrachloro1,3-butadiene (brmt+/mcat+), 1,1,4,4-tetrachloro-1,3-butadiene (brmt−/mcat+), 1,2,3,4-tetrachloro-1,3-butadiene (brmt+/mcat+), 1,1,2,3,4-pentachloro-1,3-butadiene (brmt−/mcat+), 1,1,2,4,4,pentachloro-1,3-butadiene (brmt−/mcat+) and HCBD (brmt−/ mcat+). 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.487
F08 Effects of purity-controlled PCB52 and PCB180 on dopamine夽 dependent behavior in rat offspring after maternal exposure Hellmuth Lilienthal 1,∗ , Paivi Heikkinen 2 , Conny Danielsson 3 , Patrik Andersson 3 , Matti Viluksela 2 1 BGFA-Research Institute of Occupational Medicine, Toxicology, Bochum, Germany, 2 THL-National Institute for Health and Welfare, Environmental Health, Kuopio, Finland, 3 Umea University, Chemistry, Umea, Sweden
In contrast to dioxin-like polychlorinated biphenyls (PCBs), systematic knowledge is lacking about non-dioxin-like PCB congeners (NDL-PCBs). Previous studies of single congeners have mostly used NDL-PCBs which were not highly purified. Thus, the outcome of these studies may have been influenced by Ah receptor-active contaminants. The EU-funded program ATHON was initiated to address this issue by exploring various toxicological aspects of highly purified NDL-PCBs. Rat dams were orally given six dose levels of PCB180 (0–1000 mg/kg b wt, total dose, prenatal) or PCB52 (0–3000 mg/kg, total dose, pre- and postnatal). Since previous results indicated pronounced effects of NDL-PCBs on dopamine concentrations in different brain areas, adult offspring were tested for dopamine-dependent behavior, using haloperidol-induced catalepsy. Rats were placed in unusual body postures 30 and 60 min after the injection with haloperidol. Latencies to movement onset were determined, namely, descent latency from a horizontal bar, paw movement on a steep grid, and leg retraction from holes on a box. Male offspring exposed to PCB180 exhibited reduced latencies with significant dose–response relations (p < 0.05). In contrast, increased latencies were detected in female offspring exposed to PCB52, but a significant dose–response relation was found only in one part of the test (foreleg retraction on the box, p < 0.05). Effects in PCB180 exposed males may be due to induction of metabolizing liver enzymes, thereby causing more rapid depletion of haloperidol, whereas latency increases in females exposed to PCB52 may result from reduced dopaminergic activity in the brain.