A computer tool for the assessment of potential combined acute effects of chemicals in mixtures
1
S262 Abstracts / Toxicology Letters 189S (2009) S57–S273 official validated methods, used for the characterization of occu- pational environments containing mixtures of volatile organic compounds, but none for the simultaneous determination of all the substances that are usually present in the leatherwear industry environment, like hexane or heptane isomers. Thus, an optimiza- tion and simplification of sample extraction and chromatographic parameters was carried out in this work to obtain a method capa- ble of a fast and efficient determination of the most frequently found volatile compounds in this industry. The methodology is able to simultaneously detect 13 organic volatile compounds (n- hexane and isomers, n-heptane and isomers, cyclohexane, toluene, benzene, ketones, trichloroethylene and ethyl acetate) in 11min. Detection and quantification limits were ranging between 0.1 and 21.6 g/mL and 0.4 and 54.3 g/mL, respectively, which for an active captation sampling about 10L of air; it represents less than 1% of the threshold limit value proposed by the EU and Spanish guidelines. The method has proved suitable for monitoring occu- pational exposure to these compounds in industries and it satisfies the simplicity, speed, sensitivity and efficacy conditions for the determination of volatile organic compounds in activated charcoal tubes. References Filley, C.M., Halliday, W., Kleinschmidt-DeMasters, B.K., 2004. The effects of toluene on the central nervous system. J. Neuropathol. Exp. Neurol. 63 (1), 1–12. Pastore, C., Marhuenda, D., Marti, J., Cardona, A., 1994. Early diagnosis of n-hexane- caused neuropathy. Muscle Nerve 17 (9), 981–986. doi:10.1016/j.toxlet.2009.06.386 P18 Mitochondrial effects of chloramphenicol and linezolid in HepG2 cells Doris Höschele ∗ , Martina Wiertz Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany Several classes of antibiotics induce mitochondrial toxicity due to inhibition of mitochondrial protein synthesis, including chlo- ramphenicol and linezolid. Clinically, inhibition of mitochondrial protein synthesis may lead to severe adverse effects in patients treated with chloramphenicol or linezolid. Inhibition of mitochon- drial protein synthesis has been well examined in several published studies for these compounds. In this study, we investigated the effects of chloramphenicol and linezolid on mitochondrial DNA (mtDNA) content, expression of mtDNA encoded proteins of res- piratory chain complexes and cellular lactate production in HepG2 cells. HepG2 cells were treated over 14 days with chloramphenicol (1, 10, or 100 M) or with linezolid (0.10 or 0.25mg/mL). MtDNA gene expression and mtDNA content were analysed by real-time PCR. Mitochondrial function was determined by measuring cellular lactate production. Both compounds induced a time- and concentration-dependent increase in cellular lactate production, suggesting impairment of mitochondrial function. For chloramphenicol a concentration- dependent increase in mtDNA content was observed, whereas expression of mtDNA encoded proteins decreased, except for ND4L and ND1 genes which increased. No alteration in mtDNA content occurred after linezolid treatment. However, a concentration- dependent increase in gene expression of all mtDNA encoded proteins was observed. This study shows that although chloramphenicol and linezolid are potent inhibitors of mitochondrial protein synthesis and induce mitochondrial dysfunction in HepG2 cells, there are some dif- ferences in mitochondrial effects between both compounds. This suggests that a universal mechanism for the mitochondrial toxicity of chloramphenicol and linezolid may not exist. doi:10.1016/j.toxlet.2009.06.387 P19 A computer tool for the assessment of potential combined acute effects of chemicals in mixtures Jonathan Côté 1,∗ , Franc ¸ ois Lemay 2 , Claude Viau 1 , Adolf Vyskocil 1 1 University of Montreal, Santé environnementale et santé au Travail, Montreal, Canada, 2 Institut de Recherche Robert-Sauvé en Santé et Sécurité au Travail, Montréal, Canada When chemicals agents are spilled in the environment because of accidents occurring during hazardous materials transport or in chemical industries, employees, first-aid workers, firefighters or the general population can be exposed for short periods to high concentrations of multiple chemicals agents. In those cases of acute exposures, the overall toxicity of a mixture may be greater than that associated with each of its individual compounds. In occupational health, consideration of this phenomenon has resulted in spe- cific recommendations by the American Conference of Governmental Industrial Hygienists and in Quebec’s Regulation respecting occupa- tional health and safety. These recommendations or prescriptions call for verification of possible addition of effects on a given organ of the human body caused by the concomitant inhalation of two or more hazardous substances in the air. This project was under- taken with the objective of developing a user-friendly computer tool to identify the possible additive acute effects of mixtures. The first step was to create a toxicological database of target organs and acute toxic effects on these organs for 200 hazardous substances. With this database, a computer tool was developed to calculate an acute mixture exposure index based on the Acute Exposure Guide- line Levels (AEGL) developed by EPA. These values were established for 5 exposure durations (10 min, 30 min, 1 h, 4 h and 8 h) and 3 toxicity levels (AEGL-1, AEGL-2 and AEGL-3). With this informa- tion, the computer tool estimates the possible addition of acute effects based on exposure concentrations of individual substances provided by the user. doi:10.1016/j.toxlet.2009.06.388 P20 The impact of drug monitoring in a case of drug resistant neonate arrhythmia Maria Toutoudaki 1,∗ , Ioannis Germanakis 2 , George Briassoulis 3 , Manolis Tzatzarakis 1 , Maria Christakis-Hampsas 1 , Aristidis Tsatsakis 1 1 University of Crete, Lab of Toxicology, Medical School, Heraklion, Greece, 2 University Hospital, Pediatric & Fetal Cardiology Unit, Dpt of Pediatrics, Heraklion, Greece, 3 University Hospital, Childrens Intensive Care Unit/Dept. of Pediatrics, Heraklion, Greece Purpose: A case of refractory neonatal supraventricular tachycar- dia, necessitating multidrug treatment including propafenone and close drug level monitoring is described.
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Transcript of A computer tool for the assessment of potential combined acute effects of chemicals in mixtures
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262 Abstracts / Toxicology L
fficial validated methods, used for the characterization of occu-ational environments containing mixtures of volatile organicompounds, but none for the simultaneous determination of allhe substances that are usually present in the leatherwear industrynvironment, like hexane or heptane isomers. Thus, an optimiza-ion and simplification of sample extraction and chromatographicarameters was carried out in this work to obtain a method capa-le of a fast and efficient determination of the most frequentlyound volatile compounds in this industry. The methodology isble to simultaneously detect 13 organic volatile compounds (n-exane and isomers, n-heptane and isomers, cyclohexane, toluene,enzene, ketones, trichloroethylene and ethyl acetate) in 11 min.etection and quantification limits were ranging between 0.1 and1.6 �g/mL and 0.4 and 54.3 �g/mL, respectively, which for anctive captation sampling about 10 L of air; it represents less than% of the threshold limit value proposed by the EU and Spanishuidelines. The method has proved suitable for monitoring occu-ational exposure to these compounds in industries and it satisfieshe simplicity, speed, sensitivity and efficacy conditions for theetermination of volatile organic compounds in activated charcoalubes.
eferences
illey, C.M., Halliday, W., Kleinschmidt-DeMasters, B.K., 2004. The effects of tolueneon the central nervous system. J. Neuropathol. Exp. Neurol. 63 (1), 1–12.
astore, C., Marhuenda, D., Marti, J., Cardona, A., 1994. Early diagnosis of n-hexane-caused neuropathy. Muscle Nerve 17 (9), 981–986.
oi:10.1016/j.toxlet.2009.06.386
18itochondrial effects of chloramphenicol and linezolid inepG2 cells
oris Höschele ∗, Martina Wiertz
Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn,ermany
everal classes of antibiotics induce mitochondrial toxicity dueo inhibition of mitochondrial protein synthesis, including chlo-amphenicol and linezolid. Clinically, inhibition of mitochondrialrotein synthesis may lead to severe adverse effects in patientsreated with chloramphenicol or linezolid. Inhibition of mitochon-rial protein synthesis has been well examined in several publishedtudies for these compounds. In this study, we investigated theffects of chloramphenicol and linezolid on mitochondrial DNAmtDNA) content, expression of mtDNA encoded proteins of res-iratory chain complexes and cellular lactate production in HepG2ells.
HepG2 cells were treated over 14 days with chloramphenicol1, 10, or 100 �M) or with linezolid (0.10 or 0.25 mg/mL). MtDNAene expression and mtDNA content were analysed by real-timeCR. Mitochondrial function was determined by measuring cellularactate production.
Both compounds induced a time- and concentration-dependentncrease in cellular lactate production, suggesting impairmentf mitochondrial function. For chloramphenicol a concentration-ependent increase in mtDNA content was observed, whereas
xpression of mtDNA encoded proteins decreased, except for ND4Lnd ND1 genes which increased. No alteration in mtDNA contentccurred after linezolid treatment. However, a concentration-ependent increase in gene expression of all mtDNA encodedroteins was observed.I
Pdc
189S (2009) S57–S273
This study shows that although chloramphenicol and linezolidre potent inhibitors of mitochondrial protein synthesis and induceitochondrial dysfunction in HepG2 cells, there are some dif-
erences in mitochondrial effects between both compounds. Thisuggests that a universal mechanism for the mitochondrial toxicityf chloramphenicol and linezolid may not exist.
oi:10.1016/j.toxlet.2009.06.387
19computer tool for the assessment of potential combined acute
ffects of chemicals in mixtures
onathan Côté 1,∗, Francois Lemay 2, Claude Viau 1, Adolf Vyskocil 1
University of Montreal, Santé environnementale et santé au Travail,ontreal, Canada, 2 Institut de Recherche Robert-Sauvé en Santé et
écurité au Travail, Montréal, Canada
hen chemicals agents are spilled in the environment becausef accidents occurring during hazardous materials transport or inhemical industries, employees, first-aid workers, firefighters orhe general population can be exposed for short periods to highoncentrations of multiple chemicals agents. In those cases of acutexposures, the overall toxicity of a mixture may be greater than thatssociated with each of its individual compounds. In occupationalealth, consideration of this phenomenon has resulted in spe-ific recommendations by the American Conference of Governmentalndustrial Hygienists and in Quebec’s Regulation respecting occupa-ional health and safety. These recommendations or prescriptionsall for verification of possible addition of effects on a given organf the human body caused by the concomitant inhalation of twor more hazardous substances in the air. This project was under-aken with the objective of developing a user-friendly computerool to identify the possible additive acute effects of mixtures. Therst step was to create a toxicological database of target organs andcute toxic effects on these organs for 200 hazardous substances.ith this database, a computer tool was developed to calculate an
cute mixture exposure index based on the Acute Exposure Guide-ine Levels (AEGL) developed by EPA. These values were establishedor 5 exposure durations (10 min, 30 min, 1 h, 4 h and 8 h) and 3oxicity levels (AEGL-1, AEGL-2 and AEGL-3). With this informa-ion, the computer tool estimates the possible addition of acuteffects based on exposure concentrations of individual substancesrovided by the user.
oi:10.1016/j.toxlet.2009.06.388
20he impact of drug monitoring in a case of drug resistanteonate arrhythmia
aria Toutoudaki 1,∗, Ioannis Germanakis 2, George Briassoulis 3,anolis Tzatzarakis 1, Maria Christakis-Hampsas 1, Aristidis
satsakis 1
University of Crete, Lab of Toxicology, Medical School, Heraklion,reece, 2 University Hospital, Pediatric & Fetal Cardiology Unit, Dpt ofediatrics, Heraklion, Greece, 3 University Hospital, Childrens
ntensive Care Unit/Dept. of Pediatrics, Heraklion, Greeceurpose: A case of refractory neonatal supraventricular tachycar-ia, necessitating multidrug treatment including propafenone andlose drug level monitoring is described.
