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Validated spectrophotometric method for the determination of F-98214-TA3 in formulations for toxicity studies
Abstracts / Toxicology Letters 180S (2008) S32–S246
R36 Validated spectrophotometric method for the determination of F-98214-TA3 in formulations for toxicity studies Lorena Gonzalez, Ana Gonzalo, Maria Luisa Lucero ∗ , Aurelio Orjales, Rosa Urzay FAES FARMA, S.A., Leioa, Spain A simple, accurate, reproducible UV-spectrophotometric method was developed and validated by FAES FARMA, S.A. for the estimation of F-98214-TA3 in formulations, a novel antidepressant currently under development by Jazz Pharmaceuticals. Early formulations are mostly prepared for drug compounds at both discovery and preclinical stages and are administrated to animals via various routes such as oral and intravenous dosing. They serve the purpose of evaluating these compounds within a broad range of pharmaceutical aims, notably pharmacology (activity/efficacy), pharmacokinetics and toxicology. In this work, formulations prepared for F-98214-TA3 toxicological evaluation of effects in several species were analyzed prior to their administration. These analyses were accomplished in order to confirm the adequate concentration of the test item. F-98214TA3 was estimated at 268 nm in test vehicles (distilled water and sodium chloride). The working range was 16–84 mg ml−1 (regression equation: absorbance = 0.0036 × concentration in g/ml + 0.0162; r2 = 0.9913) in distilled water and 2–6 mg ml−1 (regression equation: absorbance = 0.0036 × concentration in g/ml + 0.0173; r2 = 0.9986) in sodium chloride. As a result, the response was linear within the studied range. This method was tested and validated for various parameters (linearity, precision, accuracy, selectivity and stability) according to ICH guidelines. On the one hand, the recovery was found to be 103.0% in sodium chloride and 102.0% in distilled water. On the other hand, the R.S.D. values for intra and inter-day precision studies were ≤1.0%. Finally, the proposed method was successfully applied for the determination of F-98214-TA3 in formulations (oral and intravenous dosing). doi:10.1016/j.toxlet.2008.06.575 R37 Tobacco smoke constituents: Application of risk assessment models Eian Massey, Fiona Cunningham, Clive Meredith ∗ British American Tobacco Group R&D Centre, Southampton, Hampshire, United Kingdom The scientific literature detailing the identity of tobacco smoke constituents potentially responsible for the adverse health effects of cigarette smoking has grown significantly over the last 20 years. Increasingly there is a trend towards providing a quantitative risk estimate of the contribution of individual constituents. In some assessments conducted the calculated potency includes a cigarette constituent yield and a disease potency factor, usually taken from a regulatory database which uses information from a single critical publication. To provide a disease potency factor considered most representative of that from tobacco smoke exposure, for lung cancer, chronic obstructive pulmonary disease and cardiovascular disease, the literature has been reviewed and papers for each compound and disease obtained. The margins of exposure (MOE) model developed by the European Food Safety Authority have then been applied to the data from each study. A series of MOE values from the range of studies per compound, per disease has been reviewed
S71
to derive a MOE range representative of the literature rather than from a single paper, to give an estimate that may best represent the potency of tobacco smoke. For example, for formaldehyde, from 5 different publications MOEs for tumour endpoints segregate as follows: nasal 75–154, larynx and trachea 192–175, forestomach 2.3 bronchus 601–625 lung 56894. With the exception of lung, all are below the critical value of 10,000 indicating a high priority for risk management actions. doi:10.1016/j.toxlet.2008.06.576 R38 Influence of smoking, folic acid and vitamin B12 concentration on DNA stability in lymphocytes from workers occupationally exposed to low levels of ionizing radiation Mirta Milic´ ∗ , Ruˇzica Rozgaj, Vilena Kaˇsuba Institute for Medical Research and Occupational Health, Mutagenesis Unit, Zagreb, Croatia Bleomycin sensitivity test in peripheral lymphocytes was used to compare the results of 28 individuals occupationally exposed to low levels of ionizing radiation and 28 matched controls, and to search for correlation with smoking habits, folic acid and vitamin B12 concentrations. Statistical significance of the results was tested by non-parametric Mann–Whitney test. Mean duration of occupational exposure to ionizing radiation was 12.43 ± 9.11 years (range: 1–38). The mean break/cell (b/c) for the controls was 0.60 ± 0.27 and exposed workers 0.51 ± 0.26 (p > 0.01). Gender did not significantly influence the values of endpoints studied, although slightly higher folic acid concentrations have been observed in women (8.76 ± 3.64 g/l). In control group higher values for folic acid (control: 8.59 ± 4.08 g/l vs. exposed: 6.49 ± 2.87 g/l) and vitamin B12 (control: 485.89 ± 160.03 ng/l vs. exposed: 424.62 ± 156.33 ng/l) were observed. Concentration of folic acid in smokers was in significant negative correlation with b/c (Spearman R = −0.57; p = 0.0049), and age, respectively (Spearman R = −0.59; p = 0.0033). Gender-related differences in b/c values were observed in control group, both in smokers (men: 0.67 ± 0.17 vs. women: 0.36 ± 0.26; p = 0.055) and non-smokers (men: 0.80 ± 0.25 vs. women: 0.44 ± 0.19; p = 0.0088). Among exposed non-smokers we also observed significant difference regarding to gender (men: 0.55 ± 0.14 vs. women: 0.39 ± 0.14; p = 0.021). The results obtained point to the value of bleomycin sensitivity test in human biomonitoring and confirmed gender and dietary habits as important factors involved in DNA damage response. doi:10.1016/j.toxlet.2008.06.577 R39 The time-space method of territories evaluation Elena Musikhina ∗ , Elena Zelinskaya Irkutsk State Technical University, Irkutsk, Russian Federation In view of high anthropogenic pressure on environment the new approach of complex ecological territory evaluation should be found. Surrounding spaces are multi-sided, and mankind influences on the environment at local, regional and global levels. Existing damage evaluating methods, in spite of their significance, cannot give a correct damage evaluation. Most researchers agree that natural systems have complex multi-level structure, but they use the category of time incorrectly. Taking into account the struc-
R36 Validated spectrophotometric method for the determination of F-98214-TA3 in formulations for toxicity studies Lorena Gonzalez, Ana Gonzalo, Maria Luisa Lucero ∗ , Aurelio Orjales, Rosa Urzay FAES FARMA, S.A., Leioa, Spain A simple, accurate, reproducible UV-spectrophotometric method was developed and validated by FAES FARMA, S.A. for the estimation of F-98214-TA3 in formulations, a novel antidepressant currently under development by Jazz Pharmaceuticals. Early formulations are mostly prepared for drug compounds at both discovery and preclinical stages and are administrated to animals via various routes such as oral and intravenous dosing. They serve the purpose of evaluating these compounds within a broad range of pharmaceutical aims, notably pharmacology (activity/efficacy), pharmacokinetics and toxicology. In this work, formulations prepared for F-98214-TA3 toxicological evaluation of effects in several species were analyzed prior to their administration. These analyses were accomplished in order to confirm the adequate concentration of the test item. F-98214TA3 was estimated at 268 nm in test vehicles (distilled water and sodium chloride). The working range was 16–84 mg ml−1 (regression equation: absorbance = 0.0036 × concentration in g/ml + 0.0162; r2 = 0.9913) in distilled water and 2–6 mg ml−1 (regression equation: absorbance = 0.0036 × concentration in g/ml + 0.0173; r2 = 0.9986) in sodium chloride. As a result, the response was linear within the studied range. This method was tested and validated for various parameters (linearity, precision, accuracy, selectivity and stability) according to ICH guidelines. On the one hand, the recovery was found to be 103.0% in sodium chloride and 102.0% in distilled water. On the other hand, the R.S.D. values for intra and inter-day precision studies were ≤1.0%. Finally, the proposed method was successfully applied for the determination of F-98214-TA3 in formulations (oral and intravenous dosing). doi:10.1016/j.toxlet.2008.06.575 R37 Tobacco smoke constituents: Application of risk assessment models Eian Massey, Fiona Cunningham, Clive Meredith ∗ British American Tobacco Group R&D Centre, Southampton, Hampshire, United Kingdom The scientific literature detailing the identity of tobacco smoke constituents potentially responsible for the adverse health effects of cigarette smoking has grown significantly over the last 20 years. Increasingly there is a trend towards providing a quantitative risk estimate of the contribution of individual constituents. In some assessments conducted the calculated potency includes a cigarette constituent yield and a disease potency factor, usually taken from a regulatory database which uses information from a single critical publication. To provide a disease potency factor considered most representative of that from tobacco smoke exposure, for lung cancer, chronic obstructive pulmonary disease and cardiovascular disease, the literature has been reviewed and papers for each compound and disease obtained. The margins of exposure (MOE) model developed by the European Food Safety Authority have then been applied to the data from each study. A series of MOE values from the range of studies per compound, per disease has been reviewed
S71
to derive a MOE range representative of the literature rather than from a single paper, to give an estimate that may best represent the potency of tobacco smoke. For example, for formaldehyde, from 5 different publications MOEs for tumour endpoints segregate as follows: nasal 75–154, larynx and trachea 192–175, forestomach 2.3 bronchus 601–625 lung 56894. With the exception of lung, all are below the critical value of 10,000 indicating a high priority for risk management actions. doi:10.1016/j.toxlet.2008.06.576 R38 Influence of smoking, folic acid and vitamin B12 concentration on DNA stability in lymphocytes from workers occupationally exposed to low levels of ionizing radiation Mirta Milic´ ∗ , Ruˇzica Rozgaj, Vilena Kaˇsuba Institute for Medical Research and Occupational Health, Mutagenesis Unit, Zagreb, Croatia Bleomycin sensitivity test in peripheral lymphocytes was used to compare the results of 28 individuals occupationally exposed to low levels of ionizing radiation and 28 matched controls, and to search for correlation with smoking habits, folic acid and vitamin B12 concentrations. Statistical significance of the results was tested by non-parametric Mann–Whitney test. Mean duration of occupational exposure to ionizing radiation was 12.43 ± 9.11 years (range: 1–38). The mean break/cell (b/c) for the controls was 0.60 ± 0.27 and exposed workers 0.51 ± 0.26 (p > 0.01). Gender did not significantly influence the values of endpoints studied, although slightly higher folic acid concentrations have been observed in women (8.76 ± 3.64 g/l). In control group higher values for folic acid (control: 8.59 ± 4.08 g/l vs. exposed: 6.49 ± 2.87 g/l) and vitamin B12 (control: 485.89 ± 160.03 ng/l vs. exposed: 424.62 ± 156.33 ng/l) were observed. Concentration of folic acid in smokers was in significant negative correlation with b/c (Spearman R = −0.57; p = 0.0049), and age, respectively (Spearman R = −0.59; p = 0.0033). Gender-related differences in b/c values were observed in control group, both in smokers (men: 0.67 ± 0.17 vs. women: 0.36 ± 0.26; p = 0.055) and non-smokers (men: 0.80 ± 0.25 vs. women: 0.44 ± 0.19; p = 0.0088). Among exposed non-smokers we also observed significant difference regarding to gender (men: 0.55 ± 0.14 vs. women: 0.39 ± 0.14; p = 0.021). The results obtained point to the value of bleomycin sensitivity test in human biomonitoring and confirmed gender and dietary habits as important factors involved in DNA damage response. doi:10.1016/j.toxlet.2008.06.577 R39 The time-space method of territories evaluation Elena Musikhina ∗ , Elena Zelinskaya Irkutsk State Technical University, Irkutsk, Russian Federation In view of high anthropogenic pressure on environment the new approach of complex ecological territory evaluation should be found. Surrounding spaces are multi-sided, and mankind influences on the environment at local, regional and global levels. Existing damage evaluating methods, in spite of their significance, cannot give a correct damage evaluation. Most researchers agree that natural systems have complex multi-level structure, but they use the category of time incorrectly. Taking into account the struc-