This article was downloaded by: [New York University] On: 10 February 2015, At: 10:16 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Toxicology and Environmental Health: Current Issues Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteh19
Pharmacokinetics and distribution of styrene monomer in rats after intravenous administration a
Jim R. Withey & Peter G. Collins
b
a
Health Protection Branch , Bureau of Chemical Safety, Toxicology Division , Tunney's Pasture, Ottawa, Ontario, Canada , K1A 0L2 b
Health Protection Branch , Bureau of Chemical Safety, Toxicology Division , Ottawa, Ontario, Canada Published online: 20 Oct 2009.
To cite this article: Jim R. Withey & Peter G. Collins (1977) Pharmacokinetics and distribution of styrene monomer in rats after intravenous administration, Journal of Toxicology and Environmental Health: Current Issues, 3:5-6, 1011-1020, DOI: 10.1080/15287397709529635 To link to this article: http://dx.doi.org/10.1080/15287397709529635
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms
Downloaded by [New York University] at 10:16 10 February 2015
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PHARMACOKINETICS AND DISTRIBUTION OF STYRENE MONOMER IN RATS AFTER INTRAVENOUS ADMINISTRATION Jim R. Withey, Peter G. Collins
Downloaded by [New York University] at 10:16 10 February 2015
Health Protection Branch, Bureau of Chemical Safety, Toxicology Division, Tunney's Pasture, Ottawa, Ontario, Canada An interest in the pharmacokinetics of styrene monomer in the rat, arising from the presence of the monomer in the industrial work place and in foods, necessitated an investigation of the, dose dependency of the kinetics of styrene monomer when administered by the iv route. A rapid distribution of the monomer to the major organs was observed, and all of the rate coefficients describing the rates of distribution and elimination decreased with increasing dose. No change in the apparent volume of distribution with dose was observed. Some evidence for the involvement of saturabie metabolic pathways was obtained.
INTRODUCTION In previous reports (Withey, 1976a; Withey and Collins, 1977) the presence of styrene monomer in polystyrene food-packaging material and its transfer to food contents have been demonstrated. In view of the similarity in chemical structure and the in vivo metabolism of vinyl chloride and styrene monomers (El Masri et al., 1958; Ohtsuji and Ikeda, 1971; Hefner et al., 1975), a number of cancer studies with styrene monomer have been initiated [Tox-Tips, 1977). It was apparent that pharmacokinetic and distribution studies with styrene monomer would prove invaluable for the interpretation of these studies and for obtaining information on the nature of the appropriate pharmacokinetic model and of the distribution of the monomer to the principal organs. In this report the pharmacokinetics of styrene monomer after iv administration and approximate values of kinetic parameters for the elimination of styrene from the heart, lungs, liver, spleen, kidney, and brain are presented. METHODS Kinetic Studies Male Wistar rats1 weighing 350-400 g were surgically prepared with an indwelling jugular cannula. Preliminary studies (Withey, 1976b) had 1 Woodlyn Farms, Guelph, Ontario. Requests for reprints should be sent to Jim R. Withey, Health Protection Branch, Bureau of Chemical Safety, Toxicology Division, Tunney's Pasture, Ottawa, K1A 0L2, Ontario, Canada. 1011 Journal of Toxicology and Environmental Health, 3:1011-1020,1977 Copyright © 1977 by Hemisphere Publishing Corporation
Downloaded by [New York University] at 10:16 10 February 2015
1012
). R. WITHEY AND P. G. COLLINS
revealed that after iv administration of a 5.5 mg/kg dose of styrene monomer, a biexponential decay curve for the blood concentration was observed, "which indicated that the kinetics followed an open twocompartment model. It was subsequently found that rats could tolerate iv doses of up to 9 mg/kg without manifesting untoward effects. At a dose of 13 mg/kg all of the animals rapidly developed pulmonary symptoms (hyperventilation and rales) and sometimes showed CNS effects (tremors and convulsions); few of the animals dosed at this level survived beyond 90 min, which precluded kinetic studies at this dose for more than 90 min. Separate animals were therefore dosed at 1.337, 4.011, 6.695, and 9.359 mg/kg. Pure styrene monomer2 was administered via the cannula with a 10 n\ Hamilton syringe and was immediately washed into the bloodstream with 1 ml of heparinized saline. Serial blood samples, 0.1 ml, were then taken at 2, 4, 6, 8, 10, 12, 16, 20, 25, and 30 min, and then every 10 min for a maximum of 3 hr, or until the level of styrene monomer was undetectable (> 0.02 jug/ml). The blood samples were immediately analyzed by a head space technique similar to that described for the analysis of vinyl chloride monomer (Withey, 1976a). A 250 jul portion of the head space vapor was injected into a Hewlett-Packard 5730A dual hydrogen flame gas chromatograph. The column was 6 ft X 1/16 in. coiled glass packed with Durapak3 (2% Carbowax 400 on 100/120 mesh Porasil F). The temperatures of the inlet, detector, and oven were 200, 250, and 100°C, respectively, and the gas flows for air, hydrogen, and nitrogen (carrier gas) were 211, 35, and 24 ml/min. The detector signal was fed directly into an Autolab I 4 computing integrator. Calibration curves for known styrene monomer concentrations in whole rat blood gave good linear data over more than the range of anticipated values (> 200 //g/ml). Styrene monomer could be detected down to 0.02 Mg/ml with a precision of about 10%. Organ Distribution Studies Six cannulated rats were dosed with either 13.37 or 4.011 mg/kg of styrene monomer (iv) and then killed, by cervical separation, at 8, 15, 30, 45, 60, and 90 min after dosing. The heart, lungs, liver, spleen, kidney, and brain were immediately removed and frozen at —72°C (solid CO2-acetone bath). A sample of blood was also taken and immediately analyzed for styrene. About 1 g of each of the organ tissues was placed in 10 ml of water, except that for the spleen only about 0.5 g in 5 ml of water was usually available, and was sliced with a Willems Polytron5 for 30 sec and then homogenized with an Ultrasonic cell disruptor6 for 15 2
Aldrich Chemical Co., Milwaukee, Wisconsin. 3 Waters Associates, Inc., Milford, Massachusetts. 4 Spectra-Physics, Santa Clara, California. 5 Model PT10-35, Brinkmann Instruments Ltd., Toronto, Ontario. 6 Branson Sonic Power Co., New York, New York.
1013
PHARMACOKINETICS OF STYRENE MONOMER
sec. A 2 ml portion of the homogenate was then transferred by pipette to a 15 ml septum vial and analyzed by the head space technique. Calibration curves were constructed for each tissue with known amounts of styrene added and good linear data were obtained down to 0.01 Mg/g.
RESULTS Kinetic Analysis
Downloaded by [New York University] at 10:16 10 February 2015
When blood concentration was plotted against time on semilogarithmic paper, curves similar to that illustrated in Fig. 1 were obtained. The data
100 50 A = 17.223
5.0
TIT cc
B=0.696
J2. 1-0
8 0.5
J9=0.0146 min -i
GQ
0.1 0.05
0.01
0
20
40
60
80 100 120 140 TIME (MIN)
160 180 200
FIGURE 1. Semilogarithmic plot of styrene monomer elimination from rat blood, with residual plot, after administration of an iv dose of 9.359 mg/kg body weight.
1014
J. R. WITHEY AND P. G. COLLINS
were therefore assumed to be described by an open-ended twocompartment model and to follow the equation Ct = Ae~Qt + Be~ ?
Journal of Toxicology and Environmental Health: Current Issues Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteh19
Pharmacokinetics and distribution of styrene monomer in rats after intravenous administration a
Jim R. Withey & Peter G. Collins
b
a
Health Protection Branch , Bureau of Chemical Safety, Toxicology Division , Tunney's Pasture, Ottawa, Ontario, Canada , K1A 0L2 b
Health Protection Branch , Bureau of Chemical Safety, Toxicology Division , Ottawa, Ontario, Canada Published online: 20 Oct 2009.
To cite this article: Jim R. Withey & Peter G. Collins (1977) Pharmacokinetics and distribution of styrene monomer in rats after intravenous administration, Journal of Toxicology and Environmental Health: Current Issues, 3:5-6, 1011-1020, DOI: 10.1080/15287397709529635 To link to this article: http://dx.doi.org/10.1080/15287397709529635
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms
Downloaded by [New York University] at 10:16 10 February 2015
& Conditions of access and use can be found at http://www.tandfonline.com/page/ terms-and-conditions
PHARMACOKINETICS AND DISTRIBUTION OF STYRENE MONOMER IN RATS AFTER INTRAVENOUS ADMINISTRATION Jim R. Withey, Peter G. Collins
Downloaded by [New York University] at 10:16 10 February 2015
Health Protection Branch, Bureau of Chemical Safety, Toxicology Division, Tunney's Pasture, Ottawa, Ontario, Canada An interest in the pharmacokinetics of styrene monomer in the rat, arising from the presence of the monomer in the industrial work place and in foods, necessitated an investigation of the, dose dependency of the kinetics of styrene monomer when administered by the iv route. A rapid distribution of the monomer to the major organs was observed, and all of the rate coefficients describing the rates of distribution and elimination decreased with increasing dose. No change in the apparent volume of distribution with dose was observed. Some evidence for the involvement of saturabie metabolic pathways was obtained.
INTRODUCTION In previous reports (Withey, 1976a; Withey and Collins, 1977) the presence of styrene monomer in polystyrene food-packaging material and its transfer to food contents have been demonstrated. In view of the similarity in chemical structure and the in vivo metabolism of vinyl chloride and styrene monomers (El Masri et al., 1958; Ohtsuji and Ikeda, 1971; Hefner et al., 1975), a number of cancer studies with styrene monomer have been initiated [Tox-Tips, 1977). It was apparent that pharmacokinetic and distribution studies with styrene monomer would prove invaluable for the interpretation of these studies and for obtaining information on the nature of the appropriate pharmacokinetic model and of the distribution of the monomer to the principal organs. In this report the pharmacokinetics of styrene monomer after iv administration and approximate values of kinetic parameters for the elimination of styrene from the heart, lungs, liver, spleen, kidney, and brain are presented. METHODS Kinetic Studies Male Wistar rats1 weighing 350-400 g were surgically prepared with an indwelling jugular cannula. Preliminary studies (Withey, 1976b) had 1 Woodlyn Farms, Guelph, Ontario. Requests for reprints should be sent to Jim R. Withey, Health Protection Branch, Bureau of Chemical Safety, Toxicology Division, Tunney's Pasture, Ottawa, K1A 0L2, Ontario, Canada. 1011 Journal of Toxicology and Environmental Health, 3:1011-1020,1977 Copyright © 1977 by Hemisphere Publishing Corporation
Downloaded by [New York University] at 10:16 10 February 2015
1012
). R. WITHEY AND P. G. COLLINS
revealed that after iv administration of a 5.5 mg/kg dose of styrene monomer, a biexponential decay curve for the blood concentration was observed, "which indicated that the kinetics followed an open twocompartment model. It was subsequently found that rats could tolerate iv doses of up to 9 mg/kg without manifesting untoward effects. At a dose of 13 mg/kg all of the animals rapidly developed pulmonary symptoms (hyperventilation and rales) and sometimes showed CNS effects (tremors and convulsions); few of the animals dosed at this level survived beyond 90 min, which precluded kinetic studies at this dose for more than 90 min. Separate animals were therefore dosed at 1.337, 4.011, 6.695, and 9.359 mg/kg. Pure styrene monomer2 was administered via the cannula with a 10 n\ Hamilton syringe and was immediately washed into the bloodstream with 1 ml of heparinized saline. Serial blood samples, 0.1 ml, were then taken at 2, 4, 6, 8, 10, 12, 16, 20, 25, and 30 min, and then every 10 min for a maximum of 3 hr, or until the level of styrene monomer was undetectable (> 0.02 jug/ml). The blood samples were immediately analyzed by a head space technique similar to that described for the analysis of vinyl chloride monomer (Withey, 1976a). A 250 jul portion of the head space vapor was injected into a Hewlett-Packard 5730A dual hydrogen flame gas chromatograph. The column was 6 ft X 1/16 in. coiled glass packed with Durapak3 (2% Carbowax 400 on 100/120 mesh Porasil F). The temperatures of the inlet, detector, and oven were 200, 250, and 100°C, respectively, and the gas flows for air, hydrogen, and nitrogen (carrier gas) were 211, 35, and 24 ml/min. The detector signal was fed directly into an Autolab I 4 computing integrator. Calibration curves for known styrene monomer concentrations in whole rat blood gave good linear data over more than the range of anticipated values (> 200 //g/ml). Styrene monomer could be detected down to 0.02 Mg/ml with a precision of about 10%. Organ Distribution Studies Six cannulated rats were dosed with either 13.37 or 4.011 mg/kg of styrene monomer (iv) and then killed, by cervical separation, at 8, 15, 30, 45, 60, and 90 min after dosing. The heart, lungs, liver, spleen, kidney, and brain were immediately removed and frozen at —72°C (solid CO2-acetone bath). A sample of blood was also taken and immediately analyzed for styrene. About 1 g of each of the organ tissues was placed in 10 ml of water, except that for the spleen only about 0.5 g in 5 ml of water was usually available, and was sliced with a Willems Polytron5 for 30 sec and then homogenized with an Ultrasonic cell disruptor6 for 15 2
Aldrich Chemical Co., Milwaukee, Wisconsin. 3 Waters Associates, Inc., Milford, Massachusetts. 4 Spectra-Physics, Santa Clara, California. 5 Model PT10-35, Brinkmann Instruments Ltd., Toronto, Ontario. 6 Branson Sonic Power Co., New York, New York.
1013
PHARMACOKINETICS OF STYRENE MONOMER
sec. A 2 ml portion of the homogenate was then transferred by pipette to a 15 ml septum vial and analyzed by the head space technique. Calibration curves were constructed for each tissue with known amounts of styrene added and good linear data were obtained down to 0.01 Mg/g.
RESULTS Kinetic Analysis
Downloaded by [New York University] at 10:16 10 February 2015
When blood concentration was plotted against time on semilogarithmic paper, curves similar to that illustrated in Fig. 1 were obtained. The data
100 50 A = 17.223
5.0
TIT cc
B=0.696
J2. 1-0
8 0.5
J9=0.0146 min -i
GQ
0.1 0.05
0.01
0
20
40
60
80 100 120 140 TIME (MIN)
160 180 200
FIGURE 1. Semilogarithmic plot of styrene monomer elimination from rat blood, with residual plot, after administration of an iv dose of 9.359 mg/kg body weight.
1014
J. R. WITHEY AND P. G. COLLINS
were therefore assumed to be described by an open-ended twocompartment model and to follow the equation Ct = Ae~Qt + Be~ ?
