* E.I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road,Newark, Delaware 19711, and National Health and Environmental Effects Research Laboratory, Office of Research and Development,U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received October 18, 2003; accepted January 28, 2004
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: 2-chloro-1,3-butadiene; PBTK or PBPK modeling; benchmark dose; liver; lung; mouse; rat; hamster; human.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chronic inhalation studies in B6C3F1 mice and Fischer rats showing that CD is a multisite carcinogen (Melnick et al., 1999), contrasted with the lack of tumors observed in Wistar rats and Syrian hamsters (Trochimowicz et al., 1998
). In the bioassay with Wistar rats and Syrian hamsters, inhalation exposures were to 0, 10, or 50 ppm chloroprene (6 h/day, 5 days/week for up to 104 weeks and 72 weeks, respectively; Trochimowicz et al., 1998
). For Wistar rats, an increased incidence of mammary gland fibroadenoma was observed at 50 ppm. No increase in tumor incidence of any tissue type was observed in hamsters. In a bioassay with male and female B63CF1 mice and Fischer/344N rats, exposures were to 0, 12.8, 32, or 80 ppm (6 h/day, 5 days/week for up to 104 weeks; NTP, 1998
). Tumors in mice (male and female) were observed in the lung, circulatory system, Harderian gland, and forestomach. Tumors were also observed in the kidney (male mice only) and mammary gland, skin, mesentery, Zymbal gland, and liver (female mice only). Tissues affected in Fischer rats included the oral cavity, thyroid gland, and kidney (male and female), lung (male only) and mammary gland (female only). The lung tumor response for combined bronchiolar adenoma or carcinomas was greater in the male B6C3F1 mouse than male Fischer rat (Melnick et al., 1999
; Melnick and Sills, 2001
).
The mechanistic steps by which CD exposure leads to rodent tumors, while not understood fully, strongly suggest a genotoxic mode of action. CD is mutagenic in bacterial reverse mutation assays. Other in vitro and in vivo studies for either gene mutation or structural chromosomal damage were negative (see review by Valentine and Himmelstein, 2001). The in vitro microsomal metabolism of CD by cytochrome P450 oxidase produces reactive intermediate epoxides; one of these, (1-chloroethenyl)oxirane, was positive in a bacterial reverse mutation assay, but not clastogenic in an in vitro micronucleus screening study using cultured Chinese hamster V79 cells (Himmelstein et al., 2001a
,b
). This metabolite recently was shown to have in vitro reactivity toward nucleosides and calf thymus DNA (Munter et al., 2002
). A second epoxide metabolite, (2-chloro-2-ethenyl)oxirane, was inferred from carbonyl compounds found as aqueous hydrolysis products of this epoxide (Cottrell et al., 2001
). The metabolic and genotoxic profile of CD is consistent with that of the chemical analogs 1,3-butadene and isoprene. However, the physiologically based toxicokinetic (PBTK) models developed for 1,3-butadiene or isoprene have seen limited application to tumor or nontumor dose response modeling (Melnick and Kohn, 2000
; Sweeney et al., 2001
). The metabolism of CD is also analogous to ethylene and vinyl chloride as the two-carbon analogs of each end of the CD molecule. PBTK models have been developed for ethylene and vinyl chloride, and successfully applied to dose response modeling for vinyl chloride (Clewell et al., 2002
). In the current study, the application of PBTK modeling acts as an important tool for understanding CD uptake and metabolism with respect to low-to-high exposure concentrations and interspecies differences.
In the absence of definitive epidemiology studies (Acquavella and Leonard, 2001), the animal bioassay data is important for estimating the cancer risk in humans exposed to CD. The purpose of this research is two-fold: (1) to implement a PBTK model for use in estimating a relevant measure of internal dose, similar to that which has been done for other chemicals (Clewell et al., 2002
), and (2) to explore a biologically based approach for the CD inhalation dose-response assessment in humans. Recent experiments comparing the rates of CD metabolism in liver and lung microsomes provided the metabolic parameters needed for model development (Himmelstein et al., 2004
).
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals.
The selection of rodent species and rat strains was based on those used in the inhalation bioassay studies. Rodents were purchased from Charles River Laboratories (Raleigh, NC) as young adult males approximately seven weeks of age: mice (B6C3F1/CrlBR), Fischer rats (CDF(F-344)/CrlBR), Wistar rats (Crl:(WI)BR), and Golden Syrian hamsters (Lak:LVG(SYR)BR). Ranges of body weights at the time of gas uptake experimentation are given in Table 1. The animals were maintained in appropriate cages with rodent chow (Purina 5002) and water provided ad libitum and acclimated for at least 7 days prior to use. Laboratory facilities were fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All procedures involving animals were reviewed by the laboratory animal care and use committee.
|
![]() |
Closed-chamber exposures.
Exposures were conducted using a system (Exposure System 1) described previously (Cantoreggi and Keller, 1997). The objective of the experiments with this system was to investigate chemical distribution with and without metabolic inhibition. Exposures were to initial concentrations ranging from 160 to 240 ppm CD. Some animals were pretreated with the cytochrome P450 monooxygenase inhibitor, 4-methyl pyrazole (4-MP, 144 mg/kg body weight; Chow et al., 1992
; Halpert et al., 1994
), prepared in saline and administered by ip injection 1 h prior to exposure. Animals (n = 3) were placed in the exposure chamber 30 min prior to the start of exposure. The chamber atmosphere was circulated through the system at approximately 2.0 l/min with a metal bellows pump (Metal Bellows, Sharon, MA). Tubing throughout the system was stainless steel and Teflon, and the total exposure system volume was 18 l for rats and 5.6 l for mice. Oxygen was monitored using an oxygen meter (MDA Scientific, Lincolnshire, IL) and carbon dioxide was scrubbed with soda lime. The concentration of CD in the chamber was monitored by GC/FID for up to 6 h. The inhalation system was connected to a gas chromatograph (Hewlett-Packard 5890A equipped with valve 18900 F). Samples of 250 µl were injected automatically every 1012 min. The chromatography conditions were similar to those used for GC/FID analysis of CD in vitro metabolism (Himmelstein et al., 2001a
).
Additional gas uptake exposures in mice, Fischer rats, and hamsters were conducted using another system previously described (Evans et al., 1994; McGee et al., 1995
). The purpose of this system (Exposure System 2) was to measure the uptake of CD over a range of initial starting concentrations. The system differed from Exposure System 1 in several ways: O2 was added automatically instead of manually; NH3 was scrubbed; one rat was used per chamber instead of three; and hamsters were substituted for Wistar rats. A known volume of concentrated CD vapor was added to the system having a total volume of 3.8 l. The starting exposure concentrations ranged from approximately 2 to 400 ppm for the mice and rats and 10 to 270 ppm for hamsters. The chambers were tested for leaks and considered operational when empty-chamber loss rates were
5%/h. Oxygen in the chamber was monitored continuously using a silver-electrode probe (Model 3300, MDA Scientific, Lincolnshire, IL) and maintained between 19 and 21%. CO2 and NH3 were removed by circulating the system air through soda lime (Fluka) and sodium citrate (Aldrich), respectively. Animals were acclimated for 60 min prior to the introduction of test vapor. Chamber CD concentrations were monitored starting 10 min after vapor introduction and then every 10 min until the end of the exposure. An automatic gas sampling valve (250 µl) was used to introduce chamber air into the gas chromatograph for analysis by flame ionization or electron capture detection (Hewlett-Packard 5890A or Agilent 6890). The GC conditions were similar to those used for in vitro experiments (Himmelstein et al., 2001a
).
Model development.
A standard PBTK model was developed following the format used by Ramsey and Andersen (1984). The model consisted of distinct compartments for liver and lung, as well as lumped compartments for fat, slowly and rapidly perfused tissues (supplementary figure 1 is available at http://toxsci.oupjournals.org). Individual tissues were modeled as homogenous, well-mixed compartments connected by the systemic circulation. Modeled exposures occurred via partitioning into the arterial blood in the lung (Andersen et al., 1987
). Metabolism of CD was localized to the lung and the liver compartments and described by Michaelis-Menten type saturable enzyme kinetics. The model was used to estimate the CD concentration in each of the defined compartments as well as the blood. Model simulation was conducted using the Advanced Continuous Simulation Language (ACSL version 11.8.4, AEgis Technologies Group, Huntsville, AL). The model code is available upon request.
|
|
Dose response analysis.
The selection of the tissue dosimetry endpoints followed the approach recommended by Clewell et al. (2002). Because the known metabolism of CD involves two epoxide metabolites, but only one metabolite could be quantified in vitro
AMPLU was selected for comparison with the incidence of combined bronchiolar adenoma/carcinoma in male rodents (Melnick et al., 1999; Trochimowicz et al., 1998
). A dose response analysis for rodent liver was not possible because of a bacterial infection in the bioassay with male B6C3F1 mouse and the absence of a response in the male Fischer rat. The NTP (1998) concluded that the infection in male mice did not adversely affect the tumor responses in other tissues. The lung tumor incidence data for the B6C3F1 mouse and Fischer rat were the values corrected for intercurrent mortality using the poly-3 survival adjustment (Melnick et al., 1999
) or the total number of Wistar rats or Syrian hamsters examined (Trochimowicz et al., 1998
). The incidence data were corrected for extra risk equal to (Pi - Po)/(1 - Po), where P is the probability of tumor incidence in "i" exposed and "o" control animals. Benchmark dose (BMD) modeling was performed using the multistage model of the USEPA Benchmark Dose Software (version 1.3.1) and a benchmark response of 10%. Initially, the analyses were performed with the definition of "dose" as exposure concentration (ppm) prior to adjustment for metabolism. Goodness of fit was based on visual inspection of the resulting graphical data and acceptance of a BMD p-value greater than 0.01.
The benchmark internal dose 95% lower bound (BMDL10%) was converted to a human equivalent exposure concentration (ppm) using the PBTK model. Human dosimetrics were also simulated over a wide range of CD exposure concentrations for continuous and discontinuous exposure scenarios. Human model exposures were run for up to two years. The 10% extra tumor risk corresponding to human exposure was determined by running the human PBTK model continuously (24 h/day, 365 days/year for two years) or discontinuously for two common workplace shift schedules (e.g., 8 h/day, 5 days/week or 12 h/day, 3 days/week for two years). Full lifetime exposure of 70 years (or 40 years for occupational exposure) was not necessary because the dosimetrics were calculated on a per day basis and reached a constant value after two simulation days.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Internal Dose
The known lung tumor incidence in male B6C3F1 mouse and the male Fischer rat, and the major role that the liver has in the overall metabolism of CD drove the selection of these tissues for internal dose estimation. A key finding was that the internal dose for total CD metabolism per gram lung per day was greater in the mouse than in the rats or hamster (Table 4). The liver internal dose (AMP) was linear over the range of the bioassay concentrations (data not shown). The lung internal dose (AMPLU) was linear for the rats and hamster but suggests saturable behavior for the mouse (Table 4). As noted above, a Helicobacter infection in the male B6C3F1 mouse bioassay excluded the use of the liver tumor incidence for dose response analysis (Melnick et al., 1999). The NTP (1998)
assumed that the infection did not alter the response of other tumor types, thus metabolism was assumed to be unaltered as well.
|
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The selection of PBTK model parameters was dependent on the suspected mode of action in the animal species used in the bioassay studies. To the extent possible, metabolic and partitioning parameters were quantified in human tissues using a parallelogram approach that has been applied to other chemicals (e.g., Csanády et al., 1992; Medinsky et al., 1994
). Results for the tissue-to-air partition coefficients were consistent with values reported by Gargas et al. (1989)
for a variety of volatile organic chemicals, who generally observed 1.5 to 2 fold higher blood-to-air partition coefficients in rat blood compared with human blood. These parameters, and the physiological parameters adopted directly from Brown et al. (1997)
carried the least inherent uncertainty. One exception was the reduced alveolar ventilation and total blood flow values required for simulation of the closed-chamber gas uptake concentration data. This modification was consistent with values for alveolar ventilation used in the gas uptake literature for various volatile chemicals (Johanson and Filser, 1992
; Medinsky et al., 1994
). The lowering of alveolar ventilation paired with cardiac output reduced the uptake of CD and gave the best overall description of the gas uptake data. Changing the scaled metabolic parameters to increase or decrease uptake was not performed because the kinetic parameters were determined experimentally. The gas uptake experiments in the current project served to verify the scaled in vitro metabolism parameters. The in vivo Vmax values for CD compared reasonably well with those for vinyl chloride and 1,3-butadiene (1.1 and 3.212.8, respectively, versus 9.1 mg/h/kg body weight for CD). The Km values were also generally consistent with values of 0.04, 0.110.28, and 0.06 mg/l (Medinsky et al., 1994
; Reitz et al., 1996
; Sweeney et al., 2001
). The liver was the major contributor to total body metabolism based on comparison of Vmax/Km with liver blood flow. For example, the Vmax/Km (152 l/h/kg) was considerably greater than liver flow calculated from Table 1 (1.8 l/h/kg = 16.20.75 * 0.227) for the human. Thus, the overall metabolism is most likely limited by blood flow perfusion as reported for other cytochrome P450 monooxygenase volatile substrates (Lipscomb et al., 2003b
; Sweeney et al., 2001
).
Scaling in vitro metabolism from liver and lung microsomal fractions is a generally accepted practice, but introduces model uncertainty. The uncertainty comes from the correction factor for loss of protein during centrifugal preparation of the microsomal fractions. Reasonable estimates were available for liver and lung from the literature (see Materials and Methods). Recent experiments describing the recovery of human liver microsomal protein provide additional confidence for protein scaling (Lipscomb et al., 2003a). The same investigators have also concluded that unsaturated metabolism of trichloroethylene by cytochrome P450 monooxygenase is flow limited, more than likely minimizing any major impact of microsomal protein content on metabolic variation (Lipscomb et al., 2003b
). Sensitivity analysis for the current study adds an additional perspective that physiological parameters were more important than metabolic parameters for prediction of internal tissue dose AMP and AMPLU associated with cytochrome P450 monooxygenase mediated metabolism of CD (Fig. 3). Using pooled human liver and lung microsomal fractions is also a source of uncertainty in that this approach does not account for the impact that human interindividual variation might have on metabolism. Further considerations of model uncertainty beyond this current effort may be needed if data from pooled microsomes are considered insufficient for application to risk assessment.
The use of PBTK-derived CD tissue dosimetry for exposure-dose-response modeling for this project was similar to previous descriptions of dichloromethane and vinyl chloride (Andersen et al., 1987; Reitz et al., 1989
, 1996
). In both cases, PBTK models were used to derive life-time average daily production of metabolite divided by liver tissue volume. The significant finding from the current project was that BMD modeling based on CD metabolism in lung tissue (AMPLU) described the greater mouse lung tumor incidence compared with other rodents. Overall metabolism by lung was considerably lower than metabolism by the liver. The exposure-dose-response modeling was applied to the predictions of AMPLU and corresponding external human equivalent exposure concentrations for CD from continuous and discontinuous exposure scenarios (Fig. 5).
Despite the less than complete understanding of mechanisms leading to tumor development, the mode of action for CD-induced tumorigenicity most likely involves metabolic activation and genotoxicity due to interaction with DNA and other cellular components (see Introduction for literature cited). The mode of action appears to be similar to chemical analogs 1,3-butadiene and isoprene (Himmelstein et al., 1997; Watson, 2001
). For example, 1,3-butadiene exposure caused lung tumors in the B6C3F1 mouse. For CD, the plausible mode of action and the greater mouse lung tumor response relative to the other rodents indicate the acceptability of the available data for risk extrapolation. The approach used generally adhered to the principles described in the EPA carcinogen risk assessment guidelines (EPA, 2003
). One key step was pooling of the rodent lung tumor response data. Successful cross-species pooling of response data using PBTK modeling was recently demonstrated for acrylonitrile-induced brain tumors in rats (Kirman et al., 2000
). The internal dose measure (AMPLU) for CD greatly improves the understanding of the lower lung tumor response for the Fischer rat and lack of response for the Wistar rat and Syrian hamster compared with the B6C3F1 mouse. Strain differences in detoxification of the reactive metabolites, which the current model does not address, may explain the greater sensitivity of the Fischer rat compared with the Wistar rat. Nonetheless, the results provide a much better description of interspecies dose response in the 10% percent extra tumor risk range that is considered representative of the range of sensitivity for bioassay studies.
In conclusion, development of a human PBTK model, in conjunction with corresponding physiological, partitioning, and metabolic parameters in rodents, led to a useful demonstration of exposure-dose-response modeling. PBTK simulation of continuous exposure in humans predicted an external concentration of 23 ppm CD to match the corresponding internal dose BMDL10% from all the rodent lung tumor data. Discontinuous workplace exposure resulted in approximately 4 to 5 fold higher external exposure concentrations. These human equivalent concentrations could serve as points of departure for extrapolation to an acceptable risk range.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
2 Data for 2002 from International Institute of Synthetic Rubber Producers, Houston, TX.
1 To whom correspondence should be addressed. Fax: (302) 366-5003. E-mail: matthew.w.himmelstein{at}usa.dupont.com
Portions of this data were presented at the 42nd annual meeting of the Society of Toxicology, March 2003, Salt Lake City, UT.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Andersen, M. E., Clewell, H. J., 3rd, Gargas, M. L., Smith, F. A., and Reitz, R. H. (1987). Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87, 185205.[ISI][Medline]
Arms, A. D., and Travis, C. C. (1988). Reference physiological parameters in pharmacokinetic modeling. US Environmental Protection Agency, Washington, DC, Report no. EPA 600/6-88/004.
Baarnhielm, C., Skanberg, I., and Borg, K. O. (1984). Cytochrome P-450-dependent oxidation of felodipine-a 1,4-dihydropyridine-to the corresponding pyridine. Xenobiotica 14, 719726.[ISI][Medline]
Boogaard, P. J., De Kloe, K. P., Bierau, J., Kuiken, G., Borkulo, P. E. D., and Van Sittert, N. J. (2000). Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro. Xenobiotica 30, 485502.[CrossRef][ISI][Medline]
Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., and Beliles, R. P. (1997). Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13, 407484.[ISI][Medline]
Cantoreggi, S., and Keller, D. A. (1997). Pharmacokinetics and metabolism of vinyl fluoride in vivo and in vitro. Toxicol. Appl. Pharmacol. 143, 130139.[CrossRef][ISI][Medline]
Chiba, M., Fujita, S., and Suzuki, T. (1990). Pharmacokinetic correlation between in vitro hepatic microsomal enzyme kinetics and in vivo metabolism of imipramine and desipramine in rats. J. Pharm. Sci. 79, 281287.[ISI][Medline]
Chow, H. H., Hutchaleelaha, A., and Mayersohn, M. (1992). Inhibitory effect of 4-methylpyrazole on antipyrine clearance in rats. Life Sci. 50, 661666.[CrossRef][ISI][Medline]
Clewell, H. J., 3rd, Andersen, M. E., and Barton, H. A. (2002). A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment. Environ. Health Perspect. 110, 8593.[ISI][Medline]
Cottrell, L, Golding, B. T., Munter, T., and Watson, W. P. (2001). In vitro metabolism of chloroprene: Species differences, epoxide stereochemistry and a de-chlorination pathway. Chem. Res. Toxicol. 14, 15521562.[CrossRef][ISI][Medline]
Csanády, G. A., Guengerich, F. P., and Bond, J. A. (1992). Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice, Carcinogenesis 13, 11431153. Erratum in Carcinogenesis 14, 784.[Abstract]
Easterling, M. R., Evans, M. V., and Kenyon, E. M. (2000). Comparative analysis of software for physiologically based pharmacokinetic modeling: Simulation, optimization, and sensitivity analysis. Toxicol. Methods 10, 203229.[CrossRef][ISI]
EPA (2000). DRAFT Benchmark Dose Technical Guidance Document (External Review Draft, October 2000). EPA/630/R-00/001. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC, pp. 187.
EPA (2003). DRAFT Final Guidelines for Carcinogen Risk Assessment (External Review Draft, February 2003). Other NCEA-F-0644A. 03 Mar 2003. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC, pp. 1125.
Evans, M. V., Crank, W. D., Yang, H., and Simmons, J. E. (1994). Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats. Toxicol. Appl. Pharmacol. 128, 3644.[CrossRef][ISI][Medline]
Gargas, M. L., Burgess, R. J., Voisard, D. E., Cason, G. H., and Andersen, M. E. (1989). Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98, 8799.[ISI][Medline]
Halpert, J. R., Guengerich, F. P., Bend, J. R., and Correia, M. A. (1994). Selective inhibitors of cytochrome P450, Toxicol. Appl. Pharmacol. 125, 163175.[CrossRef][ISI][Medline]
Himmelstein, M. W., Acquavella, J. F., Recio, L., Medinsky, M. A., and Bond, J. A. (1997). Toxicology and epidemiology of 1,3-butadiene. Crit. Rev. Toxicol. 27, 1108.[ISI][Medline]
Himmelstein, M. W., Carpenter, S. C., Hinderliter, P. M., Snow, T. A., and Valentine, R. (2001a). The metabolism of beta-chloroprene: Preliminary in-vitro studies using liver microsomes. Chem.- Biol. Interact. 135136, 267284.[ISI]
Himmelstein, M. W., Gladnick, N. L., Donner, E. M., Snyder, R. D., and Valentine, R. (2001b). In vitro genotoxicity testing of (1-chloroethenyl)oxirane, a metabolite of ß-chloroprene. Chem.-Biol. Interact. 135136, 703713.[ISI]
Himmelstein, M. W., Carpenter, S. C., and Hinderliter, P. M. (2004). Kinetic modeling of ß-chloroprene metabolism: I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans. Toxicol. Sci. 79, 1827.
Johanson, G., and Filser, J. G. (1992). Experimental data from closed chamber gas uptake studies in rodents suggest lower uptake rate of chemical than calculated from literature values on alveolar ventilation. Arch. Toxicol. 66, 291295.[ISI][Medline]
Joly, J. G., Doyon, C., and Peasant, Y. (1975). Cytochrome P-450 measurement in rat liver homogenate and microsomes. Its use for correction of microsomal losses incurred by differential centrifugation. Drug Metab. Dispos. 3, 577586.[Abstract]
Kirman, C. R., Hays, S. M., Kedderis, G. L., Gargas, M. L., and Strother, D. E. (2000). Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling: An analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat. Risk Anal. 20, 135151.[CrossRef][ISI][Medline]
Lipscomb, J. C., Teuschler, L. K., Swartout, J. C., Popken, D., Cox, T., and Kedderis, G. L. (2003b). The impact of cytochrome P450 2E1-dependent metabolic variance on a risk-relevant pharmacokinetic outcome in humans. Risk Anal. 23, 12211238.[CrossRef][ISI][Medline]
Lipscomb, J. C., Teuschler, L. K., Swartout, J. C., Striley, C. A. F., and Snawder, J. E. (2003a). Variance of microsomal protein and cytochrome P450 2E1 and 3A forms in adult human liver. Toxicol. Mech. Methods 13, 4551.[CrossRef][ISI]
McGee, J. K., Evans, M. V., and Crank, W. D. (1995). A versatile gas uptake inhalation system used in pharmacokinetic and metabolic studies of volatile organic compounds. Toxicol. Methods 5, 199212.[ISI]
Medinsky, M. A., Leavens, T. L., Csanády, G. A., Gargas, M. L., and Bond, J. A. (1994). In vivo metabolism of butadiene by mice and rats: A comparison of physiological model predictions and experimental data. Carcinogenesis 15, 13291340.[Abstract]
Melnick, R. L., and Kohn, M. C. (2000). Dose-response analyses of experimental cancer data. Drug Metab. Rev. 32, 193209.[CrossRef][ISI][Medline]
Melnick, R. L., and Sills, R. C. (2001). Comparative carcinogenicity of butadiene, isoprene, and chloroprene in rats and mice. Chem.-Biol. Interact. 135136, 2742.[ISI]
Melnick, R. L., Sills, R. C., Portier, C. J., Roycroft, J. H., Chou, B. J.,Grumbein, S. L., and Miller, R. A. (1999). Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice. Carcinogenesis 20, 867878.
Munter, T., Cottrell, L., Hill, S., Kronberg, L., Watson, W. P., and Golding, B. T. (2002). Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus DNA. Chem. Res. Toxicol. 15, 15491560.[CrossRef][ISI][Medline]
NTP (1998). Toxicology and carcinogenesis studies of chloroprene (CAS No. 126-99-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies), Technical Report No. 467, NIH Publication No. 98-3957, National Institutes of Health, Bethesda, MD.
Ramsey, J. C., and Andersen, M. E. (1984). A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73, 159175.[ISI][Medline]
Reitz, R. H., Gargas, M. L., Andersen, M. E., Provan, W. M., and Green, T. L. (1996). Predicting cancer risk from vinyl chloride exposure with a physiologically based pharmacokinetic model. Toxicol Appl. Pharmacol. 137, 25367.[CrossRef][ISI][Medline]
Reitz, R. H., Mendrala, A. L., and Guengerich, F. P. (1989). In vitro metabolism of methylene chloride in human and animal tissues: Use in physiologically based pharmacokinetic models. Toxicol. Appl. Pharmacol. 97, 230246.[ISI][Medline]
Smith, B. R., and Bend, J. R. (1980). Prediction of pulmonary benzo[a]pyrene 4,5-oxide clearance: A pharmacokinetic analysis of epoxide-metabolizing enzymes in rabbit lung. J. Pharmacol. Exp. Ther. 214, 478482.[Abstract]
Sweeney, L. M., Himmelstein, M. W., and Gargas, M. L. (2001). Development of a preliminary physiologically based toxicokinetic (PBTK) model for 1,3-butadiene risk assessment. Chem. Biol. Interact. 135136, 303322.[ISI]
Trochimowicz, H. J., Löser, E., Feron, V. J., Clary, J. J., and Valentine, R. (1998). Chronic inhalation toxicity and carcinogenicity studies on ß-chloroprene in rats and hamsters. Inhal. Toxicol. 10, 443472.[CrossRef][ISI]
Valentine, R., and Himmelstein, M. W. (2001). Overview of the acute, subchronic, reproductive, developmental and genetic toxicology of ß-chloroprene. Chem.-Biol. Interact. 135136, 81100.[ISI]
Watson, W. P., Cottrell, L., Zhang, D., and Golding, B. T. (2001). Metabolism and molecular toxicology of isoprene. Chem.-Biol. Interact. 135136, 223238.[ISI]
|