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  • 1
    Electronic Resource
    Electronic Resource
    Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes (1998)
    Springer
    Archives of toxicology 72 (1998), S. 609-621 
    Details
    ISSN: 1432-0738
    Keywords: Key words CYP2E1 ; Metabolic inhibition ; Pharmacokinetic modeling ; Chloroethylenes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Trans- and cis-1,2-dichloroethylene (DCE) isomers inhibit their own metabolism in vivo by inactivation of the metabolizing enzyme, presumably the cytochrome P450 isoform, CYP2E1. In this study, we examined cytochrome P450 isoform-specific inhibition by three chloroethylenes, cis-DCE, trans-DCE, and trichloroethylene (TCE), and evaluated several kinetic mechanisms of enzyme inhibition with physiological models of inhibition. Trans-DCE was more potent than cis-DCE, and both were much more effective than TCE in inhibiting CYP2E1. The kinetics of in vitro loss of p-nitrophenol hydroxylase (pNP-OH) activity (a marker of CYP2E1) in microsomal incubations and of the in vivo gas uptake results were most consistent with a mechanism in which inhibition of the metabolizing enzyme (CYP2E1) was presumed to be related to interaction of a reactive DCE metabolite with remaining substrate-bound, active CYP2E1. The kinetics of inhibition by TCE, a weak inhibitor in vitro, were very different from that of the dichloroethylenes. With TCE, parent compound concentrations influenced enzyme loss. Trans-DCE was a more potent inhibitor of CYP2E1 than cis-DCE based on both in vivo and in vitro studies. Quantitative differences in the inhibitory properties of the 1,2-DCE isomers may be due to the different stability of epoxides formed from bioactivation by CYP2E1. Epoxide intermediates of DCE metabolism, reacting by water addition, would yield dialdehyde, a potent cross-linking reagent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050551
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  • 2
    Electronic Resource
    Electronic Resource
    An Alternative Exact Solution of the Two-Stage Clonal Growth Model of Cancer (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 19 (1999), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: The approximate solution of the two-stage clonal expansion model of cancer may substantially deviate from the exact solution, and may therefore lead to erroneous conclusions in particular applications. However, for time-varying parameters the exact solution (method of characteristics) is not easy to implement, hampering the accessibility of the model to nonmathematicians. Based on intuitive reasoning, Clewell et al. (1995) proposed an improved approximate solution that is easy to implement whatever time-varying behavior the parameters may have. Here we provide the mathematical foundation for the approximation suggested by Clewell et al. (1995) and show that, after a slight modification, it is in fact an exact solution for the case of time-constant parameters. We were not able to prove that it is an exact solution for time-varying parameters as well. However, several computer simulations showed that the numerical results do not differ from the exact solution as proposed by Moolgavkar and Luebeck (1990). The advantage of this alternative solution is that the hazard rate of the first malignant cell can be evaluated by numerically integrating a single differential equation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1999.tb00381.x
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Incorporation of Pharmacokinetics in Noncancer Risk Assessment: Example with Chloropentafluorobenzene (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 14 (1994), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Noncancer risk assessment traditionally relies on applied dose measures, such as concentration in inhaled air or in drinking water, to characterize no-effect levels or low-effect levels in animal experiments. Safety factors are then incorporated to address the uncertainties associated with extrapolating across species, dose levels, and routes of exposure, as well as to account for the potential impact of variability of human response. A risk assessment for chloropentafluorobenzene (CPFB) was performed in which a physiologically based pharmacokinetic model was employed to calculate an internal measure of effective tissue dose appropriate to each toxic endpoint. The model accurately describes the kinetics of CPFB in both rodents and primates. The model calculations of internal dose at the no-effect and low-effect levels in animals were compared with those calculated for potential human exposure scenarios. These calculations were then used in place of default interspecies and route-to-route safety factors to determine safe human exposure conditions. Estimates of the impact of model parameter uncertainty, as estimated by a Monte Carlo technique, also were incorporated into the assessment. The approach used for CPFB is recommended as a general methodology for noncancer risk assessment whenever the necessary pharmacokinetic data can be obtained.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1994.tb00241.x
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  • 4
    Electronic Resource
    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 19 (1999), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 pg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 pglkglday based on studies of a fisheating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled lo00 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 pglkglday and an MRL of 0.3 pglkglday.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1999.tb00427.x
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  • 5
    Electronic Resource
    Electronic Resource
    Quantitative Estimates of Risk for Noncancer Endpoints (2005)
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Publishing, Inc.
    Risk analysis 25 (2005), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: While quantitative estimates of risk have been a standard practice in cancer risk assessment for many years, no similar practice is evident in noncancer risk assessment. We use two recent examples involving methylmercury and arsenic to illustrate the negative impact of this discrepancy on risk communication and cost-benefit analysis. We argue for a more balanced treatment of cancer and noncancer risks and suggest an approach for reaching this goal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.2005.00589.x
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  • 6
    Electronic Resource
    Electronic Resource
    Determination of an Occupational Exposure Guideline for Manganese Using the Benchmark Method (2003)
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Publishing, Inc.
    Risk analysis 23 (2003), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: An occupational risk assessment for manganese (Mn) was performed based on benchmark dose analysis of data from two epidemiological studies providing dose-response information regarding the potential neurological effects of exposure to airborne Mn below the current Occupational Safety and Health Administration (OSHA) Permissible Exposure Level (PEL) of 5 mg Mn/m3. Based on a review of the scientific evidence regarding the toxicity of Mn, it was determined that the most appropriate measure of exposure to airborne Mn for the subclinical effects measured in these studies is recent (rather than historical or cumulative) concentration of Mn in respirable (rather than total) particulate. For each of the studies analyzed, the individual exposure and response data from the original study had been made available by the investigators. From these two studies benchmark concentrations calculated for eight endpoints ranged from 0.09 to 0.27 mg Mn/m3. From our evaluation of these results, and considering the fact that the subtle, subclinical effects represented by the neurological endpoints tested in these studies do not represent material impairment, we believe an appropriate occupational exposure guideline for manganese would be in the range of 0.1 to 0.3 mg Mn/m3, based on the respirable particulate fraction only, and expressed as an 8-hour time-weighted average.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/1539-6924.00379
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    Paper (German National Licenses)
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  • 7
    Electronic Resource
    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007017116171
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    Paper (German National Licenses)
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  • 8
    Electronic Resource
    Electronic Resource
    An Alternative Exact Solution of the Two-Stage Clonal Growth Model of Cancer (1999)
    Springer
    Risk analysis 19 (1999), S. 9-14 
    Details
    ISSN: 1539-6924
    Keywords: Cancer model ; cell proliferation ; two-stage model ; approximate solution ; MVK model ; hazard rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract The approximate solution of the two-stage clonal expansion model of cancer may substantially deviate from the exact solution, and may therefore lead to erroneous conclusions in particular applications. However, for time-varying parameters the exact solution (method of characteristics) is not easy to implement, hampering the accessibility of the model to nonmathematicians. Based on intuitive reasoning, Clewell et al. (1995) proposed an improved approximate solution that is easy to implement whatever time-varying behavior the parameters may have. Here we provide the mathematical foundation for the approximation suggested by Clewell et al. (1995) and show that, after a slight modification, it is in fact an exact solution for the case of time-constant parameters. We were not able to prove that it is an exact solution for time-varying parameters as well. However, several computer simulations showed that the numerical results do not differ from the exact solution as proposed by Moolgavkar and Luebeck (1990). The advantage of this alternative solution is that the hazard rate of the first malignant cell can be evaluated by numerically integrating a single differential equation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006993924445
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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