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H J Clewell

Publications and source records attributed to H J Clewell.

At least 19 recordsLinked to original sources
PubMed1997

Investigation of the potential impact of benchmark dose and pharmacokinetic modeling in noncancer risk assessment.

There has been relatively little attention given to incorporating knowledge of mode of action or of dosimetry of active toxic chemical to target tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference concentration (RfC) process on delivered dose adjustments for inhaled materials. The studies reported here attempt to continue in the spirit of the new RfC guidelines by incorporating both mechanistic and delivered dose information using a physiologically based pharmacokinetic (PBPK) model, along with quantitative dose-response information using the benchmark dose (BMD) method, into the noncancer risk assessment paradigm. Two examples of the use of PBPK and BMD techniques in noncancer risk assessment are described: methylene chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK analysis of these chemicals were generally similar to those based on the traditional process, but individual MRLs ranged from roughly 10-fold higher to more than 10-fold lower than existing MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modeling, and in these two cases the BMD models were unable to provide an acceptable fit to the overall dose-response of the data, even using pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequate to support BMD modeling. Three general observations regarding the use of PBPK and BMD modeling in noncancer risk assessment were noted. First, a full PBPK model may not be necessary to support a more accurate risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Second, pharmacokinetic and mode of action considerations are a crucial factor in conducting noncancer risk assessments that involve animal-to-human extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the toxicological literature should include both means and standard deviations for each dose group in the case of quantitative endpoints, such as relative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.

Animals↗
PubMed1997

Pharmacodynamic model of the rat estrus cycle in relation to endocrine disruptors.

Several strains of laboratory rats have a high background incidence of mammary tumors and develop a persistent, anovulatory estrus condition at about 12 mo of age. The increased tumor incidence is believed to be associated with elevated estradiol (E2) and prolactin during the period of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analyze the physiological basis of early-onset persistent estrus and to examine the potential sites of interactions in the hypothalamic-pituitary-ovarian axis for endocrine-modulating xenobiotics that accelerate the onset of persistent estrus. This initial estrus cycle model focused solely on cyclical changes in E2 and luteinizing hormone (LH). An LH surge was scheduled when a hypothetical estrus cycle-related protein (EC-RP) under transcriptional control by the E2 receptor reached a critical concentration. In the model, aging-related cumulative hypothalamic E2 exposure impaired the LH surge by reducing the rate of production of the EC-RP. The progressively decreasing intercycle resynthesis rate leads first to longer, variable-length cycles and finally to persistent estrus at about 12 mo of age. This model construct is consistent with early-onset persistent estrus related to neonatal E2 exposures, with acyclicity associated with high-dose E2 exposure in the adult, and with persistent estrus conditions associated with exposures to xenobiotic endocrine modulators that are either weak E2 antagonists or weak E2 agonists. With further development these pharmacodynamic estrus cycle models should be useful in aiding risk assessments for compounds causing mammary-tissue tumors associated with persistent estrus states.

Aging↗
PubMed1997

Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data.

A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.

Animals↗
PubMed1997

A physiologically based pharmacokinetic model for retinoic acid and its metabolites.

BACKGROUND: A physiologically based pharmacokinetic (PBPK) model for all-trans-retinoic acid (tretinoin) was developed to provide a coherent description of tretinoin absorption, distribution metabolism, and excretion across species and routes of administration. OBJECTIVE: The goal of developing such a model is to provide a measure of internal dose that would be a biologically relevant surrogate for administered dose in assessing human teratogenic risk from topically applied tretinoin emollient cream. METHODS: The developed PBPK model included compartments for plasma, liver, gut, intestinal lumen, fat, skin, richly and slowly perfused tissues, placenta, and embryo. Tretinoin metabolism to 13-cis retinoic acid, oxidation, and glucuronidation were incorporated. Dose surrogates, including the maximum plasma concentration (Cmax) and area under the concentration-versus-time curve were calculated from the model. RESULTS: The ability of the model to predict tretinoin pharmacokinetics and to extrapolate across species and routes of administration was tested and validated. Model-derived estimates of dose surrogates demonstrated that the internal exposure to retinoids after topical treatment with 0.05% tretinoin emollient cream is minimal in comparison to that for teratogenic oral doses. The ratio of areas under the curve for total active retinoids after teratogenic oral doses in monkeys versus therapeutic topical doses in human beings, for example, was greater than 450,000 to 1. CONCLUSION: For topical application of tretinoin in human beings, detoxification via the glucuronidation pathway predominates, resulting in a much lower internal exposure to active retinoids than was inferred from total radioactivity data. The model predicts that topical application of tretinoin results in an internal exposure that is four to six orders of magnitude lower than a minimally teratogenic dose.

Abnormalities, Drug-Induced↗
PubMed1996

Investigation of the impact of pharmacokinetic variability and uncertainty on risks predicted with a pharmacokinetic model for chloroform.

A sensitivity and uncertainty analysis was performed on the Reitz et al. (Toxicol. Appl. Pharmacol., 1990: 105, 443) physiologically based pharmacokinetic (PBPK) risk assessment model for chloroform. The analytical approach attempted to separately consider the impacts of interindividual variability and parameter uncertainty on the predicted values of the dose metrics in the model, as well as on liver cancer risk estimates obtained with the model. An important feature of the analytical approach was that an attempt was made to incorporate information on correlation between important parameters, for example, the observed correlation between total blood flow and alveolar ventilation rate. Using the published PBPK model for chloroform, the best estimate of the average population risk based on the preferred pharmacodynamic dose metric (PTDEAD), representing cell death, is 9.2 x 10(-7); this estimate is more than 500-fold lower than the risk estimate of 5.3 x 10(-4) based on an alternative pharmacokinetic dose metric (AVEMMB), which represents tissue adduct formation. However, when interindividual variability was considered the range of individual risks (from the 5th to the 95th percentile of the population) predicted with PTDEAD was extremely broad (from 3.0 x 10(-13) to 3.2 x 10(-4)), while individual risks predicted with AVEMMB only varied over a factor of four (from 1.9 x 10(-4) to 7.4 x 10(-4)). As a result, the upper 95th percentile of the distribution of individual risk estimates based on the preferred cell death metric were within a factor of three of the 95th percentile for the pharmacokinetic alternative. The crucial factor with respect to the much greater variability of chloroform risk estimates based on cell death is that the dose metric, PTDEAD, is exquisitely sensitive to variation of the parameters in the model defining the response of cells to the cytotoxicity of chloroform. Unfortunately, these key parameters are also highly uncertain, as well as strongly correlated. As a result it proved impossible to accurately quantify the additional impact of parameter uncertainty on the dose metrics and risk estimates for chloroform. In general, however, the approach used in this study should be useful for differentiating the impact of interindividual variability and parameter uncertainty on PBPK-based risk assessments of other chemicals where the sensitivity, uncertainty, and correlation of the key parameters are more limited.

Animals↗
PubMed1996

Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk.

Because of the heterogeneity of the human population, it is generally expected that there will be a broad range of observed susceptibilities to the biological effects of exposure to chemicals or drugs. Often it is possible to distinguish specific classes of individuals, such as infants or the elderly, who appear to be more susceptible to a specific effect. Non-cancer risk assessment often address this variability by dividing the experimentally determined acceptable exposure level by an uncertainty factor of 10 to protect sensitive individuals; cancer risk assessments typically do not address this issue in any quantitative fashion. Physiologically based pharmacokinetic (PBPK) modeling provides the capability to quantitatively describe the potential impact of pharmacokinetic factors on the variability of individual risk. In particular, PBPK models can be used to determine the impact of differences in key metabolism enzymes, whether due to multiple genotypic expression, such as cytochrome P450 polymorphisms, or just due to normal variation in enzyme activities within the general population. Other potential modulators of sensitivity which can be addressed quantitatively with a PBPK model include physical condition, level of activity, disease states, age, hormonal status, and interactions with other chemicals and drugs. In each case, the PBPK model provides a quantitative structure for determining the effect of these various factors on the relationship between the external (environmental) exposure and the internal (biologically effective) target tissue exposure. When coupled with Monte Carlo analysis, the PBPK model provides a method to assess the quantitative impact of these sources of variability on individual risk (as opposed to average population risk) by comparing model-predicted risks over the distribution of individual parameter values.

Animals↗
PubMed1995

Incorporating biological information in quantitative risk assessment: an example with methylene chloride.

The interplay between chemical risk assessment and scientific research is discussed in the context of recent attempts to improve the scientific basis for estimates of the human carcinogenic risk from methylene chloride. A combination of basic biochemical research and risk assessment oriented research, both mechanistic and pharmacokinetic, provided the initial impetus for re-evaluating the use of the default risk estimation approach. Resulting efforts to incorporate the new scientific information into the risk assessment process in turn identified specific additional research needed to reduce uncertainty in the estimated risk. This healthy interchange between the two disciplines has served both to refine the human risk estimates for methylene chloride and to more clearly identify key scientific issues for chemical risk assessment in general.

Animals↗
PubMed1995

Applying simulation modeling to problems in toxicology and risk assessment--a short perspective.

The goals of this perspective have been to examine areas where quantitative simulation models may be useful in toxicology and related risk assessment fields and to offer suggestions for preparing manuscripts that describe these models. If developments in other disciplines serve as a bell-wether, the use of mathematical models in toxicology will continue to increase, partly, at least, because the new generations of scientists are being trained in an electronic environment where computation of all kinds is learned at an early age. Undoubtedly, however, the utility of these models will be directly tied to the skills of investigators in accurately describing models in their research papers. These publications should convey descriptions of both the insights obtained and the opportunities provided by these models to integrate existing data bases and suggest new and useful experiments. We hope these comments serve to facilitate the expansion of good modeling practices as applied to toxicological problems.

Computer Simulation↗
PubMed1995

Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl chloride and trichloroethylene.

Risk assessments for vinyl chloride (VC) and trichloroethylene (TCE) are presented as examples of approaches for incorporating chemical-specific pharmacokinetic and mechanistic information into a more scientifically plausible cancer risk assessment. For VC, the evidence regarding mode of action includes direct reaction of a metabolite with DNA, resulting in DNA adducts and mistranscription, and cross-species target-tissue correspondence of a rare tumor type. Risk estimates for human exposure to VC predicted with a physiologically-based pharmacokinetic (PBPK) model and the linearized multistage (LMS) model were lower than those currently used in environmental decision-making by a factor of 30 to 50, and were more consistent with human epidemiological data. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and the tumors typically represent an increase in the incidence of a commonly observed, species-specific lesion. Virtually safe exposure estimates for human exposure to TCE predicted with a PBPK model and a margin of exposure (MOE) approach were higher than those obtained by the conventional LMS approach by roughly a factor of 100. The MOE approach is recommended as an alternative to the LMS approach for chemicals with a carcinogenic mode of action which entails increased cell proliferation, leading to the expectation of a highly nonlinear cancer dose-response.

Animals↗
PubMed1995

The application of physiologically based pharmacokinetic modeling in human health risk assessment of hazardous substances.

Physiologically based pharmacokinetic (PBPK) modeling is an important tool for improving the accuracy of human health risk assessments for hazardous substances in the environment. The proper use of PBPK modeling can reduce uncertainties that currently exist in risk assessment procedures by providing more scientifically credible extrapolations across species and routes of exposure, and from high experimental doses to potential environmental exposures. Current applications of PBPK models range from relatively straightforward uses for the extrapolation of chemical kinetics across species, route, and duration of exposure to much more demanding chemical risk assessment applications requiring a description of complex pharmacodynamic phenomena such as mitogenicity and hyperplasia secondary to cytotoxicity. PBPK modeling helps to identify the factors that are most important in determining the health risks associated with exposure to a chemical, and provides a means for estimating the impact of those factors both on the average risk to a population and on the specific risk to an individual. The chief challenge in the application of PBPK modeling in human health risk assessment lies in the need to generate chemical-specific data to support the development and validation of the models. Extensive use of rapidly developing in vitro and structure-activity relationship techniques is needed to provide the data required for the large number of hazardous chemicals currently contaminating the environment.

Animals↗
PubMed1995

An improved approximation to the exact solution of the two-stage clonal growth model of cancer.

Multistage clonal growth models are of interest for cancer risk assessment because they can explicitly incorporate data on cell replication. Both approximate and exact formulations of the two stage growth model have been described. The exact solution considers the conditional probability of tumors arising in previously tumor-free animals; the approximate solution estimates total probability of tumor formation. The exact solution is much more computationally intensive when time-dependent cell growth parameters are included. The approximate solution deviates from the exact solution at high incidences and probabilities of tumor. This report describes a computationally tractable, 'improved approximation' to the exact solution. Our improved approximation includes a correction term to adjust the unconditional expectation of intermediate cells based on the time history of formation of intermediate cells by mutation of normal cells (recruitment) or by cell division in the intermediate cell population (expansion). The improved approximation provided a much better match to the exact solution than the approximate solution for a wide range of parameter values. The correction term also appears to provide insight into the biological factors that contribute to the variance of the expectation for the number of intermediate cells over time.

Algorithms↗
PubMed1994

Kinetics of water vapor sorption in porcine stratum corneum.

The kinetics of water vapor absorption-desorption was studied in the porcine stratum corneum (sc) at 25 degrees C. Dry sc samples were exposed to several relative humidities followed by exposure to dry air, and the change in weight was monitored over time by use of a thermal gravimetric analysis technique. Diffusion coefficients were estimated by simulation and data fit optimization to modifications of the non-steady-state solution of Fick's law. Very good fits of experimental data to theoretical equations were obtained. The stratum corneum-water absorption isotherm was characterized by a linear increase from the origin, extending to about 55% relative humidity (10% water gain), followed by an upward curve where water gain increased further by increasing relative humidity. Water absorption and water desorption in the porcine sc were asymmetrical processes, desorption being the slower one. Water diffusivity for the absorption process was related to sc water content in two phases. In the first (water gain < 9%) diffusion coefficients increased as water concentration increased. In the second (water gain > 9%) diffusion coefficients were independent of water concentration, equal to 1.17 x 10(-10) cm2/s. Water diffusivity in the desorption phase was shown to decrease linearly as sc water content decreased. Analysis of the absorption isotherm and of the derived diffusion coefficients suggested at least two forms of water associated with the sc. The first, termed "firmly bound water" and characterized by low diffusion coefficients, was most apparent with dry sc and with a sc water gain of up to 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Gas uptake studies of deuterium isotope effects on dichloromethane metabolism in female B6C3F1 mice in vivo.

In common with a diverse group of low-molecular-weight volatile substrates, dichloromethane (DCM; methylene chloride) is a high-affinity, low-capacity substrate for oxidation by several cytochrome P450 isoenzymes in vivo. DCM oxidation, catalyzed primarily by the 2E1 and 2B1 cytochrome P450 isoforms, yields carbon monoxide (CO) and carbon dioxide. We have studied the characteristics of DCM oxidation in vivo by examining the metabolism of DCM and of both deuterated forms ([2H2]-DCM and [2H]DCM) in female B6C3F1 mice with gas uptake methods. Gas uptake and CO production curves were analyzed by physiologically based pharmacokinetic (PBPK) modeling techniques, permitting differentiation of isotope effects on specific metabolic parameters from those associated with blood flow or diffusion limitations in vivo. A marked isotope effect was observed on the moles of CO produced per mole of DCM oxidized (0.76 +/- 0.06, 0.33 +/- 0.006, and 0.31 +/- 0.07, with DCM, [2H]DCM, and [2H2]DCM, respectively). Based on these ratios, the calculated kH/kD ratio for the rate constant of disproportionation of the putative formyl chloride intermediate was about 7, indicating a significant role of C-H bond breaking in this reaction. Deuterium substitution altered the apparent Km for metabolism; there was 14-fold increase in the apparent Km between DCM and [2H2]DCM (6.5 +/- 0.69 to 97 +/- 3.5 microM) with little effect on Km with [2H]DCM (14.4 +/- 0.015 microM). Vmax was not greatly affected by deuteration (151 +/- 1.2, 116 +/- 0.82, and 149 +/- 2.3 mumol/hr/kg with DCM, [2H]DCM, and [2H2]DCM, respectively). Two kinetic mechanisms are discussed, both of which are consistent with these observations. One, a conventional cytochrome P450 mechanism has a rate-limiting product-release step after the isotopically sensitive step; a second, more like a peroxidase mechanism, has a flux-limiting oxygen activation step followed by a second-order reaction between an activated oxygen-enzyme complex and DCM. Regardless of the correct mechanism, the in vivo kinetic constants for oxidation of DCM are complex and represent more than simple rate-limiting bond-breaking (Vmax) and enzyme-substrate binding (Km). Current PBPK models for metabolism of these volatiles may have to be restructured to account for this unusual kinetic mechanism.

Administration, Inhalation↗
PubMed1994

Incorporation of pharmacokinetics in noncancer risk assessment: example with chloropentafluorobenzene.

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.

Animals↗
PubMed1994

Sensitivity of physiologically based pharmacokinetic models to variation in model parameters: methylene chloride.

The parameters in a physiologically based pharmacokinetic (PBPK) model of methylene chloride were varied systematically, and the resulting variation in a number of model outputs was determined as a function of time for mice and humans at several exposure concentrations. The importance of the various parameters in the model was highly dependent on the conditions (concentration, species) for which the simulation was performed and the model output (dose surrogate) being considered. Model structure also had a significant impact on the results. For sensitivity analysis, particular attention must be paid to conservation equations to ensure that the variational calculations do not alter mass balance, introducing extraneous effects into the model. All of the normalized sensitivity coefficients calculated in this study ranged between -1.12 and 1, and most were much less than 1 in absolute value, indicating that individual input errors are not greatly amplified in the outputs. In addition to ranking parameters in terms of their impact on model predictions, time-dependent sensitivity analysis can also be used as an aid in the design of experiments to estimate parameters by predicting the experimental conditions and sampling points which will maximize parameter identifiability.

Animals↗
PubMed1994

Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.

Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would greatly improve OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. DFP tissue/blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain, as well as AChE inhibition and AChE resynthesis data, were successfully simulated for a single iv injection. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain were also well simulated except for an apparent decrease in basal AChE activity in the brain which persisted 35 days after the last dose. The psychologically based pharmacokinetic (PBPK) model parameter values specific for DFP in humans, for example, tissue/blood partition coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and bimolecular inhibition rate constants for target enzymes were scaled from rodent data or obtained from the literature. Good agreement was obtained between model predictions and human exposure data on the inhibition of red blood cell AChE and plasma butyrylcholinesterase after an intramuscular injection of 33 micrograms/kg DFP and at 24 hr after acute doses of DFP (10-54 micrograms/kg), as well as for repeated DFP exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1994

Physiologically based pharmacokinetic analyses of simple mixtures.

Exposure to multiple chemicals may cause significant alterations of tissue dose of the toxic moiety of one or more of the individual chemicals. The change in target tissue dose of a chemical present in simple mixtures can be predicted when the determinants of disposition of each chemical, and the mechanism of toxicokinetic interaction between chemicals are understood at a quantitative level. Determinants of disposition include physiological (e.g., breathing rates, cardiac output, tissue volumes, blood flow rates), biochemical (e.g., kinetic constants for metabolism and protein binding), and physicochemical factors (e.g., blood air and tissue blood partition coefficients). Mechanisms of toxicokinetic interactions refer to the manner in which coexposure alters these determinants of disposition as compared to exposure to the individual chemicals. Interactions between chemicals can be described quantitatively with physiologically based pharmacokinetic (PBPK) models, which integrate these mechanic determinants and permit prediction of alterations in tissue dose for various exposure situations by computer simulation. PBPK modeling studies of binary chemical interactions conducted so far indicate that inhibitory rather than potentiating metabolic interactions are more likely to be observed during multiple chemical exposures. As PBPK models of representative binary, tertiary and quaternary mixtures are developed, it will become increasingly possible to draw reliable conclusions about the risk associated with human exposure to chemical mixtures.

Animals↗