Forward Dosimetry Research Articles

Modeled Rat Hepatic and Plasma Concentrations of Chemicals after Virtual Administrations Using Two Sets of in Silico Liver-to-Plasma Partition Coefficients.

The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CLh,int) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (Kp,h). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for Kp,h for a variety of chemicals. In this study, two sets of in silico Kp,h values for 14 model substances were assessed using experimentally reported in vivo steady-state Kp,h data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats. The Kp,h values for 14 chemicals independently calculated using the primary Poulin and Theil method in this study were significantly correlated with those obtained using the updated Rodgers and Rowland method and with reported in vivo steady-state Kp,h data in rats. When pharmacokinetic parameters were derived based on individual in vivo time-dependent data for diazepam, phenytoin, and nicotine in rats, the modeled liver and plasma concentrations after intravenous administration of the selected substrates in rats using two sets of in silico Kp,h values were mostly similar to the reported time-dependent in vivo internal exposures. Similar results for modeled liver and plasma concentrations were observed with input parameters estimated by machine-learning systems for hexobarbital, fingolimod, and pentazocine, with no reference to experimental pharmacokinetic data. These results suggest that the output values from rat pharmacokinetic models based on in silico Kp,h values derived from the primary Poulin and Theil model would be applicable for estimating toxicokinetics or internal exposure to substances.

Liver and Plasma Concentrations of Food Chemicals after Virtual Oral Doses Extrapolated Using in silico Estimated Input Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats.

The estimation of health risks of chemical substances was historically investigated using animal studies; however, current research focuses on reducing the number of animal experiments. The toxicity of chemicals in fish screening systems is reportedly correlated with their hydrophobicity. The inverse relationship between absorption rates (intestinal cell permeability) and virtual hepatic/plasma pharmacokinetics of diverse chemicals has been previously evaluated by modeling oral administration in rats. In the current study, internal exposures, i.e., virtual maximum plasma concentrations (Cmax) and areas under the concentration-time curves (AUC), of 56 food chemicals with reported hepatic lowest-observed-effect levels (LOELs) of ≤1000 mg/kg/day in rats were pharmacokinetically modeled using in silico estimated input pharmacokinetic parameters. After a virtual single oral dose of 1.0 mg/kg of 56 food chemicals, the output Cmax and AUC values in rat plasma generated by modeling using the corresponding in silico estimated input parameters were not significantly correlated with the reported hepatic LOEL values. However, significant inverse relationships between hepatic/plasma concentrations of selected lipophilic food chemicals (i.e., octanol-water partition coefficient logP >1) using forward dosimetry and reported LOEL values (≤300 mg/kg/day) were observed (n = 14, r = -0.52-0.66, p ≤ 0.05). This simple modeling approach, which uses no experimental pharmacokinetic data, has the potential to play a significant role in reducing the use of animals to estimate toxicokinetics or internal exposures of lipophilic food components after oral doses. Therefore, these methods are valuable for estimating hepatic toxicity by using forward dosimetry in animal toxicity experiments.

Integrating Physiologically Based Pharmacokinetic Modeling-Based Forward Dosimetry and in Vitro Bioassays to Improve the Risk Assessment of Organophosphate Esters on Human Health

The ability to accurately assess the health risks of contaminants is limited by the shortcomings of toxicological standards. Using organophosphate esters (OPEs) as an example, this study attempted to integrate physiologically based pharmacokinetic (PBPK)-based forward dosimetry and in vitro bioassays to assess the likelihood of contaminants inducing biological effects in humans. The total exposure level of OPEs for Chinese residents was 19.5 ± 8.71 ng/kg/day with inhalation being the main exposure pathway. Then, human PBPK models were developed for individual OPEs to predict their steady-state concentrations in human tissues, and the predicted median levels in blood were close to the measurements. The reference doses (RfDs) of OPEs based on in vitro bioassays were comparable to in vivo animal-derived RfDs, demonstrating the reliability of in vitro bioassays. Therefore, the likelihood of OPEs inducing bioactivities in humans (RQin-vitro) was calculated using in vitro toxicity data and OPE levels in human tissues. The RQin-vitros of tris(2-chloroisopropyl) phosphate, tris(1,3-dichloropropyl) phosphate, and triphenyl phosphate (7.68 × 10-5-3.18 × 10-3) were comparable to the risks assessed using traditional RfDs (5.22 × 10-5-1.94 × 10-3), indicating the credibility of the method proposed in this study. This study establishes a new framework to improve the health risk assessment of contaminants without sufficient toxicity data and minimize the need for animal experimentation.

Updated in Silico Prediction Methods for Fractions Absorbed and Key Input Parameters of 355 Disparate Chemicals for Physiologically Based Pharmacokinetic Models for Time-Dependent Plasma Concentrations after Virtual Oral Doses in Humans.

Human metabolic profiles for substances such as toxic food-derived compounds are usually allometrically extrapolated from traditionally determined in vivo rat concentration profiles. To evaluate internal exposures in humans without any reference to experimental data, physiologically based pharmacokinetic (PBPK) modeling could be used if the model input parameters could be estimated in silico. This approach would simplify the use of PBPK models for forward dosimetry after oral doses. In this study, the in silico estimation of input parameters for PBPK models (i.e., fraction absorbed × intestinal availability, absorption rate constants, and volumes of the systemic circulation) was updated for an panel of 355 chemicals (212 previously analyzed and 143 additional substances) using a light gradient boosting machine learning algorithms (LightGBM) based on between 11 and 29 in silico-calculated chemical descriptors. Simplified human PBPK models were then used to calculate virtual maximum plasma concentrations (Cmax) and areas under the concentration-time curve (AUC) based on two sets of input parameters, i.e., traditionally derived values from in vivo data and those calculated in silico using the current updated systems. Both sets of Cmax and AUC data were well correlated (r = 0.87 and r = 0.73, respectively; p < 0.01, n = 355). Therefore, input parameters for human PBPK models for a diverse range of compounds could be successfully estimated using chemical descriptors and in silico tools. This approach to pharmacokinetic modeling has potential for application in computational toxicology and in the clinical setting for assessing the potential risk of general chemicals.

Plasma Concentration Profiles for Hepatotoxic Pyrrolizidine Alkaloid Senkirkine in Humans Extrapolated from Rat Data Sets Using a Simplified Physiologically Based Pharmacokinetic Model.

The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

Exposure assessment of Spanish lactating mothers to acrylamide via human biomonitoring

Acrylamide (AA) is an organic compound classified as “Probably carcinogenic to humans” (Group 2 A) that can be found principally in processed carbohydrate-rich foods and tobacco smoke. In humans, after exposure, AA is rapidly metabolized and excreted in urine, predominantly as N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA3) and N-Acetyl-3-[(3-amino-3-oxopropyl)sulfinyl]-L-alanine (AAMA-Sul), which can be used as short-term biomarkers of exposure to AA.In this study, the presence of AA metabolites in urine samples of lactating mothers living in Spain (n = 114) was analyzed by “dilute and shoot” and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All urinary metabolites were detected in 100% of the analyzed samples, with geometric means of 70, 33 and 15 ng ml−1, for AAMA, AAMA-Sul and GAMA3, respectively. The consumption of coffee, bread and precooked food products were found to be significant predictors of internal exposure to AA. An estimated daily intake (EDI) of AA based on its urinary metabolites was calculated, obtaining mean values between 1.2 and 1.9 μg AA·kg bw−1·day−1 in the target population. The risk assessment was evaluated using both reverse and forward dosimetry, showing an average margin of exposure (MOE) of 349 and a hazard quotient (HQ) of 5.5. Therefore, AA exposure should be considered a medium priority for risk assessment follow-up in the Spanish population, since a health concern with respect to non-neoplastic toxicity could not be discarded.

In Silico Prediction of Input Parameters for Simplified Physiologically Based Pharmacokinetic Models for Estimating Plasma, Liver, and Kidney Exposures in Rats after Oral Doses of 246 Disparate Chemicals.

Recently developed computational models can estimate plasma, hepatic, and renal concentrations of industrial chemicals in rats. Typically, the input parameter values (i.e., the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance) for simplified physiologically based pharmacokinetic (PBPK) model systems are calculated to give the best fit to measured or reported in vivo blood substance concentration values in animals. The purpose of the present study was to estimate in silico these three input pharmacokinetic parameters using a machine learning algorithm applied to a broad range of chemical properties obtained from several cheminformatics software tools. These in silico estimated parameters were then incorporated into PBPK models for predicting internal exposures in rats. Following this approach, simplified PBPK models were set up for 246 drugs, food components, and industrial chemicals with a broad range of chemical structures. We had previously generated PBPK models for 158 of these substances, whereas 88 for which concentration series data were available in the literature were newly modeled. The values for the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance could be generated in silico by equations containing between 14 and 26 physicochemical properties. After virtual oral dosing, the output concentration values of the 246 compounds in plasma, liver, and kidney from rat PBPK models using traditionally determined and in silico estimated input parameters were well correlated (r ≥ 0.83). In summary, by using PBPK models consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central (main) compartments with in silico-derived input parameters, the forward dosimetry of new chemicals could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of hematotoxic, hepatotoxic, or nephrotoxic potential as a part of risk assessment.

Metabolic profiles for the pyrrolizidine alkaloid neopetasitenine and its metabolite petasitenine in humans extrapolated from rat in vivo and in vitro data sets using a simplified physiologically based pharmacokinetic model.

Naturally occurring food substances may constitute safety hazards. The risks associated with plant-derived pyrrolizidine alkaloids have been extensively evaluated. Petasites japonicus (common Japanese name, fuki) is a widely consumed water-soluble pyrrolizidine alkaloid-producing plant. In this study, neopetasitenine (acetylfukinotoxin) was selected as a model food substrate (for which human pharmacokinetics were estimated) because of its high concentration in fuki, along with petasitenine (fukinotoxin), its carcinogenic deacetylated metabolite. Although neopetasitenine was rapidly absorbed and converted to petasitenine after oral administration of 1.0 mg/kg in rats, petasitenine was slowly cleared from plasma. Forward dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling formulated on experimental pharmacokinetic rat data. From ~2 hr after the oral administration of neopetasitenine in rats, the plasma concentrations of petasitenine were higher than those of neopetasitenine under the present conditions. A human PBPK model was established following an allometric scaling approach applied to rat parameters (without considering interspecies factors) to estimate human intrinsic hepatic clearances from empirical rat values. Human in silico neopetasitenine and petasitenine plasma concentration curves were simulated after daily oral administrations of 3.0 and 1.3 mg/kg neopetasitenine. These doses were taken from reported acute/short-term cases of pyrrolizidine alkaloid toxicity. In vitro hepatotoxicity of neopetasitenine and petasitenine was caused by their high concentrations in the medium for human hepatocyte-like cell line HepaRG cells as an index of lactate dehydrogenase leakage. Neopetasitenine was estimated to be rapidly absorbed and converted to deacetylated carcinogenic petasitenine, even after hepatotoxic doses of 1.0 mg/kg in humans. If the water-soluble pyrrolizidine alkaloid-producing plant P. japonicus were daily consumed as food, current simulation results suggest that dangerous amounts of deacetylated petasitenine could be continuously present in human plasma.

Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats.

Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration-time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration-time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration-time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.

Metabolic profiles of coumarin in human plasma extrapolated from a rat data set with a simplified physiologically based pharmacokinetic model.

Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro-in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.

Simple Electronic Portal Imager-Based Pretreatment Quality Assurance using Acuros XB: A Feasibility Study.

Objective:This study demonstrates a novel electronic portal imaging device (EPID)-based forward dosimetry approach for pretreatment quality assurance aided by a treatment planning system (TPS).Materials and Methods:Dynamic multileaf collimator intensity-modulated radiation therapy (IMRT) plans were delivered in EPID and fluence was captured on a beam-by-beam basis (FEPID). An open field having dimensions equal to those of the largest IMRT field was used in the TPS to obtain the transmitted fluence. This represented the patient-specific heterogeneity correction (Fhet). To obtain the resultant heterogeneity-corrected fluence, EPID measured fluence was corrected for the TPS generated heterogeneity (FResultant = FEPID × Fhet). Next, the calculated fluence per beam basis was collected from TPS (FTPS). Finally, FResultant and FTPS were compared using a 3% percentage dose difference (% DD)-3 mm distance to agreement [DTA] gamma analysis in an isocentric plane (two-dimensional [2D]) and multiple planes (quasi three-dimensional [3D]) orthogonal to the beam axis.Results:The 2D heterogeneity-corrected dose reconstruction revealed a mean γ passing of the pelvis, thorax, and head-and-neck cases of 96.3% ±2.0%, 96.3% ±1.8%, and 96.1% ±2.2%, respectively. Quasi-3D γ passing for the pelvis, thorax, and head-and-neck cases were 97.5% ±1.4%, 96.3% ±2.4%, and 97.5% ±1.0%, respectively.Conclusion:EPID dosimetry produced an inferior result due to no heterogeneity corrections for sites such as the lung and esophagus. Incorporating TPS-based heterogeneity correction improved the EPID dosimetry result for those sites with large heterogeneity.

Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.

Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.

Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for 1,4-dioxane in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a developed PBPK model in rats. The model consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for 1,4-dioxane. Evaluation of the rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after daily oral treatment with 1,4-dioxane (500 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of 1,4-dioxane in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. 1,4-Dioxane was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for 1,4-dioxane is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for dichlorodiphenyltrichloroethane [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, DDT] in humans based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing liver compartment, and a central compartment for DDT. Evaluation of the rat model was performed by making comparisons between predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after daily oral treatment with DDT (10 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of DDT in vitro were established from data from rat liver microsomes and from pooled human liver microsomes. The ratio of intrinsic clearance values of DDT based on rat in vivo and rat in vitro experiments was used as the scaling factor for estimating in vivo hepatic intrinsic clearance in humans in the final human PBPK model. These results indicate that a simplified PBPK model for DDT is useful for a forward dosimetry approach in rats and/or humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Altered stefoid metabolism in human breast tomor: A proposal for alternate estrogenic steroids

Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.