Evaluation of an integrated in vitro-in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability

PK express module is a physiologically based model of first pass metabolism, which integrates in vitro data with an in silico physiologically based pharmacokinetic (PBPK) model to predict human bioavailability (F(H)). There are three required inputs: FDp (Fraction dose absorbed, final parameter from iDEA absorption module), protein binding (fu) and disappearance kinetics in human hepatocytes. Caco-2 permeability, aqueous solubility (at multiple pH's), estimated dose and chemical structure are inputs required for the estimation of FDp (Norris et al., 2000; Stoner et al., 2004) and were determined for all compounds in our laboratory or obtained from literature. Protein binding data was collected from literature references and/or Pfizer database. Human hepatocyte data was generated in-house using an automated human hepatocyte method (using Tecan Genesis Workstation) as described previously (). Sixteen compounds (commercial and Pfizer compounds) were chosen to evaluate the PK express model and the bioavailability predicted from the module was compared with known clinical endpoints. For majority of the 16 compounds (approximately 80%), the PK express model F(H) values were comparable to the known human bioavailability (F(H)) (within 23.7 units of the known human (true) F, except for PF 3, PF 4, PF 6). In conclusion, the PK express model integrates a number of key readily available discovery parameters and provides estimates of human performance by integrating in silico and experimental variables built on a physiological based pharmacokinetic model. Information from this model in conjunction with other ADME data (e.g., P450 inhibition) will enable progression of most promising compounds for further in vivo PK and/or efficacy studies.     

抗肿瘤药物多柔比星的PBPK模型研究进展

多柔比星（doxorubicin， DOX）在临床广泛应用于实体肿瘤、淋巴瘤和白血病等的治疗。DOX的细胞毒性作用和心脏毒性作用，使得其在发挥抗肿瘤作用的同时也产生严重毒副作用，限制了临床应用。这促使研究者不断深入了解其体内药动学、作用机制，找到适宜的临床治疗方案，以及开发出新的制剂或给药系统。在DOX的研究过程中，基于生理的药物动力学模型（physiologically based pharmacokinetic model，PBPK）发挥了非常重要的作用。本文从DOX的PBPK模型发展到应用于DOX给药方案设计、药动学影响因素分析、细胞毒性和心脏毒性作用机制以及指导DOX前药及新制剂开发研究等方面进行介绍，对DOX的PBPK模型发展及其应用进展进行了概述。     

A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer

Potential differences in pharmacokinetics (PK) between healthy subjects and patients with cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with cancer. Demographic data such as age, sex and body weight, and clinical laboratory measurements such as albumin, alpha‐1 acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with cancer were older compared with the age distribution in a built‐in healthy volunteer profile in Simcyp. Hematocrit and albumin levels were lower and AAG levels were higher in patients with cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates, saquinavir and midazolam. Higher saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered drug binding due to elevated AAG levels in patients with cancer. Consistent with historical clinical data, similar midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the CYP3A activity is not altered in patients with cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed. Copyright © 2012 John Wiley & Sons, Ltd.     

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure

Introduction

Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen).

Materials and methods

We assessed the accuracy of the models’ predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1 h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated.

Results

With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52–4.19 mg/L with the Bos model, 1.42–4.04 mg/L with the Mumtaz model, and 1.81–4.31 mg/L with the Jongeneelen model compared to 0.27–5.44 mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4–2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels.

Conclusions

The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.     

Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles

Abstract

Nano-sized titanium dioxide particles (nano-TiO₂) can be found in a large number of foods and consumer products, such as cosmetics and toothpaste, thus, consumer exposure occurs via multiple sources, possibly involving different exposure routes. In order to determine the disposition of nano-TiO₂ particles that are taken up, a physiologically based pharmacokinetic (PBPK) model was developed. High priority was placed on limiting the number of parameters to match the number of underlying data points (hence to avoid overparameterization), but still reflecting available mechanistic information on the toxicokinetics of nano-TiO₂. To this end, the biodistribution of nano-TiO₂ was modeled based on their ability to cross the capillary wall of the organs and to be phagocytosed in the mononuclear phagocyte system (MPS). The model’s predictive power was evaluated by comparing simulated organ levels to experimentally assessed organ levels of independent in vivo studies. The results of our PBPK model indicate that: (1) within the application domain of the PBPK model from 15 to 150?nm, the size and crystalline structure of the particles had a minor influence on the biodistribution; and (2) at high internal exposure the particles agglomerate in vivo and are subsequently taken up by macrophages in the MPS. Furthermore, we also give an example on how the PBPK model may be used for risk assessment. For this purpose, the daily dietary intake of nano-TiO₂ was calculated for the German population. The PBPK model was then used to convert this chronic external exposure into internal titanium levels for each organ.     

Monte Carlo analysis of the human chlorpyrifos-oxonase (PON1) polymorphism using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model

Susceptibility to organophosphate (OP) insecticides, like chlorpyrifos (CPF), may result from differences in the extent of metabolic detoxification of the active metabolite, CPF-oxon. A genetic polymorphism in the arylesterase (PON1; CPF-oxonase) detoxification of OPs, results in the expression of a range of enzyme activities within humans. This study utilized Monte Carlo analysis and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling to investigate the impact of human CPF-oxonase status on the theoretical concentration of CPF-oxon in the brain. At low doses ( approximately 5 microg/kg) the model is insensitive to changes in CPF-oxonase. However, with increasing dose (>0.5 mg/kg) the model suggests a dose-dependent non-linear increase in the brain CPF-oxon concentration, which is associated with CPF-oxonase activity. Following repeated high dose exposure, the model predicted brain CPF-oxon concentration was approximately 8x higher (5 mg/kg) versus a single exposure, whereas, at low doses (5 microg/kg), the brain concentrations were comparable regardless of exposure duration. This suggests that at low environmentally relevant exposures other esterase detoxification pathways may compensate for lower CPF-oxonase activity.     

The application of physiologically based pharmacokinetic modelling in the analysis of occupational exposure to perchloroethylene.

A physiologically based pharmacokinetic model for perchloroethylene was parameterized, calibrated and validated using anatomic, physiologic, biochemical and physicochemical data obtained from the literature. The model was used to analyse human exposure data obtained under controlled conditions and from dry cleaning establishments in the Padua area of northern Italy. Whilst the model satisfactorily simulated the urinary excretion of trichloroacetic acid, following experimental inhalation exposure to 10, 20 and 40 ppm perchloroethylene under controlled conditions the opposite was true for the occupational exposure data. However, further model refinement to incorporate inter-individual variability of anatomical, physiological and biochemical parameters which have an impact on model output, would further improve the predictive capabilities of the model. The possibility of perchloroethylene and trichloroethylene co-exposure in the occupational setting was indicated by the model.     

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.     

Effect of albumin on human liver microsomal and recombinant CYP1A2 activities: impact on in vitro-in vivo extrapolation of drug clearance

Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and Escherichia coli-expressed recombinant human CYP1A2 (rCYP1A2) as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the K(m) values of the high-affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting V(max). The K(m) (or S(50)) values for PHEN and LID deethylation by rCYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 μM concentrations each of oleic acid and linoleic acid plus 1.5 μM arachidonic acid, doubled the K(m) value for PHEN O-deethylation by rCYP1A2. Inhibition was reversed by the addition of BSA. K(i) values for the individual fatty acids ranged from 4.7 to 16.7 μM. Single-point in vitro-in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN O-deethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems used for IV-IVE.     

Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs

AIMS: To create a general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs. METHODS: Physiological data for neonates, 0.5-, 1-, 2-, 5-, 10- and 15-year-old children, and adults, of both sexes were compiled from the literature. The data comprised body weight and surface area, organ weights, vascular and interstitial spaces, extracellular body water, organ blood flows, cardiac output and glomerular filtration rate. Tissue: plasma partition coefficients were calculated from rat data and unbound fraction (f u) of the drug in human plasma, and age-related changes in unbound intrinsic hepatic clearance were estimated from CYP1A2 and CYP2E1 (theophylline) and CYP3A4 (midazolam) activities in vitro. Volume of distribution (V dss), total and renal clearance (CL and CL R) and elimination half-life (t(1/2)) were estimated by PBPK modelling, as functions of age, and compared with literature data. RESULTS: The predicted V dss of theophylline was 0.4-0.6 l kg(-1) and showed only a modest change with age. The median prediction error (MPE) compared with literature data was 3.4%. Predicted total CL demonstrated the time-course generally reported in the literature. It was 20 ml h(-1) kg(-1) in the neonate, rising to 73 ml h(-1) kg(-1) at 5 years and then decreasing to 48 ml h(-1) kg(-1) in the adult. Overall, the MPE was - 4.0%. Predicted t(1/2) was 18 h in the neonate, dropping rapidly to 4.6-7.2 h from 6 months onwards, and the MPE was 24%. The predictions for midazolam were also in good agreement with literature data. V dss ranged between 1.0 and 1.7 l kg(-1) and showed only modest change with age. CL was 124 ml h(-1) kg(-1) in the neonate and peaked at 664 ml h(-1) kg(-1) at 5 years before decreasing to 425 ml h(-1) kg(-1) in the adult. Predicted t(1/2) was 6.9 h in the neonate and attained 'adult' values of 2.5-3.5 h from 1 year onwards. CONCLUSIONS: A general PBPK model for the prediction of drug disposition over the age range neonate to young adult is presented. A reference source of physiological data was compiled and validated as far as possible. Since studies of pharmacokinetics in children present obvious practical and ethical difficulties, one aim of the work was to utilize maximally already available data. Prediction of the disposition of theophylline and midazolam, two model drugs with dissimilar physicochemical and pharmacokinetic characteristics, yielded results that generally tallied with literature data. Future use of the model may demonstrate further its strengths and weaknesses.     

Physiologically based pharmacokinetic modelling of human exposure to 2-butoxyethanol

A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-butoxyethanol (2-BE) was developed in order to predict the urinary concentration of its major metabolite, butoxyacetic acid (BAA) under a range of exposure scenarios. Based on Corley et al. [Corley, R.A., Bormett, G.A., Ghanayem, B.I., 1994. Physiologically based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol. Appl. Pharmacol. 129, 61-79], the model included such features as multiple entry routes into the body, varying workload conditions, metabolism in the liver and elimination of free BAA in urine by glomerular filtration and acid transport. A bladder compartment simulating the fluctuations in metabolite concentration in urine caused by micturition formed a novel aspect of the model. Good agreement between model predictions and existing experimental data of total BAA levels in the blood and urine over various exposure conditions were observed. The mechanistically based PBPK model allowed comparison of disparate studies and also enabled the prediction of urinary concentrations of BAA post-shift. By calculating the total amount of BAA, any inter-individual variability in conjugation is taken into account. This led us to conclude that a biological monitoring guidance value should be proposed for total rather than free BAA with a value of 250 mmol/mol of creatinine (post-shift), based on an 8h exposure to 25 ppm 2-BE at resting working conditions.     

Assessing the non-cancer risk for RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) using physiologically based pharmacokinetic (PBPK) modeling

RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) is an explosive used in military applications. It has been detected in ground water surrounding US military installations and at manufacturing facilities. RDX has been shown to produce hepatotoxicity, testicular, and neurological effects in animals, the latter also in humans. The current chronic oral reference dose (RfD) of 0.003 mg/kg/day was derived based on prostate effects in rats. Here, we provide a reevaluation of the risk associated with RDX exposure by examining old and new data and using physiologically based pharmacokinetic (PBPK) modeling approaches. Candidate non-cancer endpoints in rodents were evaluated and the most plausible mode(s) of action were determined. A PBPK model was used to derive appropriate internal doses based on the mode of action, and then a benchmark dose (BMD) and the lower confidence limit on the BMD (BMDL) were determined using these internal doses in animals. Uncertainty factors (UF) were applied to the animal BMDL or no-observed effect level and a human PBPK model was used to determine a human equivalent dose resulting in the candidate RfDs (cRfDs). A proposed chronic RfD of 0.07 mg/kg/day, based on multiple effects observed in rats, was selected from among the cRfDs.     

The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene

A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe ‘whole-body’ disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration–time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.     

The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide

AIMS: The primary aim of the study was to investigate the possible effect of the CYP2C8*3 allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose. METHODS: Thirty-six healthy male subjects, genotyped for CYP2C8*3 (11 genotyped as CYP2C8*1/*3, one as CYP2C8*3/*3 and 24 as CYP2C8*1/*1), participated in a randomized, cross-over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide. RESULTS: Neither the mean AUC(0-infinity) (geometric mean ratio: 1.01; 95% CI: 0.93-1.1, P = 0.88) nor the mean C(max) (geometric mean ratio: 1.05; 95% CI: 0.94-1.2, P = 0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8*3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75-0.87, P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC(0-infinity) of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04-1.2, P = 0.0048), but had no statistically significant effect on the t(1/2). There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg. CONCLUSIONS: The pharmacokinetics of repaglinide in subjects carrying the CYP2C8*3 mutant allele did not differ significantly from those in the wild-types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.     

Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats,rabbits, and humans

Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8?hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.     

Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites

A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to arsenate (As(V)), arsenite (As(III)) or organoarsenical pesticides. The model consists of interconnected individual PBPK models for inorganic arsenic (As(V) and As(III)), monomethylarsenic acid (MMA(V)), and, dimethylarsenic acid (DMA(V)). Reduction of MMA(V) and DMA(V) to their respective trivalent forms also occurs in the lung, liver, and kidney including excretion in urine. Each submodel was constructed using flow limited compartments describing the mass balance of the chemicals in GI tract (lumen and tissue), lung, liver, kidney, muscle, skin, heart, and brain. The choice of tissues was based on physiochemical properties of the arsenicals (solubility), exposure routes, target tissues, and sites for metabolism. Metabolism of inorganic arsenic in liver was described as a series of reduction and oxidative methylation steps incorporating the inhibitory influence of metabolites on methylation. The inhibitory effects of As(III) on the methylation of MMA(III) to DMA, and MMA(III) on the methylation of As(III) to MMA were modeled as noncompetitive. To avoid the uncertainty inherent in estimation of many parameters from limited human data, a priori independent parameter estimates were derived using data from diverse experimental systems with priority given to data derived using human cells and tissues. This allowed the limited data for human excretion of arsenicals in urine to be used to estimate only parameters that were most sensitive to this type of data. Recently published urinary excretion data, not previously used in model development, are also used to evaluate model predictions.     

Application of physiologically based toxicokinetic modelling to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of toluene in rats

The toxicity of inhalatory exposure to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study physiologically based toxicokinetic (PBTK) modelling has been used to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of the model solvent toluene in rats. After construction of the model with parameters from literature, toxicokinetic data were collected from rats exposed to either a constant concentration or fluctuating concentrations at total external dose levels of 20,000 and 10,000 ppm x h for model validation. At the same exposure conditions the effects on learned performance were evaluated in separate groups of rats using a visual discrimination task. In general, the PBTK model provided reliable predictions of the toxicokinetics of toluene at different exposure scenarios, but it also tended to underestimate the blood and brain concentrations in the descending parts of the tissue concentration-time curves. At these high dose levels the differences in toxicokinetics between the constant and the fluctuating exposure groups were relatively small. The visual discrimination experiments demonstrated a slowing of response speed and disinhibition of responding in all toluene-exposed groups. The results suggest that the brain concentration of toluene is one of the major determinants of its effect on disinhibition of responding.     

Route-to-route extrapolation of 1,2-dichloroethane studies from the oral route to inhalation using physiologically based pharmacokinetic models

To help develop a comprehensive, quantitative understanding of the hazards of 1,2-dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) exposure by the inhalation route, the results of existing subchronic studies and an extended one-generation reproductive toxicity (EOGRT) study recently conducted by the oral route in rats were extrapolated using a physiologically based pharmacokinetic (PBPK) model. The no observed adverse effects levels (NOAELs) for the endpoints of neurotoxicity and reproductive/developmental toxicity were the highest tested doses of 169 and 155 mg/kg-day, respectively. These NOAELs were equivalent to continuous exposure of rats to minimums of 76 ppm and 62 ppm EDC, respectively, using total metabolism of EDC as the dose metric that is equivalent in the oral and inhalation scenarios. In contrast, the subchronic study NOAEL of 37.5 mg/kg-day corresponded to continuous inhalation of 4.4 ppm EDC, based on equivalent extrahepatic metabolism. The selection of the internal metric which serves to establish route-to-route equivalency was found to profoundly influence the NOAEL-equivalent inhalation exposure concentration and thus will be a key determinant of inhalation toxicity reference criteria developed on the basis of EDC studies conducted by the oral route.