Extrapolation of plasma clearance to understand species differences in toxicokinetics of bisphenol A.

1. Understanding species differences in the toxicokinetics of bisphenol A (BPA) is central to setting acceptable exposure limits for human exposures to BPA. BPA toxicokinetics have been well studied, with controlled oral dosing studies in several species and across a wide dose range. 2. We analyzed the available toxicokinetic data for BPA following oral dosing to assess potential species differences and dose dependencies. BPA is rapidly conjugated and detoxified in all species. The toxicokinetics of BPA can be well described using non-compartmental analyses. 3. Several studies measured free (unconjugated) BPA in blood and reported area under the curve (AUC) of free BPA in blood of mice, rats, monkeys, chimpanzees and humans following controlled oral doses. Extrinsic clearance was calculated and analyzed across species and dose using allometric scaling. 4. The results indicate free BPA clearance is well described using allometric scaling with high correlation coefficients across all species and doses up to 10 mg/kg. The results indicate a human equivalent dose factor (HEDf) of 0.9 is appropriate for extrapolating a point of departure from mice and rats to a human equivalent dose (HED), thereby replacing default uncertainty factors for animal to human toxicokinetics.

Use of a probabilistic PBPK/PD model to calculate Data Derived Extrapolation Factors for chlorpyrifos.

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model combined with Monte Carlo analysis of inter-individual variation was used to assess the effects of the insecticide, chlorpyrifos and its active metabolite, chlorpyrifos oxon in humans. The PBPK/PD model has previously been validated and used to describe physiological changes in typical individuals as they grow from birth to adulthood. This model was updated to include physiological and metabolic changes that occur with pregnancy. The model was then used to assess the impact of inter-individual variability in physiology and biochemistry on predictions of internal dose metrics and quantitatively assess the impact of major sources of parameter uncertainty and biological diversity on the pharmacodynamics of red blood cell acetylcholinesterase inhibition. These metrics were determined in potentially sensitive populations of infants, adult women, pregnant women, and a combined population of adult men and women. The parameters primarily responsible for inter-individual variation in RBC acetylcholinesterase inhibition were related to metabolic clearance of CPF and CPF-oxon. Data Derived Extrapolation Factors that address intra-species physiology and biochemistry to replace uncertainty factors with quantitative differences in metrics were developed in these same populations. The DDEFs were less than 4 for all populations. These data and modeling approach will be useful in ongoing and future human health risk assessments for CPF and could be used for other chemicals with potential human exposure.

Deriving Biomonitoring Equivalents for selected E- and P-series glycol ethers for public health risk assessment.

Glycol ethers are a widely used class of solvents that may lead to both workplace and general population exposures. Biomonitoring studies are available that have quantified glycol ethers or their metabolites in blood and/or urine amongst exposed populations. These biomonitoring levels indicate exposures to the glycol ethers, but do not by themselves indicate a health hazard risk. Biomonitoring Equivalents (BEs) have been created to provide the ability to interpret human biomonitoring data in a public health risk context. The BE is defined as the concentration of a chemical or metabolite in a biological fluid (blood or urine) that is consistent with exposures at a regulatory derived safe exposure limit, such as a tolerable daily intake (TDI). In this exercise, we derived BEs for general population exposures for selected E- and P-series glycol ethers based on their respective derived no effect levels (DNELs). Selected DNELs have been derived as part of respective Registration, Evaluation, Authorisation and Regulation of Chemicals (REACh) regulation dossiers in the EU. The BEs derived here are unique in the sense that they are the first BEs derived for urinary excretion of compounds following inhalation exposures. The urinary mass excretion fractions (Fue) of the acetic acid metabolites for the E-series GEs range from approximately 0.2 to 0.7. The Fues for the excretion of the parent P-series GEs range from approximately 0.1 to 0.2, with the exception of propylene glycol methyl ether and its acetate (Fue = 0.004). Despite the narrow range of Fues, the BEs exhibit a larger range, resulting from the larger range in DNELs across GEs. The BEs derived here can be used to interpret human biomonitoring data for inhalation exposures to GEs amongst the general population.

Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential.

Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.S. FDA led us to assess the potential for developmental toxicity under relevant product-use scenarios. Estimates from a physiologically based pharmacokinetic modeling approach suggest that occupational use of alcohol-based topical antiseptics in the healthcare industry can generate low, detectable concentrations of ethanol in blood. This unintended systemic dose probably reflects contributions from both dermal absorption and inhalation of volatilized product. The resulting internal dose is low, even under hypothetical, worst case intensive use assumptions. A significant margin of exposure (MOE) exists compared to demonstrated effect levels for developmental toxicity under worst case use scenarios, and the MOE is even more significant for typical anticipated occupational use patterns. The estimated internal doses of ethanol from topical application of alcohol-based hand sanitizers are also in the range of those associated with consumption of non-alcoholic beverages (i.e., non-alcoholic beer, flavored water, and orange juice), which are considered safe for consumers. Additionally, the estimated internal doses associated with expected exposure scenarios are below or in the range of the expected internal doses associated with the current occupational exposure limit for ethanol set by the Occupational Safety and Health Administration. These results support the conclusion that there is no significant risk of developmental or reproductive toxicity from repeated occupational exposures and high frequency use of ABHSs or surgical scrubs. Overall, the data support the conclusion that alcohol-based hand sanitizer products are safe for their intended use in hand hygiene as a critical infection prevention strategy in healthcare settings.

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition.

A number of biomonitoring surveys have been performed for chlorpyrifos (CPF) and its metabolite (3,5,6-trichloro-2-pyridinol, TCPy); however, there is no available guidance on how to interpret these data in a health risk assessment context. To address this gap, Biomonitoring Guidance Values (BGVs) are developed using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. The PBPK/PD model is used to predict the impact of age and human variability on the relationship between an early marker of cholinesterase (ChE) inhibition in the peripheral and central nervous systems [10% red blood cell (RBC) ChE inhibition] and levels of systemic biomarkers. Since the PBPK/PD model characterizes variation of sensitivity to CPF in humans, interspecies and intraspecies uncertainty factors are not needed. Derived BGVs represent the concentration of blood CPF and urinary TCPy associated with 95% of the population having less than or equal to 10% RBC ChE inhibition. Blood BGV values for CPF in adults and infants are 6100 ng/L and 4200 ng/L, respectively. Urinary TCPy BGVs for adults and infants are 2100 µg/L and 520 µg/L, respectively. The reported biomonitoring data are more than 150-fold lower than the BGVs suggesting that current US population exposures to CPF are well below levels associated with any adverse health effect.

Chlorpyrifos PBPK/PD model for multiple routes of exposure.

1. Chlorpyrifos (CPF) is an important pesticide used to control crop insects. Human Exposures to CPF will occur primarily through oral exposure to residues on foods. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been developed that describes the relationship between oral, dermal and inhalation doses of CPF and key events in the pathway for cholinergic effects. The model was built on a prior oral model that addressed age-related changes in metabolism and physiology. This multi-route model was developed in rats and humans to validate all scenarios in a parallelogram design. 2. Critical biological effects from CPF exposure require metabolic activation to CPF oxon, and small amounts of metabolism in tissues will potentially have a great effect on pharmacokinetics and pharmacodynamic outcomes. Metabolism (bioactivation and detoxification) was therefore added in diaphragm, brain, lung and skin compartments. Pharmacokinetic data are available for controlled human exposures via the oral and dermal routes and from oral and inhalation studies in rats. The validated model was then used to determine relative dermal versus inhalation uptake from human volunteers exposed to CPF in an indoor scenario.

A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: development and validation.

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages.

Physiologically-based pharmacokinetic (PBPK) models in toxicity testing and risk assessment.

Physiologically-based pharmacokinetic (PBPK) modeling offers a scientifically-sound framework for integrating mechanistic data on absorption, distribution, metabolism and elimination to predict the time-course of parent chemical, metabolite(s) or biomarkers in the exposed organism. A major advantage of PBPK models is their ability to forecast the impact of specific mechanistic processes and determinants on the tissue dose. In this regard, they facilitate integration of data obtained with in vitro and in silico methods, for making predictions of the tissue dosimetry in the whole animal, thus reducing and/or refining the use of animals in pharmacokinetic and toxicity studies. This chapter presents the principles and practice of PBPK modeling, as well as the application of these models in toxicity testing and health risk assessments.

Development of a source-to-outcome model for dietary exposures to insecticide residues: an example using chlorpyrifos.

Probabilistic models of interindividual variation in exposure and response were linked to create a source-to-outcome population model. This model was used to investigate cholinesterase inhibition from dietary exposures to an insecticide (chlorpyrifos) in populations of adults and 3 year old children. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was used to calculate the variation in sensitivity occurring from interindividual variability in physiology, metabolism, and physical activity levels. A dietary intake model characterizes the variation in dietary insecticide exposures and variation in anthropometry in the populations. Published equations were used to describe the necessary physiology for each simulated individual based on the anthropometry from the dietary intake model. The model of the interindividual variation in response to chlorpyrifos was developed by performing a sensitivity analysis on the PBPK/PD model to determine the parameters that drive variation in pharmacodynamics outcomes (brain and red blood cell acetylcholinesterase inhibition). Distributions of interindividual variation were developed for parameters with the largest impact; the probabilistic model sampled from these distributions. The impact of age and interindividual variation on sensitivity at the doses that occur from dietary exposures, typically orders of magnitude lower than exposures assessed in toxicological studies, was assessed using the source-to-outcome model. The resulting simulations demonstrated that metabolic detoxification capacity was sufficient to prevent significant brain and red blood cell acetylcholinesterase inhibition, even in individuals with the lowest detoxification potential. Age-specific pharmacokinetic and pharmacodynamic parameters did not predict differences in susceptibility between adults and children. In the future, the approach of this case study could be used to assess the risks from low level exposures to other chemicals.

Application of a source-to-outcome model for the assessment of health impacts from dietary exposures to insecticide residues.

The paper presents a case study of the application of a "source-to-outcome" model for the evaluation of the health outcomes from dietary exposures to an insecticide, chlorpyrifos, in populations of adults (age 30) and children (age 3). The model is based on publically-available software programs that characterize the longitudinal dietary exposure and anthropometry of exposed individuals. These predictions are applied to a validated PBPK/PD model to estimate interindividual and longitudinal variation in brain and RBC AChE inhibition (key events) and chlorpyrifos concentrations in blood and TCPy in urine (biomarkers of exposure). The predicted levels of chlorpyrifos and TCPy are compared to published measurements of the biomarkers. Predictions of RBC AChE are compared to levels of inhibition associated with reported exposure-related effects in humans to determine the potential for the occurrence of adverse cholinergic effects. The predicted distributions of chlorpyrifos in blood and TCPy in urine were found to be reasonably consistent with published values, supporting the predictive value of the exposure and PBPK portions of the source-to-outcome model. Key sources of uncertainty in predictions of dietary exposures were investigated and found to have a modest impact on the model predictions. Future versions of this source-to-outcome model can be developed that consider advances in our understanding of metabolism, to extend the approach to other age groups (infants), and address intakes from other routes of exposure.

In vitro age-dependent enzymatic metabolism of chlorpyrifos and chlorpyrifos-oxon in human hepatic microsomes and chlorpyrifos-oxon in plasma.

Age-dependent chlorpyrifos (CPF) metabolism was quantified by in vitro product formation in human hepatic microsomes (ages 13 days to 75 years) and plasma (ages 3 days to 43 years) with gas chromatography-mass spectrometry. Hepatic CPF cytochrome P450 desulfuration [CPF to chlorpyrifos-oxon (CPF-oxon)] and dearylation (CPF to 3,5,6-trichloro-2-pyridinol) V(max) values were 0.35 ± 0.21 and 0.73 ± 0.38 nmol · min(-1) · mg microsomal protein (-1) (mean ± S.D.), respectively. The mean (±S.D.) hepatic CPF-oxon hydrolysis (chlorpyrifos-oxonase [CPFOase]) V(max) was 78 ± 44 nmol · min(-1) · mg microsomal protein (-1). None of these hepatic measures demonstrated age-dependent relationships on a per microsomal protein basis using linear regression models. Ratios of CPF bioactivation to detoxification (CPF desulfuration to dearylation) V(max) values were consistent across ages. CPFOase in plasma demonstrated age-dependent increases on a volume of plasma basis, as did total plasma protein levels. Mean (±S.D.) CPF-oxon hydrolysis V(max) values for children <6 months of age and adults (≥16 years) were 1900 ± 660 and 6800 ± 1600 nmol · min(-1) · ml(-1), respectively, and at environmental exposure levels, this high- capacity enzyme is likely to be sufficient even in infants. Plasma samples were phenotyped for paraoxonase status, and frequencies were 0.5, 0.4, and 0.1 for QQ, QR, and RR phenotypes, respectively. These results will be integrated into a physiologically based pharmacokinetic and pharmacodynamic model for CPF and, once integrated, will be useful for assessing biological response to CPF exposures across life stages.

Hydroquinone PBPK model refinement and application to dermal exposure.

A physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ) was refined to include an expanded description of HQ-glucuronide metabolites and a description of dermal exposures to support route-to-route and cross-species extrapolation. Total urinary excretion of metabolites from in vivo rat dermal exposures was used to estimate a percutaneous permeability coefficient (K(p); 3.6×10(-5) cm/h). The human in vivo K(p) was estimated to be 1.62×10(-4) cm/h, based on in vitro skin permeability data in rats and humans and rat in vivo values. The projected total multi-substituted glutathione (which was used as an internal dose surrogate for the toxic glutathione metabolites) was modeled following an exposure scenario based on submersion of both hands in a 5% aqueous solution of HQ (similar to black and white photographic developing solution) for 2 h, a worst-case exposure scenario. Total multi-substituted glutathione following this human dermal exposure scenario was several orders of magnitude lower than the internal total glutathione conjugates in rats following an oral exposure to the rat NOEL of 20 mg/kg. Thus, under more realistic human dermal exposure conditions, it is unlikely that toxic glutathione conjugates (primarily the di- and, to a lesser degree, the tri-glutathione conjugate) will reach significant levels in target tissues.

Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats.

Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1mg nicotine/kg or saline, and to either a single oral dose of 35mg CPF/kg or a repeated dose of 5mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy peak concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine within the first 24-h post last dose. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. A physiologically based pharmacokinetic model for CPF was used to simulate the effect of increasing the dearylation V(max) based upon previously conducted in vitro metabolism studies. Predicted CPF-oxon concentrations in blood and brain were lower following the expected V(max) increase in nicotine treated groups. These model results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, resulting in altered brain AChE inhibition.

Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat.

Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of both in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual's contact with both the parent pesticide and exposure to these metabolites in the environment. In the current study, simultaneous dosing of 13C- or 2H-isotopically labeled CPF (13C-labeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 micromol/kg; approximately 5 mg/kg CPF). Major differences in the pharmacokinetics between CPF and metabolite doses were observed within the first 3h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (> or =3h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or (2)H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact their pharmacokinetics.

Quantitative risk analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark dose modeling.

Establishing an occupational exposure limit (OEL) for N-methyl pyrrolidone (NMP) is important due to its widespread use as a solvent. Based on studies in rodents, the most sensitive toxic end point is a decrease in fetal/pup body weights observed after oral, dermal, and inhalation exposures of dams to NMP. Evidence indicates that the parent compound is the causative agent. To reduce the uncertainty in rat to human extrapolations, physiologically based pharmacokinetic (PBPK) models were developed to describe the pharmacokinetics of NMP in both species. Since in utero exposures are of concern, the models considered major physiological changes occurring in the dam or mother over the course of gestation. The rat PBPK model was used to determine the relationship between NMP concentrations in maternal blood and decrements in fetal/pup body weights following exposures to NMP vapor. Body weight decrements seen after vapor exposures occurred at lower NMP blood levels than those observed after oral and dermal exposures. Benchmark dose modeling was used to better define a point of departure (POD) for fetal/pup body weight changes based on dose-response information from two inhalation studies in rats. The POD and human PBPK model were then used to estimate the human equivalent concentrations (HECs) that could be used to derive an OEL value for NMP. The geometric mean of the PODs derived from the rat studies was estimated to be 350 mg h/l (expressed in terms of internal dose), a value which corresponds to an HEC of 480 ppm (occupational exposure of 8 h/day, 5 days/week). The HEC is much higher than recently developed internationally recognized OELs for NMP of 10-20 ppm, suggesting that these OELs adequately protect workers exposed to NMP vapor.

In vitro glutathione conjugation of methyl iodide in rat, rabbit, and human blood and tissues.

Methyl iodide (MeI) is an intermediate in the manufacture of some pesticides and pharmaceuticals, and is under review for US registration as a non-ozone depleting alternative for methyl bromide for pre-plant soil fumigation. MeI is primarily metabolized via conjugation with glutathione (GSH), with further metabolism to S-methyl cysteine and methanethiol. To facilitate extrapolations of animal pharmacokinetic data to humans, rate constants for the GSH metabolism of MeI were determined in cytosols prepared from the liver and kidneys of rats, human donors, female rabbits, and rabbit fetuses, from rabbit olfactory and respiratory epithelium, and from rabbit and rat blood using a headspace vial equilibration technique and two-compartment mathematical model. MeI was metabolized in liver and kidney from adults of all three species, but metabolism was not detectable in fetal rabbit kidney. Maximal metabolic rates (V(max)) were similar in liver from rat and human donors (approximately 40 and 47 nmol/min/mg, respectively) whereas the V(max) rates in kidney cytosols varied approximately three-fold between the three species. No difference was observed in the loss of MeI from active and inactive whole blood from either rats or rabbits. The metabolism in olfactory and respiratory epithelial cytosol had Michaelis-Menten constant (K(m)) values that were several times higher than for any other tissue, suggesting essentially first-order metabolism in the nose. The metabolism of MeI in human liver cytosol prepared from five individual donors indicated two potential populations, one high affinity/low capacity and one with a lower affinity but higher capacity.

Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat.

Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. A number of toxicity and mechanistic studies have been conducted in animals, where CPF has been administered via a variety of different exposure routes and dosing vehicles. This study compared chlorpyrifos (CPF) pharmacokinetics using oral, intravenous (IV), and subcutaneous (SC) exposure routes and corn oil, saline/Tween 20, and dimethyl sulfoxide (DMSO) as dosing vehicles. Two groups of rats were co-administered target doses (5 mg/kg) of CPF and isotopically labeled CPF (L-CPF). One group was exposed by both oral (CPF) and IV (L-CPF) routes using saline/Tween 20 vehicle; whereas, the second group was exposed by the SC route using two vehicles, corn oil (CPF) and DMSO (L-CPF). A third group was only administered CPF by the oral route in corn oil. For all treatments, blood and urine time course samples were collected and analyzed for 3,5,6-trichloro-2-pyridinol (TCPy), and isotopically labeled 3,5,6-trichloro-2-pyridinol (L-TCPy). Peak TCPy/L-TCPy concentrations in blood (20.2 micromol/l), TCPy/L-TCPy blood AUC (94.9 micromol/lh), and percent of dose excreted in urine (100%) were all highest in rats dosed orally with CPF in saline/Tween 20 and second highest in rats dosed orally with CPF in corn oil. Peak TCPy concentrations in blood were more rapidly obtained after oral administration of CPF in saline/Tween 20 compared to all other dosing scenarios (>1.5 h). These results indicate that orally administered CPF is more extensively metabolized than systemic exposures of CPF (SC and IV), and vehicle of administration also has an effect on absorption rates. Thus, equivalent doses via different routes and/or vehicles of administration could potentially lead to different body burdens of CPF, different rates of bioactivation to CPF-oxon, and different toxic responses. Simulations using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF are consistent with these possibilities. These results suggest that exposure route and dosing vehicle can substantially impact target tissue dosimetry. This is of particular importance when comparing studies that use varying exposure paradigms, which are then used for extrapolation of risk to humans.

The effect of plasma lipids on the pharmacokinetics of chlorpyrifos and the impact on interpretation of blood biomonitoring data.

Lipophilic molecules, like chlorpyrifos (CPF), present a special problem for interpretation of biomonitoring data because both the environmental dose of CPF and the physiological (pregnancy, diet, etc.) or pathological levels of blood lipids will affect the concentrations of CPF measured in blood. The objective of this study was to investigate the distribution of CPF between plasma and tissues when lipid levels are altered in late pregnancy. CPF was sequestered more in the low-density lipid fraction of the blood during the late stages of gestation in the rat and returned to nonpregnant patterns in the dam after birth. Plasma partitioning of CPF increased with increases in plasma lipid levels and the increased partitioning of CPF into plasma lipids resulted in less CPF in other tissue compartments. Gavage dosing with corn oil also increased plasma lipids that led to a moderate increase of CPF partitioning into the plasma. To mechanistically investigate the potential pharmacokinetic effects of blood lipid changes, an existing CPF physiologically based pharmacokinetic/pharmacodynamic model for rats and humans was modified to account for altered lipid-tissue partition coefficients and for major physiological and biochemical changes of pregnancy. The model indicated that plasma CPF levels are expected to be proportional to the well-known changes in plasma lipids during gestation. There is a rapidly growing literature on the relationship of lipid profiles with different disease conditions and on birth outcomes. Increased blood concentrations of lipophilic chemicals like CPF may point to altered lipid status, as well as possibly higher levels of exposure. Thus, proper interpretation of blood biomonitoring data of lipophilic chemicals requires a careful consideration of blood lipids.

In vitro measurements of metabolism for application in pharmacokinetic modeling.

Human risk and exposure assessments require dosimetry information. Species-specific tissue dose response will be driven by physiological and biochemical processes. While metabolism and pharmacokinetic data are often not available in humans, they are much more available in laboratory animals; metabolic rate constants can be readily derived in vitro. The physiological differences between laboratory animals and humans are known. Biochemical processes, especially metabolism, can be measured in vitro and extrapolated to account for in vivo metabolism through clearance models or when linked to a physiologically based pharmacological (PBPK) model to describe the physiological processes, such as drug delivery to the metabolic organ. This review focuses on the different organ, cellular, and subcellular systems that can be used to measure in vitro metabolic rate constants and how those data are extrapolated to be used in biologically based modeling. NOTICE: The views expressed in this paper are those of the authors and do not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans.

1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.