Internal Dose Metrics Research Articles

Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates.

The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species- and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra- and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH.

A constrained maximum likelihood approach to evaluate the impact of dose metric on cancer risk assessment: Application to β-chloroprene

β-Chloroprene (2-chloro-1,3-butadiene, CD) is used in the manufacture of polychloroprene rubber. Chronic inhalation studies have demonstrated that CD is carcinogenic in B6C3F1 mice and Fischer 344 rats. However, epidemiological studies do not provide compelling evidence for an increased risk of mortality from total cancers of the lung. Differences between the responses observed in animals and humans may be related to differences in toxicokinetics, the metabolism and detoxification of potentially active metabolites, as well as species differences in sensitivity. The purpose of this study was to develop and apply a novel method that combines the results from available physiologically based kinetic (PBK) models for chloroprene with a statistical maximum likelihood approach to test commonality of low-dose risk across species. This method allows for the combined evaluation of human and animal cancer study results to evaluate the difference between predicted risks using both external and internal dose metrics. The method applied to mouse and human CD data supports the hypothesis that a PBK-based metric reconciles the differences in mouse and human low-dose risk estimates and further suggests that, after PBK metric exposure adjustment, humans are equally or less sensitive than mice to low levels of CD exposure.

A chronic oral reference dose for hexavalent chromium-induced intestinal cancer.

High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1). © 2013 The Authors. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.

Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults

The objective of this study was to assess the impact of the exposure duration and intensity on the human kinetic adjustment factor (HKAF). A physiologically based pharmacokinetic model was used to compute target dose metrics (i.e. maximum blood concentration (Cmax) and amount metabolized/L liver/24 h (Amet)) in adults, neonates (0–30 days), toddlers (1–3 years), and pregnant women following inhalation exposure to benzene, styrene, 1,1,1-trichloroethane and 1,4-dioxane. Exposure scenarios simulated involved various concentrations based on the chemical’s reference concentration (low) and six of U.S. EPA’s Acute Exposure Guideline Levels (AEGLs) (high), for durations of 10 min, 60 min, 8 h, and 24 h, as well as at steady-state. Distributions for body weight (BW), height (H), and hepatic CYP2E1 content were obtained from the literature or from P3M software, whereas blood flows and tissue volumes were calculated from BW and H. The HKAF was computed based on distributions of dose metrics obtained by Monte Carlo simulations [95th percentile in each subpopulation/median in adults]. At low levels of exposure, ranges of Cmax-based HKAF were 1–6.8 depending on the chemical, with 1,4-dioxane exhibiting the greatest values. At high levels of exposure, this range was 1.1–5.2, with styrene exhibiting the greatest value. Neonates were always the most sensitive subpopulation based on Cmax, and pregnant women were most sensitive based on Amet in the majority of the cases (1.3–2.1). These results have shown that the chemical-specific HKAF varies as a function of exposure duration and intensity of inhalation exposures, and sometimes exceeds the default value used in risk assessments.

CLIMATE CHANGE AND INCREASED PRECIPITATIONS: THE IMPACT OF HEAVY RAINFALLS ON SURFACE WATER TOTAL ORGANIC CARBON (TOC) AND RESULTING HUMAN EXPOSURE TO TRIHALOMETHANES

Background and aims: Several studies suggest that climate change will be accompanied with increased precipitations. Heavy rainfalls can impact surface water total organic carbon (TOC) and, upon treatment, lead to higher trihalomethane levels in drinking water. These meteorological events could therefore exacerbate human exposure to these toxic disinfection by-products. This study aimed at i) assessing the impact of heavy rainfalls on surface water TOC and ii) evaluating subsequent exposure to chloroform and its internal dose metrics in humans. Methods: Surface water TOC was measured in samples taken from an established sampling point used for drinking water production in a small river in Brittany (France) during dry days and following high precipitations (> 10 mm). Trihalomethane production during water treatment was estimated based on TOC levels, temperature and chlorine dose using an established multivariate model. Finally, drinking water chloroform levels were used to construct different scenarios of exposure (i.e., water consumption, shower/bath and inhalation) in newborns, children, adults and pregnant women using a published physiologically based pharmacokinetic (PBPK) model. Results: Following high precipitations, surface water TOC increased from a median of 6.2 to 8.9 mg/L. Consequently, median total trihalomethane levels in drinking water were estimated to increase from 29.7 to 33.1 µg/L. Human exposures to chloroform after > 10 mm rainfalls increased hepatic metabolite levels by 11 % when compared to levels reached during dry days. This increase did not vary substantially between exposure routes or physiologic condition. Conclusions: This study suggests that the occurrence of heavy rainfalls can increase surface water TOC levels. The higher levels of trihalomethanes in drinking water following these precipitations may lead to increased tissue levels in humans. In the context of climate change, risk assessors may need to consider higher exposure to drinking water contaminants.

An assessment of the impact of physico-chemical and biochemical characteristics on the human kinetic adjustment factor for systemic toxicants

The objective of this study was to evaluate the magnitude of the human kinetic adjustment factor (HKAF) as a function of physico- and bio-chemical characteristics impacting the systemic clearance of chemicals. This factor is intended to replace the default value of 3.16 in non-cancer risk assessments and aims at accounting for interindividual variability in toxicokinetics. A steady-state algorithm was used to compute the internal dose metrics (blood concentration ( C blood) and rate of metabolite produced/L liver (RAM)) of hypothetical chemicals in neonates, adults, elderly, and pregnant women. After evaluating the algorithm with chemical-specific experimental data, C blood and RAM were calculated for hypothetical chemicals exhibiting blood:air partition coefficients (Pb) between 1 and 10,000 and hepatic extraction ratios in the average adult ( E) between 0.01 and 0.99. Based on Monte Carlo simulation results, HKAF values were computed as the ratio of the 95th percentile value for each subpopulation to the 50th percentile value in adults. The highest HKAF among those obtained for each subpopulation was reported in route-, pathway-, and dose metric-specific HKAF matrices as a function of Pb and E. These matrices allowed the recognition of cases where the default HKAF could be exceeded, and these occurred in neonates based on C blood in two situations. First, when the average adult-to-neonate ratio of body weight-adjusted systemic clearance was at least equal to 2.2 for a given systemic exposure (i.e., for CYP1A2 substrates only). Second, when E = 0.01–0.2 and Pb ≥ 300 or when E = 0.3–0.7 and Pb ≥ 100 for inhalation exposures to CYP2E1 substrates, with comparable values for the other substrates (higher for CYP1A2). Overall, this study showed the dependency of the HKAF on the dose metrics, chemical characteristics, metabolic pathways, and subpopulations considered.

On the Definition of Internal Dose Metrics

ABSTRACT Internal dose metrics, as computed with pharmacokinetic models, are increasingly used as a means for extrapolating animal toxicological data to humans and to extrapolate across routes of administration. These internal dose metrics are thought to provide a more scientific means of comparing toxicological effects across animal species. The use of internal dose metrics is based on the universal assumption that toxic effects are equal across species if and only if the concentration of the toxic moieties in the target tissue is equal across species. Herein it is shown that this assumption is inconsistent with empirical toxicological data. It is shown that measurement of internal dose metrics in chronological time, as is done for AUC (Area under the concentration curve) and rate of metabolite production per kg of target tissue, does not produce equal toxic effects across species. A consequence of this observation is that the application of pharmacokinetics in risk assessments for such important chemicals as trichloroethylene, vinyl chloride, perchloroethylene, and perchlorate may need reassessment.

An Assessment of the Interindividual Variability of Internal Dosimetry during Multi-Route Exposure to Drinking Water Contaminants

The objective of this study was to evaluate inter-individual variability in absorbed and internal doses after multi-route exposure to drinking water contaminants (DWC) in addition to the corresponding variability in equivalent volumes of ingested water, expressed as liter-equivalents (LEQ). A multi-route PBPK model described previously was used for computing the internal dose metrics in adults, neonates, children, the elderly and pregnant women following a multi-route exposure scenario to chloroform and to tri- and tetra-chloroethylene (TCE and PERC). This scenario included water ingestion as well as inhalation and dermal contact during a 30-min bathroom exposure. Monte Carlo simulations were performed and distributions of internal dose metrics were obtained. The ratio of each of the dose metrics for inhalation, dermal and multi-route exposures to the corresponding dose metrics for the ingestion of drinking water alone allowed computation of LEQ values. Mean BW-adjusted LEQ values based on absorbed doses were greater in neonates regardless of the contaminant considered (0.129–0.134 L/kg BW), but higher absolute LEQ values were obtained in average adults (3.6–4.1 L), elderly (3.7–4.2 L) and PW (4.1–5.6 L). LEQ values based on the parent compound’s AUC were much greater than based on the absorbed dose, while the opposite was true based on metabolite-based dose metrics for chloroform and TCE, but not PERC. The consideration of the 95th percentile values of BW-adjusted LEQ did not significantly change the results suggesting a generally low intra-subpopulation variability during multi-route exposure. Overall, this study pointed out the dependency of the LEQ on the dose metrics, with consideration of both the subpopulation and DWC.

Evaluation of the impact of the exposure route on the human kinetic adjustment factor

The objective of this study was to assess the impact of the exposure route on the human kinetic adjustment factor (HKAF), for which a default value of 3.16 is used in non-cancer risk assessment. A multi-route PBPK model was modified from the literature and used for computing the internal dose metrics in adults, neonates, children, elderly and pregnant women following three route-specific scenarios to chloroform, bromoform, tri- or per-chloroethylene (TCE or PERC). These include 24-h inhalation exposure, body-weight adjusted oral exposure and 30min dermal exposure to contaminated drinking water. Distributions for body weight (BW), height (BH) and hepatic cytochrome P450 2E1 (CYP2E1) content were obtained from the literature, whereas model parameters (flows, volumes) were calculated from BW and BH. Monte Carlo simulations were performed and the HKAF was calculated as the ratio of the 95th percentile value of internal dose metrics in subpopulation to the 50th percentile value in adults. On the basis of the area under the parent compound’s arterial blood concentration vs time curve (AUCpc), highest HKAFs were obtained in neonates for every scenario considered, and were the highest for bromoform (range: 3.6–7.4). Exceedance of the default value based on AUCPC was also observed for an oral exposure to chloroform in neonates (4.9). In all other cases, HKAFs remained below the default value. Overall, this study has pointed out the dependency of the HKAF on the exposure route, dose metrics and subpopulation considered, as well as characteristics of the chemicals investigated.

The Impact of Dose Rate on Ethylene Glycol Developmental Toxicity and Pharmacokinetics in Pregnant CD Rats

High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low-level exposures that do not saturate GA metabolism have a low potential for developmental effects. Toward the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an sc implantable pump. In the sc bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, whereas increases in 2 malformations and 2 variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure versus sc infusion of EG. Although dose rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.

Predicting the acute behavioral effects in rats inhaling toluene for up to 24 h: Inhaled vs. internal dose metrics and tolerance

Predicting the acute behavioral effects in rats inhaling toluene for up to 24 h: Inhaled vs. internal dose metrics and tolerance

Pharmacokinetic modeling of perfluorooctanoic acid during gestation and lactation in the mouse

Perfluorooctanoic acid (PFOA) is a processing aid for the polymerization of commercially valuable fluoropolymers. Its widespread environmental distribution, presence in human blood, and adverse effects in animal toxicity studies have triggered attention to its potential adverse effects to humans. PFOA is not metabolized and exhibits dramatically different serum/plasma half-lives across species. Estimated half-lives for humans, monkeys, mice, and female rats are 3–5 years, 20–30 days, 12–20 days, and 2–4h, respectively. Developmental toxicity is one of the most sensitive adverse effects associated with PFOA exposure in rodents, but its interpretation for risk assessment is currently hampered by the lack of understanding of the inter-species pharmacokinetics of PFOA. To address this uncertainty, a biologically supported dynamic model was developed whereby a two-compartment system linked via placental blood flow described gestation and milk production linked a lactating dam to a growing pup litter compartment. Postnatal serum levels of PFOA for 129S1/SvImJ mice at doses of 1mg/kg or less were reasonably simulated while prenatal and postnatal measurements for CD-1 mice at doses of 1mg/kg or greater were simulated via the addition of a biologically based saturable renal resorption description. Our results suggest that at low doses a linear model may suffice for describing the pharmacokinetics of PFOA while a more complex model may be needed at higher doses. Although mice may appear more sensitive based on administered dose of PFOA, the internal dose metrics estimated in this analysis indicate that they may be equal or less sensitive than rats.

Modeling the Toxicokinetics of Inhaled Toluene in Rats: Influence of Physical Activity and Feeding Status

Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals, whether exposure duration is acute or chronic. The goals of this physiologically based pharmacokinetic (PBPK) model development effort were twofold: (1) to evaluate and explain the influence of feeding status and activity level on toluene pharmacokinetics utilizing our own data from toluene-exposed Long Evans (LE) rats, and (2) to evaluate the ability of the model to simulate data from the published literature and explain differing toluene kinetics. Compartments in the model were lung, slowly and rapidly perfused tissue groups, fat, liver, gut, and brain; tissue transport was blood-flow limited and metabolism occurred in the liver. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Sensitivity analysis revealed that the single most influential parameter for our experimental conditions was alveolar ventilation; other moderately influential parameters (depending upon concentration) included cardiac output, rate of metabolism, and blood flow to fat. Based on both literature review and sensitivity analysis, other parameters (e.g., partition coefficients and metabolic rate parameters) were either well defined (multiple consistent experimental results with low variability) or relatively noninfluential (e.g. organ volumes). Rats that were weight-maintained compared to free-fed rats in our studies could be modeled with a single set of parameters because feeding status did not have a significant impact on toluene pharmacokinetics. Heart rate (HR) measurements in rats performing a lever-pressing task indicated that the HR increased in proportion to task intensity. For rats acclimated to eating in the lab during the day, both sedentary rats and rats performing the lever-pressing task required different alveolar ventilation rates to successfully predict the data. Model evaluation using data from diverse sources together with statistical evaluation of the resulting fits revealed that the model appropriately predicted blood and brain toluene concentrations with some minor exceptions. These results (1) emphasize the importance of experimental conditions and physiological status in explaining differing kinetic data, and (2) demonstrate the need to consider simulation conditions when estimating internal dose metrics for toxicity studies in which kinetic data were not collected.

Application of PBPK modeling in support of the derivation of toxicity reference values for 1,1,1-trichloroethane

PBPK modeling has been increasingly applied in chemical risk assessment for dose, route, and species extrapolation. The use of PBPK modeling was explored in deriving toxicity reference values for 1,1,1-trichloroethane (1,1,1-TCE). This effort involved a 5-step process: (i) reconstruction of several published PBPK models for 1,1,1-TCE in the rat and human; (ii) selection of appropriate pharmacokinetic datasets for model comparison; (iii) determination of the most suitable PBPK model for supporting reference value derivation; (iv) PBPK model simulation of two critical studies to estimate internal dose metrics; and (v) calculation of internal dose metrics for human exposure scenarios for reference value derivation. The published model by Reitz et al. [Reitz, R.H., McDougal, J.N., Himmelstein, M.W., Nolan, R.J., Schumann, A.M., 1988. Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations. Toxicol. Appl. Pharmacol. 95, 185–199] was judged the most suitable. This model has liver, fat, and rapidly and slowly perfused compartments, contains a saturable process for 1,1,1-TCE hepatic metabolism, and accommodates multiple exposure pathways in three species. Data from a human volunteer study involving acute inhalation exposure [Mackay, C.J., Campbell, L., Samuel, A.M., Alderman, K.J., Idzikowski, C., Wilson, H.K., Gompertz, D., 1987. Behavioral changes during exposure to 1,1,1-trichloroethane: time-course and relationship to blood solvent levels. Am. J. Ind. Med. 11, 223–239] and a chronic rat inhalation study [Quast, J.F., Calhoun, L.L., Frauson, L.E., 1988. 1,1,1-Trichloroethane formulation: a chronic inhalation toxicity and oncogenicity study in Fischer 344 rats and B6C3F1 mice. Fundam. Appl. Toxicol. 11, 611–625] were selected to simulate appropriate internal dosimetry data from which to derive reference value points of departure. Duration, route, and species extrapolations were performed based on internal dose metrics.

Effectiveness of Various Exposure Metrics in Defining Dose-Response Relationships for Mink (Mustela vison) Exposed to Polychlorinated Biphenyls

We conducted a quantitative analysis of published results from more than 50 tests of polychlorinated biphenyl (PCB) effects on mink reproduction, which provided a basis for evaluating how well different methods of measuring and assessing PCB concentrations can approximate a toxicologically relevant dose for this endpoint. Several dose metrics were identified for comparison. Dietary dose metrics included the daily intake of total PCBs and the daily intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalence concentrations (TECs), calculated using World Health Organization toxicity equivalence factors (TEFs). Internal dose metrics included whole-body total PCBs, whole-body TECs calculated using World Health Organization TEFs, and whole-body TECs calculated using alternative TEFs specifically identified for internal dose assessment. Accounting for the bioaccumulative potential (i.e., internal dose) of ingested PCBs proved to be more important than accounting for the concentrations of dioxin-like PCB congeners in explaining the observed variation in reproductive success. This was true regardless of whether internal doses were estimated from dietary data based on homolog concentrations (whole-body total PCBs) or congener concentrations (whole-body TECs). For each of the PCB dose metrics, a range of toxicity reference values is identified based on the species-specific PCB toxicity database compiled for this evaluation.

Recommended Relative Potency Factors for 2,3,4,7,8-Pentachlorodibenzofuran: The Impact of Different Dose Metrics

The recent National Toxicology Program (NTP) cancer bioassays for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) permit a reevaluation of the current TEF value of 4-PeCDF. The data also allow for the derivation of relative potency factors (RPFs) for cancer, which are based not only on administered dose but also on potentially more informative dose metrics, such as liver concentration, area under the liver concentration curve, and lifetime average body burden. Our analyses of these data indicate that chi-squared tests of observed versus predicted liver tumor incidence for 4-PeCDF reject the current TEF value of 0.5 value as too high. 4-PeCDF RPFs were derived using estimation methods that either did or did not assume parallelism of the 4-PeCDF and TCDD dose-response curves. The resulting parallelism-based RPFs for administered dose, liver concentration at terminal sacrifice, liver concentration AUC, and lifetime average body burden are 0.26, 0.014, 0.021, and 0.036, respectively. The administered dose RPF estimate is approximately one-half the current TEF value of 0.5. However, the use of administered dose fails to take into account pharmacokinetic differences between congeners and the generally acknowledged belief that body burden or some other measure of cumulative dose is more appropriate for estimating the health risk posed by persistent chemicals. The other three dose metrics do account for these important factors, and the corresponding RPFs are at least 10-fold lower than the current TEF for 4-PeCDF. In summary, our analyses support an administered dose TEF no greater than 0.25 and one in the 0.05-0.1 range for internal dose metrics such as lifetime average liver concentration or body burden.

Revised assessment of cancer risk to dichloromethane: Part I Bayesian PBPK and dose–response modeling in mice

The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA’s current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose–response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose–response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM.

Application of a Physiologically Based Pharmacokinetic Model for Isopropanol in the Derivation of a Reference Dose and Reference Concentration

An interspecies physiologically based pharmacokinetic (PBPK) model describing isopropanol (IPA) and its major metabolite, acetone, was applied to perform route-to-route and cross-species dosimetry to derive reference dose (RfD) and reference concentration (RfC) values for IPA. Adult PBPK models for rats and humans were extended to simulate exposure to IPA during pregnancy and used to estimate internal dose metrics in the mother and fetus during development. Endpoints from chronic, developmental, and reproductive toxicity studies were considered for the derivation of RfDs and RfCs. Due to uncertainties in the mode of action of toxicity for IPA and acetone, the dose metric used for most responses was the total area under the blood concentration curve (AUC) for the combination of IPA and acetone. This combined dose metric provided a more conservative estimate than those based on AUCs for IPA or acetone. Peak blood concentration of IPA was the dose metric for neurobehavioral effects. The recommended RfD and RfC for IPA are 10 mg/kg/day and 40 ppm, respectively, based on decreased fetal body weights. All of the PBPK-derived RfD or RfC values for various endpoints were similar (within a factor of 3), regardless of route of exposure in the animal study.

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species.

The effects of perchlorate on the incorporation of iodide into thyroid hormones have been studied for more than 40 years in many species and under varying exposure conditions. Nevertheless, the database for this drinking water contaminant is still incomplete, particularly with regard to human developmental risk. A method for integrating the available data and forming meaningful conclusions for risk assessment is needed. To this end, an initial suite of physiologically based pharmacokinetic (PBPK) models has been developed, which incorporates physiological data for the relevant species and life stages and kinetic data for perchlorate and iodide, as well as the interaction between the two anions. The validated models successfully describe perchlorate-induced inhibition of thyroid iodide uptake and perchlorate and iodide kinetics in the male, pregnant, lactating, fetal, and neonatal rats and the adult humans. The relationships of model-predicted internal dose metrics and kinetic parameters allow a direct comparison of internal dose metrics across life stages in rats and humans. By incorporating all the available data, these models provide a framework for species and life stage extrapolation where the lack of specific data sets would otherwise limit predictive capability. This paper demonstrates two approaches for calculating life stage-specific equivalent doses in a risk assessment for perchlorate: the direct combination of validated model predictions, and the development of preliminary PBPK models for the human-sensitive populations based on the relationship of the parameters in the validated rat and human models. Either approach can be used to perform the needed dosimetry. However, the second approach provides the advantage of a preliminary human life stage-specific PBPK model that can be used for identification of key data gaps and estimation of uncertainty.

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment--exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics): response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use. These judgments occur in the selection of critical studies, internal dose metrics, pharmacokinetic models, approaches for interspecies extrapolation of pharmacodynamics, and uncertainty factors. Potentially limiting end points included developmental eye malformations, liver effects, immunotoxicity, and kidney toxicity from oral exposure and neurological, liver, and kidney effects by inhalation. Each end point was evaluated quantitatively using several methods. Default analyses used the traditional no-observed adverse effect level divided by uncertainty factors and the benchmark dose divided by uncertainty factors methods. Subsequently, mode-of-action and pharmacokinetic information were incorporated. Internal dose metrics were estimated using a physiologically based pharmacokinetic (PBPK) model for TCE and its major metabolites. This approach was notably useful with neurological and kidney toxicities. The human PBPK model provided estimates of human exposure doses for the internal dose metrics. Pharmacodynamic data or default assumptions were used for interspecies extrapolation. For liver and neurological effects, humans appear no more sensitive than rodents when internal dose metrics were considered. Therefore, the interspecies uncertainty factor was reduced, illustrating that uncertainty factors are a semiquantitative approach fitting into the organizational framework. Incorporation of pharmacokinetics and pharmacodynamics can result in values that differ significantly from those obtained with the default methods.