Internal Dose Metrics Research Articles

Advancing ecotoxicological studies: Utilizing new approach methodologies to enable cross-species extrapolation and reduce avian testing

Ecological risk assessments of agrochemicals have traditionally depended on in vivo guideline tests using northern bobwhite and mallard to provide relevant endpoints for avian species. However, these studies have limitations, including animal welfare concerns, the time and cost involved, limited potential for extrapolation to more realistic exposure conditions, and the lack of mechanistic understanding. The proof-of-concept work presented a case study for thiamethoxam in three avian species, demonstrating the potential of physiologically based kinetic (PBK) modeling to enable dosimetry extrapolations that inform hazard characterization in risk assessment, and reduce the use of avian testing. The model structure for northern bobwhite and mallard contained ten compartments, while an additional ovulation model was included for chicken in the physiological state of egg-laying. The model was first parameterized and evaluated for chicken and northern bobwhite using in vitro kinetic measurements and in vivo toxicokinetic (TK) data. The chicken model was then extrapolated to mallard based on allometric scaling. The models were then used to map the TK profiles across species by simulating internal dose metrics in different avian toxicology studies. These metrics, including peak blood concentrations (Cmax) and area under the curve (AUC) for blood concentration, were determined for acute, subacute, or chronic toxicity endpoints for mallard and northern bobwhite, enabling a quantitative cross-species and cross-route comparison of dosimetry. The results suggested that the chronic toxicological response of birds exposed to thiamethoxam is highly dependent on internal exposure, while mallard appeared to be more dynamically sensitive to thiamethoxam on an acute oral exposure basis. The case study increases the confidence in using new approach methodologies (NAMs) for interpreting avian toxicity studies and facilitating in vitro-in silico-based ecological risk assessments of agrochemicals.

A Generic Pharmacokinetic Model for Quantifying Mother-to-Offspring Transfer of Lipophilic Persistent Environmental Chemicals.

Lipophilic persistent environmental chemicals (LPECs) can accumulate in a woman's body and transfer to her developing child across the placenta and via breast milk. To assess health risks associated with developmental exposures to LPECs, we developed a pharmacokinetic (PK) model that quantifies mother-to-offspring transfer of LPECs during pregnancy and lactation and facilitates internal dosimetry calculations for offspring. We parameterized the model for mice, rats, and humans using time-varying functions for body mass and milk consumption rates. The only required substance-specific parameter is the elimination half-life of the LPEC in the animal species of interest. We used the model to estimate whole-body concentrations in mothers and offspring following maternal exposures to hexachlorobenzene (HCB) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) and compared these with measured concentrations from animal studies. We also compared estimated concentrations for humans to those generated using a previously published human LPEC PK model. Finally, we compared human equivalent doses (HEDs) calculated using our model and an allometric scaling method. Estimated and observed whole-body concentrations of HCB and PCB 153 in offspring followed similar trends and differed by less than 60%. Simulations of human exposure yielded concentration estimates comparable to those generated using the previously published model, with concentrations in offspring differing by less than 12%. HEDs calculated using our PK model were about 2 orders of magnitude lower than those generated using allometric scaling. Our PK model can be used to calculate internal dose metrics for offspring and corresponding HEDs and thus informs assessment of developmental toxicity risks associated with LPECs.

Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling

Dibenzo[def,p]chrysene (DBC) is an environmental polycyclic aromatic hydrocarbon (PAH) that causes tumors in mice and has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Animal toxicity studies often utilize higher doses than are found in relevant human exposures. Additionally, like many PAHs, DBC requires metabolic bioactivation to form the ultimate toxicant, and species differences in DBC and DBC metabolite metabolism have been observed. To understand the implications of dose and species differences, a physiologically based pharmacokinetic model (PBPK) for DBC and major metabolites was developed in mice and humans. Metabolism parameters used in the model were obtained from experimental in vitro metabolism assays using mice and human hepatic microsomes. PBPK model simulations were evaluated against mice dosed with 15 mg/kg DBC by oral gavage and human volunteers orally microdosed with 29 ng of DBC. DBC and its primary metabolite DBC-11,12-diol were measured in blood of mice and humans, while in urine, the majority of DBC metabolites were obeserved as conjugated DBC-11,12-diol, conjugated DBC tetrols, and unconjugated DBC tetrols. The PBPK model was able to predict the time course concentrations of DBC, DBC-11,12-diol, and other DBC metabolites in blood and urine of human volunteers and mice with reasonable accuracy. Agreement between model simulations and measured pharmacokinetic data in mice and human studies demonstrate the success and versatility of our model for interspecies extrapolation and applicability for different doses. Furthermore, our simulations show that internal dose metrics used for risk assessment do not necessarily scale allometrically, and that PBPK modeling provides a reliable approach to appropriately account for interspecies differences in metabolism and physiology.

3D printer particle emissions: Translation to internal dose in adults and children

Desktop fused deposition modeling (FDM®) three-dimensional (3D) printers are becoming increasingly popular in schools, libraries, and among home hobbyists. FDM® 3D printers have been shown to release ultrafine airborne particles in large amounts, indicating the potential for inhalation exposure and consequent health risks among FDM® 3D printer users and other room occupants including children. These particles are generated from the heating of thermoplastic polymer feedstocks during the FDM® 3D printing process, with the most commonly used polymers being acrylonitrile butadiene styrene (ABS) and poly-lactic acid (PLA). Risk assessment of these exposures demands estimation of internal dose, especially to address intra-human variability across life stages. Dosimetry models have proven to effectively translate particle exposures to internal dose metrics relevant to evaluation of their effects in the respiratory tract. We used the open-access multiple path particle dosimetry (MPPD v3.04) model to estimate inhaled particle deposition in different regions of the respiratory tract for children of various age groups from three months to eighteen years old adults. Mass concentration data for input into the MPPD model were calculated using particle size distribution and density data from experimental FDM® 3D printer emissions tests using both ABS and PLA. The impact of changes in critical parameters that are principal determinants of inhaled dose, including: sex, age, and exposure duration, was examined using input parameter values available from the International Commission on Radiological Protection. Internal dose metrics used included regional mass deposition, mass deposition normalized by pulmonary surface area, surface area of deposited particles by pulmonary surface area, and retained regional mass. Total mass deposition was found to be highest in the 9-year-old to 18-year-old age groups with mass deposition by pulmonary surface area highest in 3-month-olds to 9-year-olds and surface area of deposited particles by pulmonary surface area to be highest in 9-year-olds. Clearance modeling revealed that frequent 3D printer users are at risk for an increased cumulative retained dose.

In vitro-in vivo and cross-life stage extrapolation of uptake and biotransformation of benzo[a]pyrene in the fathead minnow (Pimephales promelas)

Understanding internal dose metrics is integral to adequately assess effects environmental contaminants might have on aquatic wildlife, including fish. In silico toxicokinetic (TK) models are a leading approach for quantifying internal exposure metrics for fishes; however, they often do not adequately consider chemicals that are actively biotransformed and have not been validated against early-life stages (ELS) that are often considered the most sensitive to the exposure to contaminants. To address these uncertainties, TK models were parameterized for the rapidly biotransformed chemical benzo[a]pyrene (B[a]P) in embryo-larval and adult life stages of fathead minnows. Biotransformation of B[a]P was determined through measurements of in vitro clearance. Using in vitro-in vivo extrapolation, in vitro clearance was integrated into a multi-compartment TK model for adult fish and a one-compartment model for ELS. Model predictions were validated using measurements of B[a]P metabolites from in vivo flow-through exposures to graded concentrations of water-borne B[a]P. Significantly greater amounts of B[a]P metabolites were observed with exposure to greater concentrations of parent compound in both life stages. However, when assessing biotransformation capacity, no differences in phase I or phase II biotransformation were observed with greater exposures to B[a]P. Results of modelling suggested that biotransformation of B[a]P can be successfully implemented into in silico models to accurately predict life stage-specific abundances of B[a]P metabolites in either whole-body larvae or the bile of adult fish. Models developed increase the scope of applications in which TK models can be used to support environmental risk assessments.

An assessment of the impact of multi-route co-exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants.

This study aimed to assess the impact of multi-route co-exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi-route interaction models were developed for adults and four younger subpopulations. Drinking water-mediated multi-route exposures were simulated for benzene alone or in co-exposure with toluene, ethylbenzene and m-xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for "low" and "high" exposure scenarios, involving respectively the US EPA's short-term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the "low" (VIL ) and "high" (VIH ) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve-based VIL for single exposures vs. co-exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VIH varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VIL and VIH for the amount of benzene metabolized via CYP2E1 pathway decreased in co-exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the "high" exposure, but "low" co-exposures did not impact the toxicokinetics of individual substances. In conclusion, multi-route co-exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child/adult differences in toxicokinetics.

An international effort to promote the regulatory use of PBK models based on non-animal data

Abstract The Organisation for Economic Co-operation and Development (OECD) coordinates international efforts to promote the regulatory use of Physiologically Based Kinetic (PBK) models based on non-animal data. The new generation PBK models rely on in vitro and in silico ADME (Absorption, Distribution, Metabolism and Excretion) data and aim to provide internal dose metrics that are considered more predictive when establishing biological responses that are needed in chemical risk assessment. However, the uncertainty derived from the chemical-dependent parameters (physicochemical and ADME properties) of PBK models for chemicals with no in vivo data need to be clearly communicated to the regulators evaluating data derived from these tools. This manuscript highlights these international efforts that aim to enhance regulatory acceptance of new generation PBK models through the development of a harmonised approach for characterising, validating and reporting them.

Risk characterization of bisphenol-A in the Slovenian population starting from human biomonitoring data

The current study aims to characterize exposure and risk associated to bisphenol-A (BPA) exposure in Slovenia, starting from biomonitoring data. Based on the urinary data, daily intake for the individuals was back-calculated using a physiology based biokinetic (PBBK) model properly parameterized for BPA, coupled with an exposure reconstruction algorithm. Re-running the PBBK model in forward mode allowed the estimation of biologically effective dose (free plasma BPA) and the respective daily area under the curve (AUC). Finally, risk characterization ratio was derived using both external and internal dose metrics. The urinary BPA levels were found low, with GM of 0.79, 1.51 and 0.20 μg/g creatinine for mothers, children and fathers respectively, similar to the levels of other European countries. Based on the above and accounting for the dynamics of exposure and biokinetics, daily intake was estimated, median exposure levels have been estimated equal to 0.019, 0.035 and 0.005 μg/kg_bw/d for mothers, fathers and children respectively. The highest estimated intake level was found in a child, equal to 0.87 μg/kg_bw/d, while the maximum intake for mothers and fathers were 0.7 and 0.8 μg/kg_bw/d respectively. The respective RCR levels using the EFSA t-TDI of 4 μg/kg_bw/d were 2 magnitudes of order lower below 1, independently of the selected method. It has to be noted that had daily intake been estimated solely based on the urinary concentrations mass balance, the estimated intake would be lower, as a result of the oversimplification on exposure and elimination time dynamics. This highlights the importance for using PBBK modelling based exposure reconstruction schemes for rapidly metabolized and excreted compounds such as BPA, as well as the study design of efficient sampling for rapidly metabolized compounds.

Dosimetry considerations for in vivo and in vitro test data and a novel surrogate iTTC approach for read-across based on metabolites

In the context of REACH and the EU ban on animal testing of cosmetic ingredients, development, adoption and acceptance of non-animal methods is urgent. Read-across is the predominate non-animal method being used for higher tier endpoints (repeat dose and developmental and reproductive toxicity). The limitations of read-across include the lack of suitable analogs and analog data for all chemicals of interest, as well as concerns with missing a potential adverse response that results from small differences in chemical structure. In this manuscript we explore two possible enhancements to read-across approaches in the context of a single case study: read-across assessments based on metabolite data and incorporation of in vitro data to support the read-across hypothesis. We use this case study to explore possible paths forward in implementing these enhancements, but more importantly to raise issues that need to be resolved prior to extensive use and hopefully acceptance of these expanded approaches. For the case of read-across based on metabolites, we explore the potential application of an internal dose TTC (iTTC) approach to address uncertainty associated with potential toxicity from exposure to residual parent chemical. This is a relevant scenario for the many cosmetic ingredients containing ester structures. For the use of in vitro data we explore considerations that must be taken before the application of ToxCast™ data to the read-across to ensure positive responses are reliable and relevant. As more cosmetic ingredients are tested in in vitro systems, guidance on the appropriate interpretation of these data will be essential. The concept of dosimetry is a unifying need that must be addressed in both these approaches. In the present paper, we explore how to use and apply internal dose metrics to address some issues associated with expanded approaches in read-across.

A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based End Point for Chlorpyrifos.

Background:Organophosphorus (OP) compounds are the most widely used group of insecticides in the world. Risk assessments for these chemicals have focused primarily on 10% inhibition of acetylcholinesterase in the brain as the critical metric of effect. Aside from cholinergic effects resulting from acute exposure, many studies suggest a linkage between cognitive deficits and long-term OP exposure.Objective:In this proof-of-concept study, we focused on one of the most widely used OP insecticides in the world, chlorpyrifos (CPF), and utilized an existing physiologically based pharmacokinetic (PBPK) model and a novel pharmacodynamic (PD) dose–response model to develop a point of departure benchmark dose estimate for cognitive deficits following long-term, low-dose exposure to this chemical in rodents.Methods:Utilizing a validated PBPK/PD model for CPF, we generated a database of predicted biomarkers of exposure and internal dose metrics in both rat and human. Using simulated peak brain CPF concentrations, we developed a dose–response model to predict CPF-induced spatial memory deficits and correlated these changes to relevant biomarkers of exposure to derive a benchmark dose specific to neurobehavioral changes. We extended these cognitive deficit predictions to humans and simulated corresponding exposures using a model parameterized for humans.Results:Results from this study indicate that the human-equivalent benchmark dose (BMD) based on a 15% cognitive deficit as an end point is lower than that using the present threshold for 10% brain AChE inhibition. This predicted human-equivalent subchronic BMD threshold compares to occupational exposure levels determined from biomarkers of exposure and corresponds to similar exposure conditions where deficits in cognition are observed.Conclusions:Quantitative PD models based on neurobehavioral testing in animals offer an important addition to the methodologies used for establishing useful environmental public health indicators and BMDs, and predictions from such models could help inform the human health risk assessment for chlorpyrifos. https://doi.org/10.1289/EHP1743

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin-of-exposure values for hexavalent chromium.

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg−1 day−1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg−1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg−1 day−1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg−1 day−1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.

A global human health risk assessment for octamethylcyclotetrasiloxane (D4)

Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight volatile cyclic siloxane, primarily used as an intermediate in the production of some widely-used industrial and consumer silicone based polymers and may be present as a component in a variety of consumer products. A global “harmonized” risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA’s Integrated Risk Information System (IRIS), Health Canada’s Chemical Management Program (CMP) and various independent scientific committees of the European Commission (e.g. the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee on Health and Environmental Risks (SCHER)), as well as to provide guidance for chemical safety assessments under REACH in Europe. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure. Utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model was included to estimate internal dose metrics, benchmark modeling was used to determine a point of departure (POD), and a margin of safety (MOS) evaluation was used to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D4 including high lipophilicity, high volatility with low blood-to-air partition coefficients and an extensive metabolic clearance that regulates tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D4 using a MOS approach based on an internal dose metric removes the subjective application of varying uncertainty factors from various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects.

The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data – A case study with caffeine

Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (Cmax), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.

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.

Locomotor activity and tissue levels following acute administration of lambda- and gamma-cyhalothrin in rats

Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29mg/kg) compared to λ-cyhalothrin (2.65mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administered dose, the differences based on internal concentrations were less, with γ-cyhalothrin being 1.3- to 1.6-fold more potent than λ-cyhalothrin. These potency differences are consistent with the purity of the λ-isomer (approximately 43%) compared to the enriched isomer γ-cyhalothrin (approximately 98%). Thus, administered dose as well as differences in cyhalothrin isomers is a good predictor of behavioral effects.

The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM)

A rate for hepatic metabolism (Vmax) determined in vitro must be scaled for in vivo use in a physiologically based pharmacokinetic (PBPK) model. This requires the use of scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in MPPGL and FVL impacts variation in Vmax, and hence PBPK model-derived estimates of internal dose used in dose response analysis. The impacts of adult human variation in MPPGL and FVL on estimates of internal dose were assessed using a human PBPK model for bromodichloromethane (BDCM), a water disinfection byproduct, for multiple internal dose metrics for two exposure scenarios (single 0.25 liter drink of water or 10 min shower) under plausible (5 μg/L) and high level (20 μg/L) water concentrations. For both concentrations, all internal dose metrics were changed less than 5% for the showering scenario (combined inhalation and dermal exposure). In contrast, a 27-fold variation in area under the curve (AUC) for BDCM in venous blood was observed at both oral exposure concentrations, whereas total amount of BDCM metabolized in liver was relatively unchanged. This analysis demonstrates that variability in the scaling factors used for in vitro to in vivo extrapolation (IVIVE) for metabolic rate parameters can have a significant route-dependent impact on estimates of internal dose under environmentally relevant exposure scenarios. This indicates the need to evaluate both uncertainty and variability for scaling factors used for IVIVE.

A global human health risk assessment for Decamethylcyclopentasiloxane (D5)

Decamethylcyclopentasiloxane (D5) is a low-molecular-weight cyclic siloxane used primarily as an intermediate in the production of several widely-used industrial and consumer products and intentionally added to consumer products, personal products and some dry cleaning solvents. The global use requires consideration of consumer use information and risk assessment requirements from various sources and authoritative bodies. A global “harmonized” risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada and various independent scientific committees of the European Commission, as well as provide guidance for chemical safety assessments under REACH in Europe, and other relevant authoritative bodies. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure, utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model to estimate internal dose metrics, benchmark modeling to determine a point of departure (POD), and a margin of safety (MOS) evaluation to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D5 including high lipophilicity, high volatility with low blood-to-air partition coefficients and extensive metabolic clearance that regulate tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D5 using a MOS approach based on an internal dose metric removes the subjective application of uncertainty factors that may be applied across various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects.

Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species.

Assessing Human Variability in Kinetics for Exposures to Multiple Environmental Chemicals: A Physiologically Based Pharmacokinetic Modeling Case Study with Dichloromethane, Benzene, Toluene, Ethylbenzene, and m-Xylene

The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to “low” (RfC-like) or “high” (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant “low” exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16–24%, vs. 12–15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO’s CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For “high” exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11–16% to 2–6%) and TODD (CV= 12–13% to 7–9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

Unraveling bisphenol A pharmacokinetics using physiologically based pharmacokinetic modeling

Physiologically based pharmacokinetic (PBPK) models integrate both chemical- and system-specific information into a mathematical framework, offering a mechanistic approach to predict the internal dose metrics of a chemical and an ability to perform species and dose extrapolations. Bisphenol A (BPA), because of its ubiquitous presence in a variety of consumer products, has received a considerable amount of attention from the public and regulatory bodies. PBPK models using deuterated BPA were developed for immature and adult rats and non-human primates and for adult humans to understand better the dosimetry of BPA. The focus of the present paper is to provide a rationale for interpreting species- and age-related pharmacokinetics of BPA. Gastrointestinal tract metabolism was an important consideration to predict unconjugated BPA serum kinetic profiles in adult and immature rats and monkeys. Biliary excretion and enterohepatic recirculation of BPA conjugates (BPA-c) accounted for the slowed systemic clearance of BPA-c in rats. For monkeys, renal reabsorption was proposed as a mechanism influencing systemic clearance of BPA-c. The quantitative understanding of the processes driving the pharmacokinetics of BPA across different species and life stages using a computational modeling approach provides more confidence in the interpretation of human biomonitoring data and the extrapolation of experimental animal findings to humans.